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Norepinephrine Reviews
(75 References)
Ables, A. Z. and O. L. Baughman, 3rd (2003). "Antidepressants: update on new agents and indications." Am Fam Physician 67(3): 547-54.
A number of antidepressants have emerged in the U.S. market in the past two decades. Selective serotonin reuptake inhibitors have become the drugs of choice in the treatment of depression, and they are also effective in the treatment of obsessive-compulsive disorder, panic disorder, and social phobia. New indications for selective serotonin reuptake inhibitors include post-traumatic stress disorder, premenstrual dysphoric disorder, and generalized anxiety disorder. Extended-release venlafaxine has recently been approved by the U.S. Food and Drug Administration for the treatment of generalized anxiety disorder. Mirtazapine, which is unrelated to the selective serotonin reuptake inhibitors, is unique in its action--stimulating the release of norepinephrine and serotonin. The choice of antidepressant drug depends on the agent's pharmacologic profile, secondary actions, and tolerability. Sexual dysfunction related to the use of antidepressants may be addressed by reducing the dosage, switching to another agent, or adding another drug to overcome the sexual side effects. Augmentation with lithium or triiodothyronine may be useful in patients who are partially or totally resistant to antidepressant treatment. Finally, tapering antidepressant medication may help to avoid discontinuation syndrome or antidepressant withdrawal.
Alemany, M., X. Remesar, et al. (2003). "Drug strategies for the treatment of obesity." IDrugs 6(6): 566-72.
There are three major classes of drugs for the treatment of obesity: (i) inhibitors of food intake, which reduce hunger perception and, consequently, food intake; the most representative are centrally acting neurotransmitters and intestinal or neural satiety peptides; (ii) inhibitors of nutrient absorption, which reduce energy disposal through a peripheral gastrointestinal mechanism; and (iii) thermogenic drugs, which increase energy expenditure. At present, there are only two drugs for long-term use: sibutramine, an inhibitor of both serotonin and norepinephrine reuptake, and orlistat, a lipase inhibitor that targets pancreatic lipases and reduces absorption of dietary fat. New treatments and better drugs are expected in the near future because of the rapid expansion of research in body-weight regulation mechanisms.
Ali, S. and R. Milev (2003). "Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature." Can J Psychiatry 48(4): 258-64.
OBJECTIVE: To review the literature for reported cases of mania related to discontinuing antidepressant treatment, as well as for possible explanations of this phenomenon, and to present a case report. METHOD: We undertook a literature review through the PubMed index, using the key words mania, antidepressant withdrawal, and antidepressants in bipolar disorder. We reviewed 11 articles featuring 23 cases. Where available, we noted and tabulated certain parameters for both bipolar disorder (BD) and unipolar depression. We use a case example to illustrate the phenomenon of mania induced by antidepressant withdrawal. RESULTS: For patients with unipolar depression, we found 17 reported cases of mania induced by antidepressant withdrawal. Antidepressants implicated included tricyclic antidepressants (TCAs) (12/17), monoamine oxidase inhibitors (MAOIs) (2/17), trazodone (1/17), mirtazapine (1/17), and paroxetine (1/17). For patients with BD, we found 19 reported cases of mania induced by antidepressant withdrawal, including our own case example. Of these, selective serotonin reuptake inhibitors (SSRIs) (10/19), TCAs (4/19), MAOIs (2/19), and serotonin norepinephrine reuptake inhibitors (SNRIs) (2/19) were implicated. CONCLUSION: Our case report supports the observation of antidepressant withdrawal-induced mania in patients with BD. It is distinguishable from antidepressant-induced mania, physiological drug withdrawal, and mania as a natural course of the illness. Many theories have been put forward to explain this occurrence. Noradrenergic hyperactivity and "withdrawal-induced cholinergic overdrive and the cholinergic-monoaminergic system" are the 2 most investigated and supported models. The former is limited by poor clinical correlation and the latter by its applicability only to anticholinergic drugs.
Andersson, K. E. (2003). "Erectile physiological and pathophysiological pathways involved in erectile dysfunction." J Urol 170(2 Pt 2): S6-13; discussion S13-4.
PURPOSE: The importance of signaling pathways in penile smooth muscles involved in normal erection and erectile dysfunction (ED) is discussed based on a review of the literature. MATERIALS AND METHODS: Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents but also by visual, olfactory and imaginary stimuli. The generated nervous signals will influence the balance between the contractant and relaxant factors, which control the degree of contraction of penile smooth muscles and, thus, determine the functional state of the penis. The different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals may be changed in different types of erectile dysfunction. RESULTS: Recent findings have suggested an important role for RhoA/Rho kinase in the regulation of cavernosal smooth muscle tone and that changes in this pathway may contribute to ED in various patient subgroups, eg diabetes and vascular disease. Neurogenic nitric oxide is still considered the most important factor for immediate relaxation of penile vessels and corpus cavernosum. However, endothelially generated nitric oxide seems essential for maintaining erection. Endothelial dysfunction can contribute to ED in several patient subgroups. In addition, in conditions associated with reduced function of nerves and endothelium, such as aging, hypertension, smoking, hypercholesterolemia and diabetes, circulatory and structural changes in the penile tissues can result in arterial insufficiency and defect muscle relaxation. CONCLUSIONS: Different types of ED often have overlapping pathophysiologies but may also have common pathways contributing to ED. Such pathways may be potential treatment targets.
Anisman, H., Z. Merali, et al. (2003). "Sensitization associated with stressors and cytokine treatments." Brain Behav Immun 17(2): 86-93.
Like stressors, interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) increase hypothalamic-pituitary-adrenal (HPA) activity and monoamine turnover at hypothalamic and extrahypothalamic sites. These effects can be re-elicited more readily upon reintroduction of these challenges (sensitization), depending on their time of re-exposure and the particular system being assessed. Following TNF-alpha administration, the co-expression of corticotropin releasing hormone (CRH) and arginine vasopressin increased within the median eminence, peaking 7-14 days after treatment, and was associated with an early corticosterone sensitization. However, the re-elicitation of sickness symptoms and corticosterone release was most pronounced at lengthy re-exposure intervals (28 days), possibly reflecting histamine release from mast cells. In addition, the cytokine engendered the sensitization of norepinephrine and serotonin utilization, and CRH immunoreactivity at mesocorticolimbic sites, but these effects were most prominent at brief re-exposure intervals (1-7 days). Cytokines may independently prime multiple regulatory systems, and by virtue of the neurochemical changes imparted, have both immediate and proactive influences on the evolution of psychopathology.
Babisch, W. (2003). "Stress hormones in the research on cardiovascular effects of noise." Noise Health 5(18): 1-11.
In recent years, the measurement of stress hormones including adrenaline, noradrenaline and cortisol has been widely used to study the possible increase in cardiovascular risk of noise exposed subjects. Since endocrine changes manifesting in physiological disorders come first in the chain of cause-effect for perceived noise stress, noise effects in stress hormones may therefore be detected in populations after relatively short periods of noise exposure. This makes stress hormones a useful stress indicator, but regarding a risk assessment, the interpretation of endocrine noise effects is often a qualitative one rather than a quantitative one. Stress hormones can be used in noise studies to study mechanisms of physiological reactions to noise and to identify vulnerable groups. A review is given about findings in stress hormones from laboratory, occupational and environmental studies.
Bailer, U. F. and W. H. Kaye (2003). "A review of neuropeptide and neuroendocrine dysregulation in anorexia and bulimia nervosa." Curr Drug Target CNS Neurol Disord 2(1): 53-9.
Neuropeptides play an important role in the regulation of feeding behavior and obesity. The mechanisms for controlling food intake involve a complicated interplay between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monamines (serotonin, dopamine, norepinephrine). In addition to regulating eating behavior, a number of CNS neuropeptides participate in the regulation of neuroendocrine pathways. Thus, clinical studies have evaluated the possibility that CNS neuropeptide alterations may contribute to dysregulated secretion of the gonadal hormones, cortisol, thyroid hormones and growth hormone in the eating disorders. Most of the neuroendocrine and neuropeptide alterations apparent during symptomatic episodes of AN and BN tend to normalize after recovery. This observation suggests that most of the disturbances are consequences rather than causes of malnutrition, weight loss and/or altered meal patterns. Still, an understanding of these neuropeptide disturbances may shed light on why many people with AN or BN cannot easily "reverse" their illness and even after weight gain and normalized eating patterns, many individuals who have recovered from AN or BN have physiological, behavioral and psychological symptoms that persist for extended periods of time.
Barbarich, N. C., W. H. Kaye, et al. (2003). "Neurotransmitter and imaging studies in anorexia nervosa: new targets for treatment." Curr Drug Target CNS Neurol Disord 2(1): 61-72.
Anorexia and Bulimia Nervosa are disorders of unknown etiology that invariably begin during adolescence and near in time to puberty in young women. These disorders are associated with aberrant eating behaviors, body image distortions, impulse and mood disturbances, as well as characteristic temperament and personality traits. It is well known that malnutrition produces changes in neuroendocrine function. More recently, disturbances in neuronal systems have been found to play a role in the modulation of feeding, mood, and impulse control. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monoamines (serotonin, dopamine, norepinephrine). Disturbances of most of these neuronal systems have been found when people are ill with an eating disorder, but it was not certain whether they were a cause or consequence of symptoms. In order to address these questions, a growing number of studies have investigated whether neuromodulatory disturbances persist after recovery. Studies from several centers tend to show altered serotonin activity persists after prolonged normalization of weight, nutrition, and menstrual function, as do anxiety, obsessionality, and perfectionism. While there are fewer data, there may be persistent alterations of dopamine or some neuropeptides in some subjects in a recovered state. The inaccessibility of the central nervous system has made it difficult to understand brain and behavior. In the past decade, new tools, such as brain imaging, have offered the possibility of better characterization of complex neuronal function and behavior. Such studies have tended to consistently find that alterations of brain regions, such as the temporal lobe, occur in people who are ill with anorexia nervosa and appear to persist after some degree of weight gain and recovery. New imaging technology, that marries Positron Emission Tomography (PET) imaging with selective neurotransmitter radioligands, confirms that altered serotonin neuronal pathway activity persists after recovery from an eating disorder and supports the possibility that these psychobiological alterations might contribute to traits, such as increased anxiety or extremes of impulse control, that, in turn, may contribute to a vulnerability to the development of an eating disorder. In summary, studies of pathophysiology are starting to nominate new candidates for treatment leading to the possibility of finding effective treatments for this often chronic or fatal disorder.
Barbeau, H. and K. E. Norman (2003). "The effect of noradrenergic drugs on the recovery of walking after spinal cord injury." Spinal Cord 41(3): 137-43.
Clonidine, a noradrenergic agonist has been associated with improved walking in both spinal cat and spinal cord injured (SCI) subjects.OBJECTIVES: The objective of this brief review is to compare the effects of clonidine on walking capabilities in SCI subjects with functionally complete and incomplete spinal cord injuries. STUDY DESIGN/METHODS: Both oral administration and intrathecal injection of clonidine were investigated. A motorized treadmill was used and harness support provided in most of the SCI subjects as no walking capabilities could be observed overground. A single subject design was used in these chronic SCI subjects. SETTING: Canada and France. RESULTS: In complete SCI subjects while receiving clonidine, none of the subjects was able to initiate independent stepping. In contrast, the greatest effects were found in SCI subjects with injuries that are incomplete but still severely disabling while minimal effects could be observed in the more functional SCI subjects. These effects on walking are observed in measures of walking speed, and electromyographic and kinematic patterns. Regardless of effects on walking, however, a consistent decrease of the flexor reflex amplitude could be observed in all SCI subjects independent of the severity of the lesion. CONCLUSION: This review demonstrated that clonidine could be a powerful anti-spasmodic drug in addition to improving locomotion in a limited number of SCI subjects. The mechanism, significance and implications of these results will be discussed.
Berridge, C. W. and B. D. Waterhouse (2003). "The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes." Brain Res Brain Res Rev 42(1): 33-84.
Through a widespread efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. Initial studies provided critical insight into the basic organization and properties of this system. More recent work identifies a complicated array of behavioral and electrophysiological actions that have in common the facilitation of processing of relevant, or salient, information. This involves two basic levels of action. First, the system contributes to the initiation and maintenance of behavioral and forebrain neuronal activity states appropriate for the collection of sensory information (e.g. waking). Second, within the waking state, this system modulates the collection and processing of salient sensory information through a diversity of concentration-dependent actions within cortical and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent modulation of long-term alterations in synaptic strength, gene transcription and other processes suggest a potentially critical role of this neurotransmitter system in experience-dependent alterations in neural function and behavior. The ability of a given stimulus to increase locus coeruleus discharge activity appears independent of affective valence (appetitive vs. aversive). Combined, these observations suggest that the locus coeruleus-noradrenergic system is a critical component of the neural architecture supporting interaction with, and navigation through, a complex world. These observations further suggest that dysregulation of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective disorders, including post-traumatic stress disorder. Independent of an etiological role in these disorders, the locus coeruleus-noradrenergic system represents an appropriate target for pharmacological treatment of specific attention, memory and/or arousal dysfunction associated with a variety of behavioral/cognitive disorders.
Bremner, J. D. (2003). "Long-term effects of childhood abuse on brain and neurobiology." Child Adolesc Psychiatr Clin N Am 12(2): 271-92.
Early stress is associated with long-term alterations in brain circuits and systems that mediate the stress response. Early stressors have lasting effects on the HPA axis and norepinephrine systems. Other brain systems that are involved include benzodiazepine, opiate, dopaminergic, and various neuropeptide systems. These neurochemical systems modulate function in brain regions, including the hippocampus, amygdala, and prefrontal cortex. Long-term alterations in these brain regions are hypothesized to play a role in the maintenance of PTSD, depression, and other psychiatric symptoms after childhood abuse.
Briley, M. (2003). "New hope in the treatment of painful symptoms in depression." Curr Opin Investig Drugs 4(1): 42-5.
Depression is increasingly seen as a triad of psychological, somatic and physical symptoms that all need to be treated to achieve maximal remission. In primary care, physical symptoms such as pain, are the principal presenting symptoms, and a common psychopharmacology between pain and depression suggests that compounds that inhibit the reuptake of both serotonin and norepinephrine are likely to produce the greatest relief from depression and chronic pain. Recent, principally open, trials with members of the new selective serotonin and norepinephrine reuptake inhibitor class of antidepressants such as venlafaxine, milnacipran and duloxetine (Eli Lilly & Co/Shionogi & Co Ltd), suggest that these compounds may be effective in relieving pain both associated with, and independent of depression.
Butterweck, V. (2003). "Mechanism of action of St John's wort in depression : what is known?" CNS Drugs 17(8): 539-62.
Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.
Crandall, C. G., J. Cui, et al. (2003). "Effects of heat stress on baroreflex function in humans." Acta Physiol Scand 177(3): 321-8.
INTRODUCTION: Heat stress significantly reduces orthostatic tolerance in humans. The mechanism(s) causing this response remain unknown. The purpose of this review article is to present data pertaining to the hypothesis that reduced orthostatic tolerance in heat stressed individuals is a result of heat stress induced alterations in baroflex function. METHODS: In both normothermic and heat stressed conditions baroreflex responsiveness was assessed via pharmacological and non-pharmacological methods. In addition, the effects of heat stress on post-synaptic vasoconstrictor responsiveness were assessed. RESULTS: Generally, whole body heating did not alter baroreflex sensitivity defined as the gain of the linear portion of the baroreflex curve around the operating point. However, whole body heating shifted the baroreflex curve to the prevailing (i.e. elevated) heart rate and muscle sympathetic nerve activity. Finally, the heat stress impaired vasoconstrictor responses to exogenous administration of adrenergic agonists. CONCLUSION: Current data do not support the hypothesis that reduced orthostatic tolerance associated with heat stress in humans is due to impaired baroreflex responsiveness. This phenomenon may be partially due to the effects of heat stress on reducing vasoconstrictor responsiveness.
Dobson, H., S. Ghuman, et al. (2003). "A conceptual model of the influence of stress on female reproduction." Reproduction 125(2): 151-63.
Intriguingly, similar neurotransmitters and nuclei within the hypothalamus control stress and reproduction. GnRH neurone recruitment and activity is regulated by a balance between stimulation, suppression and permissiveness controlled by noradrenaline, neuropeptide Y and serotonin from the brain stem, impact from glutamate in the medial preoptic area and neuropeptide Y in the arcuate nucleus, in opposition to the restraining influences of gamma-aminobenzoic acid within the medial preoptic area and opioids from the arcuate nucleus. Stress also activates neuropeptide Y perikarya in the arcuate nucleus and brain stem noradrenaline neurones. The latter project either indirectly, via the medial preoptic area, or directly to the paraventricular nucleus to release corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP). Within the medial preoptic area, GnRH neurones synapse with CRH and AVP axons. Stimulation of CRH neurones in the paraventricular nucleus also activates gamma-aminobenzoic acid and opioid neurones in the medial preoptic area and reduces GnRH cell recruitment, thereby decreasing GnRH pulse frequency. Oestradiol enhances stress-induced noradrenaline suppression of LH pulse frequency but when applied in the paraventricular nucleus or brain stem, and not in the medial preoptic area or arcuate nucleus. The importance of CRH and AVP in the medial preoptic area needs confirming in a species other than the rat, which uses adrenal activation to time the onset of the GnRH surge. Another stress-activated pathway involves the amygdala and bed of the nucleus stria terminalis, which contain CRH neurones and accumulate gamma-aminobenzoic acid during stress.
Dodt, C., P. Lonnroth, et al. (2003). "Sympathetic control of white adipose tissue in lean and obese humans." Acta Physiol Scand 177(3): 351-7.
AIM: To induce lipolysis, catecholamines could reach the adipocyte via the blood stream after being released from the adrenal medulla or, alternatively, via neuronal release in the vicinity of the fat cell. Sympatho-neuronal effects on fat tissue lipolysis have been demonstrated in experimental animal models. However, the role of sympathetic nerves in the control of lipolysis in human white adipose tissue, which is sparsely innervated, has not been clarified. CONCLUSION: The present review summarizes evidence for a direct neuronal influence on lipolysis in humans.
Douglass, A. B. (2003). "Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder and schizophrenia?" CNS Spectr 8(2): 120-6.
Does narcolepsy, a neurological disease, need to be considered when diagnosing major mental illness? Clinicians have reported cases of narcolepsy with prominent hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia. In some bipolar disorder patients with narcolepsy, the HH resulted in their receiving a more severe diagnosis (ie, bipolar disorder with psychotic features or schizoaffective disorder). The role of narcolepsy in psychiatric patients has remained obscure and problematic, and it may be more prevalent than commonly believed. Classical narcolepsy patients display the clinical "tetrad"--cataplexy, hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Over 85% also display the human leukocyte antigen marker DQB1*0602 (subset of DQ6). Since 1998, discoveries in neuroanatomy and neurophysiology have greatly advanced the understanding of narcolepsy, which involves a nearly total loss of the recently discovered orexin/hypocretin (hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism. Hypocretin neurons normally supply excitatory signals to brainstem nuclei producing norepinephrine, serotonin, histamine, and dopamine, with resultant suppression of sleep. They also project to basal forebrain areas and cortex. A literature review regarding the differential diagnosis of narcolepsy, affective disorder, and schizophrenia is presented. Furthermore, it is now possible to rule out classical narcolepsy in difficult psychiatric cases. Surprisingly, psychotic patients with narcolepsy will likely require stimulants to fully recover. Many conventional antipsychotic drugs would worsen their symptoms and make them appear to become a "chronic psychotic," while in fact they can now be properly diagnosed and treated.
Dragon, S. and R. Baumann (2003). "Hypoxia, hormones, and red blood cell function in chick embryos." News Physiol Sci 18: 77-82.
The red blood cell function of avian embryos is regulated by cAMP. Adenosine A(2A) and beta-adrenergic receptor activation during hypoxic conditions cause changes in the hemoglobin oxygen affinity and CO(2) transport. Furthermore, experimental evidence suggests a general involvement of cAMP in terminal differentiation of avian erythroblasts.
Eckberg, D. L. (2003). "Bursting into space: alterations of sympathetic control by space travel." Acta Physiol Scand 177(3): 299-311.
AIM: Astronauts return to Earth with reduced red cell masses and hypovolaemia. Not surprisingly, when they stand, their heart rates may speed inordinately, their blood pressures may fall, and some may experience frank syncope. We studied autonomic function in six male astronauts (average +/- SEM age: 40 +/- 2 years) before, during, and after the 16-day Neurolab space shuttle mission. METHOD: We recorded electrocardiograms, finger photoplethysmographic arterial pressures, respiration, peroneal nerve muscle sympathetic activity, plasma noradrenaline and noradrenaline kinetics, and cardiac output, and we calculated stroke volume and total peripheral resistance. We perturbed autonomic function before and during spaceflight with graded Valsalva manoeuvres and lower body suction, and before and after the mission with passive upright tilt. RESULTS: In-flight baseline sympathetic nerve activity was increased above pre-flight levels (by 10-33%) in three subjects, in whom noradrenaline spillover and clearance also were increased. Valsalva straining provoked greater reductions of arterial pressure, and proportionally greater sympathetic responses in space than on Earth. Lower body suction elicited greater increases of sympathetic nerve activity, plasma noradrenaline, and noradrenaline spillover in space than on Earth. After the Neurolab mission, left ventricular stroke volume was lower and heart rate was higher during tilt, than before spaceflight. No astronaut experienced orthostatic hypotension or pre-syncope during 10 min of post-flight tilting. CONCLUSION: We conclude that baseline sympathetic outflow, however measured, is higher in space than on earth, and that augmented sympathetic nerve responses to Valsalva straining, lower body suction, and post-flight upright tilt represent normal adjustments to greater haemodynamic stresses associated with hypovolaemia.
Esler, M., G. Lambert, et al. (2003). "Sympathetic nerve activity and neurotransmitter release in humans: translation from pathophysiology into clinical practice." Acta Physiol Scand 177(3): 275-84.
AIM: There has been a revolution in cardiovascular neuroscience in recent years with, in some cases, translation into clinical practice of the knowledge of pathophysiology gained through application of sympathetic nerve recording and catecholamine isotope dilution methodology. OBESITY-RELATED HYPERTENSION: An earlier hypothesis, based on findings in most models, was that weight gain in obesity is due in part to sympathetic nervous underactivity reducing thermogenesis. Microneurography and regional noradrenaline spillover measurements in human obesity have disproven this hypothesis, weakening the case for the use of beta3-adrenergic agonists to stimulate thermogenesis. Sympathetic nerve firing rates in post-ganglionic fibres directed to the skeletal muscle vasculature are increased, as is renal sympathetic tone, with a doubling of the spillover rate of noradrenaline from the kidneys. Given these findings, antiadrenergic antihypertensive drugs may be the preferred agents for obesity-related hypertension, but this has not been adequately tested. ESSENTIAL HYPERTENSION: Whether stress causes high blood pressure, previously hotly debated, has been under recent review by an Australian Government body, the Specialist Medical Review Council. Despite medicolegal implications, the ruling was that stress is one proven cause of hypertension. The judgment was reached after consideration of the epidemiological evidence, but in particular the described neural pathophysiology of essential hypertension: (a) persistent sympathetic nervous stimulation is commonly present, (b) suprabulbar projections of noradrenergic brainstem neurones are activated and (c) adrenaline is released as a cotransmitter in sympathetic nerves. These were taken to be biological markers of stress. CARDIAC FAILURE: At one time, the failing heart was thought to be sympathetically denervated. Longterm administration of inotropic adrenergic agonists, to provide the cardiac catecholamine stimulation thought to be lacking, increased mortality. Noradrenaline isotope dilution methodology subsequently demonstrated that the sympathetic outflow to the heart was preferentially activated, cardiac noradrenaline spillover being increased as much as 50-fold. The level of stimulation of the cardiac sympathetic nerves was the most powerful predictor of death. These observations provide the theoretical foundation for the very successful introduction of beta-adrenergic blockers for treatment of heart failure.
Floras, J. S. (2003). "Sympathetic activation in human heart failure: diverse mechanisms, therapeutic opportunities." Acta Physiol Scand 177(3): 391-8.
Plasma noradrenaline (NA) concentrations relate both to the severity of heart failure, and to its impact on survival, but have shortcomings that limit their usefulness as measures of sympathetic discharge. Neural recordings and the isotopic dilution method for determining organ-specific rates of NA spillover into plasma have enhanced our understanding of mechanisms responsible for sympathetic activation. Because the arterial baroreceptor reflex control of heart rate is impaired in heart failure, a parallel reduction in the reflex inhibition of sympathetic outflow has been assumed. However, human heart failure is characterized by rapidly responsive arterial baroreflex regulation of muscle sympathetic nerve activity (MSNA), attenuated cardiopulmonary reflex modulation of MSNA, and activation of a cardiac-specific sympatho-excitatory reflex related to increased cardiopulmonary filling pressures. Together, these baroreceptor mediated mechanisms account only, in part, for the time course and magnitude of adrenergic activation in heart failure. Non-baroreflex sympatho-excitatory mechanisms include: a metaboreflex arising from exercising skeletal muscle, mediated, in part, by adenosine, co-existing sleep apnoea, and pre-junctional facilitation of NA release. Thus, sympathetic activation in the setting of impaired systolic function reflects the net balance and interaction between augmented excitatory and diminished inhibitory influences. Variation, between patients, in the dynamics, magnitude and progression of sympathetic activation mandates an individualized approach to investigation and therapy. Excessive sympathetic outflow to the heart and periphery can be addressed by several complimentary strategies: attenuating these sympatho-excitatory stimuli, modulating the neural regulation of NA release, and blocking the actions of catecholamines at post-junctional receptors.
Forsyth, R. and B. Jayamoni (2003). "Noradrenergic agonists for acute traumatic brain injury." Cochrane Database Syst Rev(1): CD003984.
BACKGROUND: Although there have been considerable gains in understanding the cascade of events that lead to secondary injury after traumatic brain injury (TBI), efforts to translate this understanding into new therapeutic, so-called neuroprotective, approaches have so far proven disappointing. Animal models suggest an alternative strategy: agents enhancing monoaminergic transmission, particularly amphetamines, have been shown to promote motor recovery from focal brain injury and it has been suggested that this might represent a complementary means of therapeutic intervention in the later post-injury phase. OBJECTIVES: To evaluate the evidence that amphetamines improve final outcome after traumatic brain injury. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Science Citation Index, Cochrane Controlled Trials Register and the Cochrane Injuries Group's Specialised Register of Controlled Trials. Researchers and authors of published trials were also contacted. SELECTION CRITERIA: Randomised controlled trials comparing the use of a noradrenergic agonist (together with conventional non-pharmacological rehabilitative therapy) versus conventional non-pharmacological rehabilitative therapy alone. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened records, extracted data and assessed trial quality. MAIN RESULTS: Although there is a limited clinical literature addressing this topic, none of the studies identified fully meets inclusion criteria for this review. REVIEWER'S CONCLUSIONS: At present there is insufficient evidence to support the routine use of methylphenidate or other amphetamines to promote recovery from TBI.
Frieri, M. (2003). "Neuroimmunology and inflammation: implications for therapy of allergic and autoimmune diseases." Ann Allergy Asthma Immunol 90(6 Suppl 3): 34-40.
OBJECTIVES: To review concepts of neuroendocrinoimmunology and provide an overview of the role of immune dysregulation, stress, and the understanding of the pathogenesis and treatment of allergic and autoimmune diseases. DATA SOURCES: Articles include original research papers, review articles, and references identified from the bibliographies of pertinent articles. RESULTS: Neuroendocrine hormones triggered during stress may lead to immune dysregulation or altered or amplified cytokine production, resulting in atopic, autoimmune diseases or decreased host defense. Various types of transmitter substances of the neuroendocrine-immune (NEI) network include epinephrine, norepinephrine, acetylcholine, substance P, vasoactive intestinal peptide, glucagon, insulin, cytokines, growth factors, and numerous other mediators. The stress response and induction of a dysregulation of cytokine balance can trigger the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. Disorders in which abnormalities in immune function are mediated by the NEI network include allergic diseases: allergic rhinitis, atopic dermatitis, and gastro-intestinal allergies and asthma through overproduction of neuropeptides and cytokines. The multiple roles of Th2 cells in maintaining allergic inflammation and altering the balance between Th1 and Th2 responses are important mechanisms for allergic inflammation and tissue damage. In addition, several autoimmune diseases mediated by NEI network such as rheumatoid arthritis, systemic lupus erythematosus, and diabetes mellitus can be attributable to immune dysregulation. CONCLUSIONS: Understanding the NEI network will contribute to novel treatments for immediate and late allergic reactions. Chronic stress or depression could lead to decreased host defenses, decreased response to vaccines, viral susceptibility, or malignancy. Treatment of allergic, autoimmune diseases and asthma should include stress management and behavioral intervention to prevent stress-related immune imbalances.
Gainetdinov, R. R. and M. G. Caron (2003). "Monoamine transporters: from genes to behavior." Annu Rev Pharmacol Toxicol 43: 261-84.
Modulation of fast neurotransmission by monoamines is critically involved in numerous physiological functions and pathological conditions. Plasma membrane monoamine transporters provide one of the most efficient mechanisms controlling functional extracellular monoamine concentrations. These transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), which are expressed selectively on the corresponding neurons, are established targets of many psychostimulants, antidepressants, and neurotoxins. Recently, genetic animal models with targeted disruption of these transporters have become available. These mice have provided opportunities to investigate the functional importance of transporters in homeostatic control of monoaminergic transmission and to evaluate, in an in vivo model system, their roles in physiology and pathology. The use of these mice as test subjects has been helpful in resolving several important issues on specificity and mechanisms of action of certain pharmacological agents. In the present review, we summarize recent advances in understanding the physiology and pharmacology of monoamine transporters gained in mice with targeted genetic deletion of DAT, SERT, and NET.
Garcia-Poblete, E., H. Fernandez-Garcia, et al. (2003). "Sympathetic sprouting in dorsal root ganglia (DRG): a recent histological finding?" Histol Histopathol 18(2): 575-86.
During the nineties it was described, as an original finding, the existence of afferent amyelinic nerve endings in animal dorsal root ganglia (DRG) caused by diverse experimental lesions. These works do not take into account the historical studies carried out by Ehrlich (1886), Ramon y Cajal (1890) and Dogiel (1885) among others. Ramon y Cajal (1899) confirmed the existence of these nerve endings naming them after their discoverer as "Dogiel's arborisations". Ramon y Cajal claims that these endings originate from fibres of sympathetic nature, something supported by later authors devoted to this topic. In any case, the same authors remarked already a possible relationship with pathological phenomena, nonetheless always referring to the frequent occasions in which the same images appeared in healthy animals. In this work we review the bibliography about the classically named "Terminal Dogiel's nests" which in modern literature have been referred to as sprouting of sympathetic axons in dorsal root ganglia likely related with sympathetically maintained pain. Furthermore, we present the finding, not described up to date, of multiple afferent amyelinic nervous endings related with the "Terminal Dogiel's nests" observed in different DRG from young adult healthy rabbits.
Goldstein, L. B. (2003). "Neuropharmacology of TBI-induced plasticity." Brain Inj 17(8): 685-94.
PRIMARY OBJECTIVE: The purpose of this report is to review both fundamental studies in laboratory animals and preliminary clinical data suggesting that certain drugs may affect behavioural recovery after brain injury. MAIN OUTCOMES AND RESULTS: Laboratory studies show that systemically-administered drugs that affect specific central neurotransmitters including norepinephrine and GABA influence affect recovery in a predictable manner. Although some drugs such as d-amphetamine have the potential to enhance recovery, others such as neuroleptics and other central dopamine receptor antagonists, benzodiazepines and the anti-convulsants phenytoin and phenobarbital may be detrimental. In one study, 72% of patients with traumatic brain injury received one or a combination of the drugs that may impair recovery based on both animal experiments and studies in recovering stroke patients. CONCLUSIONS: Until the true impact of these classes of drugs are better understood, care should be exercised in the use of medications that may interfere with the recovery process in patients with traumatic brain injury. Additional research needs to be completed before the clinical efficacy of drugs that may enhance recovery can be established.
Goldstein, D. S., G. Eisenhofer, et al. (2003). "Sources and significance of plasma levels of catechols and their metabolites in humans." J Pharmacol Exp Ther 305(3): 800-11.
Human plasma contains several catechols, including the catecholamines norepinephrine, epinephrine, and dopamine, their precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), and their deaminated metabolites, dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, and dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of metabolism of catechols include 3-methoxytyrosine (from L-DOPA), homovanillic acid and dopamine sulfate (from dopamine), normetanephrine, vanillylmandelic acid, and methoxyhydroxyphenylglycol (from norepinephrine), and metanephrine (from epinephrine). Plasma levels of catechols and their metabolites have related but distinct sources and therefore reflect different functions of catecholamine systems. This article provides an update about plasma levels of catechols and their metabolites and the relevance of those levels to some issues in human health and disease.
Gorman, J. M. (2003). "New molecular targets for antianxiety interventions." J Clin Psychiatry 64 Suppl 3: 28-35.
Recent advances in neuroscience and understanding in the etiology of anxiety have led researchers to new targets for treatments that are proving to be at least as effective as benzodiazepines, which have been the traditional treatment for anxiety for over 40 years. The gamma-aminobutyric acid (GABA) system has long been targeted in anxiety interventions via benzodiazepines, but better understanding of its role in anxiety disorders has led to the development of partial benzodiazepine-GABA receptor antagonists and agents that target specific subunits of the GABA-A receptor and that manipulate GABA levels. The recognition that antidepressants are effective in anxiety even in nondepressed patients has caused researchers to develop antianxiety agents that affect the serotonin and norepinephrine systems. Other neurotransmitter systems such as corticotropin-releasing factor and substance P appear to be abnormally regulated in patients with anxiety disorders, so antagonists of these neurotransmitters may prove to be beneficial anxiolytics. Meanwhile, antistress and antianxiety effects through neurogenesis may be possible with the use of agents that decrease glutamate neurotransmission, such as metabotropic glutamate receptor agonists. Finally, the stimulation of neurotrophic factors, such as brain-derived neurotrophic factor, which appears to enhance neurogenesis, may also prove to have anxiolytic effects.
Gothert, M. (2003). "Modulation of noradrenaline release in human cardiovascular tissues." Pharmacol Toxicol 92(4): 156-9.
Greden, J. F. (2003). "Physical symptoms of depression: unmet needs." J Clin Psychiatry 64 Suppl 7: 5-11.
The burden of depression on society is sizable. Innate to this burden are underdiagnosis and under-treatment of unipolar and bipolar major depressive disorder in all parts of the health care system in part due to underrecognition of the physical symptoms that commonly are core components of major depressive disorder. Physical pains especially complicate the diagnosis of depression. Many patients de-emphasize psychosocial symptoms while emphasizing pains as their primary or sole complaints. There is a high correlation between the number of physical symptoms reported and the presence of depression. Additionally, patients with residual physical and emotional symptoms following treatment for depression appear to be at higher risk of relapse compared with those who have no residual symptoms. Complex genetic vulnerabilities underlie the depressive diathesis, and stress appears to be an accentuation for the gene expression that sets off episodes of depression in persons with these predispositions. If underdiagnosis interferes and acute treatment is not implemented early and effectively for initial episodes of depression and maintained after remission, individuals with genetic vulnerabilities may experience a pattern of recurrences, cycle acceleration, and increased severity. Serotonin and norepinephrine may be shared neurochemical links that tie depression and physical symptoms together. Thus, it is reasonable to hypothesize that antidepressants that incorporate both serotonin and norepinephrine reuptake inhibition might be a more efficacious treatment approach for patients with physical symptoms of depression.
Guimaraes, S., M. Morato, et al. (2003). "Hypertension due to blockade of adenosine receptors." Pharmacol Toxicol 92(4): 160-2.
Chronic treatment of rats with 90 microg/kg/day DPSPX (1,3-dipropyl-8-sulphophenylxanthine) during seven days leads to a hypertensive state which is characterized by marked morphological changes of the blood vessel walls as well as by important functional alterations. While the angiotensin-converting enzyme (ACE) inhibitor captopril and the antagonist of angiotensin II AT 1 receptors losartan prevent the development of both hypertension and morphological changes, the selective beta1-adrenoceptor antagonist atenolol could prevent only the increase in blood pressure. It is concluded that at least two factors are involved in the development of the hypertensive state.
Hirooka, Y., T. Kishi, et al. (2003). "Effect of overproduction of nitric oxide in the brain stem on the cardiovascular response in conscious rats." J Cardiovasc Pharmacol 41 Suppl 1: S119-26.
To examine the role of nitric oxide in the brain stem on cardiovascular response in vivo, we have developed and applied a technique of endothelial nitric oxide synthase gene transfer into the nucleus tractus solitarii or the rostral ventrolateral medulla of rats in vivo. The blood pressure and heart rate were monitored using a radiotelemetry system in the conscious state. As a marker of sympathetic nerve activity, we measured 24-h urinary norepinephrine excretion. We found that overexpression of endothelial nitric oxide synthase in the nucleus tractus solitarii as well as in the rostral ventrolateral medulla causes hypotension and bradycardia via a decrease in sympathetic nerve activity. Furthermore, in the case of the local increases in nitric oxide in the rostral ventrolateral medulla, we suggest that this effect is mediated by an increase in gamma-aminobutyric acid. Moreover, in the stroke-prone spontaneously hypertensive rat, the increase in nitric oxide production evoked by the overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla caused greater depressor and sympatho-inhibitory responses than in normotensive Wistar-Kyoto rats, suggesting that an abnormality of the L-arginine-nitric oxide pathway may be involved in the central mechanisms of hypertension in this model.
Hsueh, W., M. S. Caplan, et al. (2003). "Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts." Pediatr Dev Pathol 6(1): 6-23.
Necrotizing enterocolitis (NEC), a disease affecting predominantly premature infants, is a leading cause of morbidity and mortality in neonatal intensive care units. Although several predisposing factors have been identified, such as prematurity, enteral feeding, and infection, its pathogenesis remains elusive. In the past 20 years, we have established several animal models of NEC in rats and found several endogenous mediators, especially platelet-activating factor (PAF), which may play a pivotal role in NEC. Injection of PAF induces intestinal necrosis, and PAF antagonists prevent the bowel injury induced by bacterial endotoxin, hypoxia, or challenge with tumor necrosis factor-a (TNF) plus endotoxin in adult rats. The same is true for lesions induced by hypoxia and enteral feeding in neonatal animals. Human patients with NEC show high levels of PAF and decreased plasma PAF-acetylhydrolase, the enzyme degrading PAF. The initial event in our experimental models of NEC is probably polymorphonuclear leukocyte (PMN) activation and adhesion to venules in the intestine, which initiates a local inflammatory reaction involving proinflammatory mediators including TNF, complement, prostaglandins, and leukotriene C4. Subsequent norepinephrine release and mesenteric vasoconstriction result in splanchnic ischemia and reperfusion. Bacterial products (e.g., endotoxin) enter the intestinal tissue during local mucosal barrier breakdown, and endotoxin synergizes with PAF to amplify the inflammation. Reactive oxygen species produced by the activated leukocytes and by intestinal epithelial xanthine oxidase may be the final pathway for tissue injury. Protective mechanisms include nitric oxide produced by the constitutive (mainly neuronal) nitric oxide synthase, and indigenous probiotics such as Bifidobacteria infantis. The former maintains intestinal perfusion and the integrity of the mucosal barrier, and the latter keep virulent bacteria in check. The development of tissue injury depends on the balance between injurious and protective mechanisms.
Inoue, T., Y. Kitaichi, et al. (2003). "[Treatment strategy of refractory depression and its presynaptic mechanism of action]." Nihon Shinkei Seishin Yakurigaku Zasshi 23(1): 11-20.
Most antidepressants used in Japan are reuptake inhibitors of monoamine, such as noradrenaline and serotonin. Incidence of refractory depression, which is resistant to at least two monoamine reuptake inhibitors, is 10-20%. ECT and the addition of lithium, thyroid hormones or dopamine agonists is used for the treatment of refractory depression. Bupropion and MAO inhibitors are also effective for refractory depression but not approved in Japan. The presynaptic mechanism of action of these antidepressants has been studied by in vivo microdialysis studies. Serotonin reuptake inhibitors increase extracellular serotonin concentrations in the brain. Noradrenaline reuptake inhibitors increase extracellular noradrenaline concentrations in the brain, and increase extracellular dopamine concentrations in the frontal cortex, but not in the nucleus accumbens or striatum. ECT and MAO inhibitors increase extracellular serotonin concentrations in the brain, and ECT, bupropion and MAO inhibitors increase extracellular noradrenaline concentrations in the brain. In contrast to monoamine reuptake inhibitors, ECT, bupropion and MAO inhibitors increase extracellular dopamine concentrations not only in the frontal cortex but also in the nucleus accumbens and striatum. The facilitation of mesolimbic or nigrostriatal dopamine neurotransmission may be the mechanism of action behind these treatments' efficacies for refractory depression. Although there are only a few studies concerning the mechanism of action of augmentation therapy, recent studies demonstrated that subchronic lithium treatment increases basal concentrations of extracellular serotonin in the frontal cortex and hippocampus. Subchronic lithium further increases SSRI-induced increases in extracellular serotonin concentrations, and this effect is suggested to be the mechanism of action for lithium augmentation of antidepressants.
Kafka, M. P. (2003). "The monoamine hypothesis for the pathophysiology of paraphilic disorders: an update." Ann N Y Acad Sci 989: 86-94; discussion 144-53.
A monoamine hypothesis for the pathophysiology of paraphilic disorders was first articulated in 1997 by Kafka. This hypothesis was based on four converging lines of empirical evidence. First, the monoamine neurotransmitters, dopamine, norepinephrine, and serotonin serve a modulatory role in human and mammalian sexual motivation, appetitive, and consummatory behavior. Second, the sexual effects of pharmacological agents that affect monoamine neurotransmitters can have both significant facilitative and inhibitory effects on sexual behavior. Third, paraphilic disorders appear to have Axis I comorbid associations with nonsexual psychopathologies that are associated with monoaminergic dysregulation. Last, pharmacological agents that enhance central serotonergic function in particular, have been reported to ameliorate paraphilic sexual arousal and behavior. Contemporary data supporting or refuting a monoaminergic hypothesis as a biological component associated with paraphilic sex offending behaviors will be reviewed. Particular attention will be given to pharmacological-metabolic probe studies, reports of Axis I comorbidity, the proposed role of disinhibited sexual motivation or sexual appetitive behavior, and cumulative pharmacological treatment data sets.
Katz, A. M. (2003). "Pathophysiology of heart failure: identifying targets for pharmacotherapy." Med Clin North Am 87(2): 303-16.
Recent advances in our understanding of the pathophysiology of heart failure have greatly increased the number of potential targets for therapy. The most important of these advances was the recognition that a major goal of therapy should be to modify long-term proliferative responses, as well as to achieve short-term functional improvement. This conclusion emerged from several clinical trials which showed that correction of functional abnormalities in these patients, although often of immediate clinical value, can worsen long-term prognosis. Although vasodilators alleviate the disability that is caused by excessive afterload, most increase long-term mortality: similarly, although inotropic drugs provide immediate relief of symptoms and are useful as temporary support in patients with damaged hearts, most inotropes also shorten long-term survival. Treatment of chronic heart failure should not be targeted simply at the signs and symptoms noted by Withering. Instead, a major goal of therapy should be to slow progression by modifying maladaptive growth responses in the failing heart, which were unknown when Withering discovered that digitalis can alleviate the signs and symptoms of heart failure. New targets for treatment, therefore, include the maladaptive proliferative signaling cascades that cause progressive ventricular dilatation (remodeling) and hastens cardiac cell death. The ability to inhibit maladaptive proliferative signaling in patients with heart failure was greatly enhanced by the rapid pace of discovery in molecular biology. New understanding of the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate remodeling, apoptosis, and other deleterious features of the hypertrophic response has opened important areas for research into the causes and therapy of heart failure. Similarly, potential roles for cell adhesion molecules, cytokines, and peptide growth factors in activating maladaptive proliferative responses suggests additional targets for therapy. This and other new information regarding signal transduction pathways, notably the many crossovers between functional and proliferative signaling, provide promising opportunities in this rapidly advancing area of study.
Klein, D. C., S. Ganguly, et al. (2003). "14-3-3 proteins in pineal photoneuroendocrine transduction: how many roles?" J Neuroendocrinol 15(4): 370-7.
Recent studies suggest that a common theme links the diverse elements of pineal photoneuroendocrine transduction--regulation via binding to 14-3-3 proteins. The elements include photoreception, neurotransmission, signal transduction and the synthesis of melatonin from tryptophan. We review general aspects of 14-3-3 proteins and their biological function as binding partners, and also focus on their roles in pineal photoneuroendocrine transduction.
Leclerc, K. M. and W. C. Levy (2003). "The role of norepinephrine in exercise impairment in congestive heart failure." Congest Heart Fail 9(1): 25-8.
Congestive heart failure is a disorder that includes a multitude of neurohormonal responses that become maladaptive over time. Chronic sympathetic stimulation adversely affects the well-being and survival of heart failure patients and contributes to the exercise intolerance frequently seen in these patients. Norepinephrine levels have been correlated with poorer survival in heart failure patients. Administration of norepinephrine has been shown to impair exercise responses in those with congestive heart failure, and the recent effort to incorporate beta blocker therapy into the standard management of heart failure patients addresses this abnormal neurohormonal process. Studies with central-acting sympatholytics have shown mixed results. The use of drugs such as clonidine has been suggested as potentially useful therapy in the long-term management of patients with heart failure, but definitive conclusions await further study. Regular exercise has been shown to reduce resting norepinephrine levels in heart failure subjects. This may serve as an additional rationale to recommend chronic exercise for these patients.
Lee, C. R., M. L. Watkins, et al. (2003). "Vasopressin: a new target for the treatment of heart failure." Am Heart J 146(1): 9-18.
BACKGROUND: Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. METHODS: Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. RESULTS: Through activation of V(1a) and V(2) receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V(2) and dual V(1a)/V(2) receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V(1a) receptor antagonism requires further investigation. CONCLUSIONS: Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.
Lima, M. S., A. A. Reisser, et al. (2003). "Antidepressants for cocaine dependence." Cochrane Database Syst Rev(2): CD002950.
BACKGROUND: Cocaine dependence is a common and serious condition, which has become a substantial public health problem. The past decade has witnessed a sustained search for an effective pharmacotherapeutic agent for the treatment of cocaine dependence. While administration of cocaine acutely increases intercellular dopamine, serotonin, and norepinephrine levels by blocking their presynaptic reuptake, chronic cocaine abuse leads to down-regulation of monoamine systems. Post-cocaine use depression and cocaine craving may be linked to this down-regulation. Antidepressant pharmacotherapy, by augmenting monoamine levels, may alleviate cocaine abstinence symptomatology, as well as relieving dysphoria and associated craving by general antidepressant action. OBJECTIVES: To conduct a systematic review of all RCTs on the use of antidepressants for treating cocaine dependence. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966 - 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from 1974 - 2000), Biological Abstracts (1982 to 2000). Other searches:reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of antidepressants on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. MAIN RESULTS: 18 studies were included in the review, with 1177 people randomised. Positive urine sample for cocaine metabolites was the main efficacy outcome, with no significant results obtained regardless of the type of antidepressant. Compared to other drugs, desipramine performed better but showing just a non significant trend with heterogeneity present as revealed by the chi-square test (8.6, df=3; p=0.04). One single trial showed imipramine performed better than placebo in terms of clinical response according to patient's self-report. A similar rate of patients remaining in treatment was found for both patients taking desipramine or placebo. Results from one single trial suggest fluoxetine patients on SSRIs are less likely to dropout. Similar results were obtained for trials where patients had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. REVIEWER'S CONCLUSIONS: There is no current evidence supporting the clinical use of antidepressants in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding psychotherapeutic supportive measures aiming to keep patients in treatment.
Lopez, R., F. Roig, et al. (2003). "Role of cyclooxygenase-2 in the control of renal haemodynamics and excretory function." Acta Physiol Scand 177(4): 429-35.
AIM: The available evidence supporting the importance of cyclooxygenase-2 (COX-2) in the regulation of renal haemodynamics and excretory function is summarized. Cyclooxygenase-2-derived metabolites play a very important role in regulating renal haemodynamics when sodium intake is low whereas it plays a minor role in the control of cortical blood flow when sodium intake is normal or elevated. The importance of COX-2 in the regulation of renal haemodynamics seems to be dependent on the endogenous production of other vasoactive products such as nitric oxide (NO) or noradrenaline. The activation of COX-2 in response to a decrease in NO may represent a mechanism aimed at defending the renal vasculature in the face of a decrease in NO levels. CONCLUSION: Contrary to the important role of COX-2 in the long-term regulation of renal haemodynamics, the metabolites derived from COX-2 seem to be only involved in the acute regulation of renal excretory function.
Maheu, F. S. and S. J. Lupien (2003). "[Memory in the grip of emotions and stress: a necessarily harmful impact?]." Med Sci (Paris) 19(1): 118-24.
While intense negative events are vividly recalled, information learned during stressful situations is poorly remembered. These differential effects of emotions and stress on memory have been attributed to the physiological manifestations generated during those affective states. Intense emotional and stressful events trigger the secretion of catecholamines and of glucocorticoids, in particular. These hormones would be modulatory agents of memory functions. In the first part of this paper, we review the specific effects emotions and stress have on memory. We then summarize the psychological and biological determinants responsible for these effects. Finally, we discuss different methodological issues that could explain the discrepancy found between the impact of emotions and stress on memory. Defining more precisely the effects emotion and stress have on memory will lead to a better comprehension of the cognitive problems that characterize patients dealing with emotional turmoil, such as patients suffering from depression or post-traumatic stress disorder.
Marcus, A. J., M. J. Broekman, et al. (2003). "Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases." J Pharmacol Exp Ther 305(1): 9-16.
Platelets are responsible for maintaining vascular integrity. In thrombocytopenic states, vascular permeability and fragility increase, presumably due to the absence of this platelet function. Chemical or physical injury to a blood vessel induces platelet activation and platelet recruitment. This is beneficial for the arrest of bleeding (hemostasis), but when an atherosclerotic plaque is ulcerated or fissured, it becomes an agonist for vascular occlusion (thrombosis). Experiments in the late 1980s cumulatively indicated that endothelial cell CD39-an ecto-ADPase-reduced platelet reactivity to most agonists, even in the absence of prostacyclin or nitric oxide. As discussed herein, CD39 rapidly and preferentially metabolizes ATP and ADP released from activated platelets to AMP, thereby drastically reducing or even abolishing platelet aggregation and recruitment. Since ADP is the final common agonist for platelet recruitment and thrombus formation, this finding highlights the significance of CD39. A recombinant, soluble form of human CD39, solCD39, has enzymatic and biological properties identical to the full-length form of the molecule and strongly inhibits human platelet aggregation induced by ADP, collagen, arachidonate, or TRAP (thrombin receptor agonist peptide). In sympathetic nerve endings isolated from guinea pig hearts, where neuronal ATP enhances norepinephrine exocytosis, solCD39 markedly attenuated norepinephrine release. This suggests that NTPDase (nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences. In a murine model of stroke, driven by excessive platelet recruitment, solCD39 reduced the sequelae of stroke, without an increase in intracerebral hemorrhage. CD39 null mice, generated by deletion of apyrase-conserved regions 2 to 4, exhibited a decrease in postischemic perfusion and an increase in cerebral infarct volume when compared with controls. "Reconstitution" of CD39 null mice with solCD39 reversed these changes. We hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic diatheses.
Mazzeo, R. S. and J. T. Reeves (2003). "Adrenergic contribution during acclimatization to high altitude: perspectives from Pikes Peak." Exerc Sport Sci Rev 31(1): 13-8.
We have examined the sympathoadrenal responses to both acute and chronic high-altitude exposure at the summit of Pikes Peak, CO, in both men and women. A dissociation between the adrenal medullary response (acute) with that of the sympathetic nervous system (chronic) is observed. Both alpha- and beta-adrenergic contributions to key metabolic and physiologic adjustments to high-altitude exposure are evident.
McIntyre, C. K., A. E. Power, et al. (2003). "Role of the basolateral amygdala in memory consolidation." Ann N Y Acad Sci 985: 273-93.
Memories of emotionally arousing events tend to be more vivid and to persist longer than do memories of neutral or trivial events. Moreover, memories of emotionally influenced information may endure after a single experience. Recent findings strongly suggest that the influence of emotional arousal on memory consolidation is mediated by the release of adrenal stress hormones (epinephrine and glucocorticoids) and neurotransmitters that converge in modulating the noradrenergic system within the amygdala. Considerable evidence also indicates that amygdala activation influences memory by regulating consolidation in other brain regions. The findings suggest further that this memory-modulatory system may be involved in the formation of traumatic memories and posttraumatic stress disorder in human subjects.
Millichap, J. G. and M. M. Yee (2003). "The diet factor in pediatric and adolescent migraine." Pediatr Neurol 28(1): 9-15.
Diet can play an important role in the precipitation of headaches in children and adolescents with migraine. The diet factor in pediatric migraine is frequently neglected in favor of preventive drug therapy. The list of foods, beverages, and additives that trigger migraine includes cheese, chocolate, citrus fruits, hot dogs, monosodium glutamate, aspartame, fatty foods, ice cream, caffeine withdrawal, and alcoholic drinks, especially red wine and beer. Underage drinking is a significant potential cause of recurrent headache in today's adolescent patients. Tyramine, phenylethylamine, histamine, nitrites, and sulfites are involved in the mechanism of food intolerance headache. Immunoglobulin E-mediated food allergy is an infrequent cause. Dietary triggers affect phases of the migraine process by influencing release of serotonin and norepinephrine, causing vasoconstriction or vasodilatation, or by direct stimulation of trigeminal ganglia, brainstem, and cortical neuronal pathways. Treatment begins with a headache and diet diary and the selective avoidance of foods presumed to trigger attacks. A universal migraine diet with simultaneous elimination of all potential food triggers is generally not advised in practice. A well-balanced diet is encouraged, with avoidance of fasting or skipped meals. Long-term prophylactic drug therapy is appropriate only after exclusion of headache-precipitating trigger factors, including dietary factors.
Morilak, D. A., M. Cecchi, et al. (2003). "Interactions of norepinephrine and galanin in the central amygdala and lateral bed nucleus of the stria terminalis modulate the behavioral response to acute stress." Life Sci 73(6): 715-26.
Many aspects of drug abuse and addiction share neurobiological substrates with the modulatory processes underlying the response and adaptation to acute stress. In particular, the ascending noradrenergic system has been implicated in facilitating the response to stress, and in stress-induced reinstatement of drug seeking behavior. Thus, to better understand the link between stress and addictive behaviors, it would be informative to understand better the modulatory function of the ascending noradrenergic system, and its interaction with other neurotransmitters with which it is closely associated or co-localized, such as the neuropeptide galanin. In this paper, we review a series of studies investigating the functional interactions of norepinephrine and galanin in modulating the behavioral response to acute stress in two components of the extended amygdala, the central nucleus of the amygdala and the lateral bed nucleus of the stria terminalis. We showed that norepinephrine facilitates behavioral reactivity to stress on the elevated plus-maze and social interaction tests. However, when stress-induced activation of the noradrenergic system was enhanced by blocking inhibitory adrenergic autoreceptors, galanin release was recruited in the central amygdala, acting to attenuate the behavioral response to stress. By contrast, stress-induced galanin release in the lateral bed nucleus appeared to be independent of enhanced noradrenergic activation, and unlike the central amygdala, both galanin and norepinephrine facilitated behavioral stress reactivity in the bed nucleus. The different modes of interaction and differential region- and response-specificity of galanin and norepinephrine suggest that a complex neural circuit interconnecting these two regions is involved in the modulatory effects of norepinephrine and galanin on the behavioral response to stress. Such complexity may allow for flexibility and plasticity in stress adaptation, and may also contribute to behavioral changes induced by chronic drug administration. Thus, the interaction of galanin and norepinephrine may be a viable target for the future development of novel therapeutic strategies for treating behavioral disorders related to stress or drug abuse.
Muller, W. E. (2003). "Current St John's wort research from mode of action to clinical efficacy." Pharmacol Res 47(2): 101-9.
Preparations from St. John's wort extracts are used in the treatment of depression in many countries and represent an accepted alternative to synthetic antidepressants or behavioural therapy. St. John's wort extracts are therefore used in a therapeutic area which extends well beyond the traditional field of herbal medicine. The current status of preclinical and clinical research is summarised. St. John's wort extract has a clear inhibitory effect on the neuronal uptake not only of serotonin, noradrenaline, and dopamine but also of gamma-aminobutyric acid (GABA) and L-glutamate. No other antidepressant shows an approximately equally broad inhibitory profile. In good agreement with the effects in various biochemical models of antidepressant action, many effects in a number of behavioural pharmacology models of antidepressant efficacy could also be demonstrated for St. John's wort extract. Similar doses of John's wort also cause changes in the above-mentioned neurotransmitter systems in the brain. Out of all individual substances of St. John's wort only hyperforin and its structural analogue adhyperforin inhibit the re-uptake of the investigated neurotransmitters. However, hyperforin does not act as a competitive inhibitor at the transmitter binding sites of the transporter proteins but it affects the sodium gradient which then leads to an inhibition of uptake. The broad spectrum of action which characterises St. John's wort extracts has only been described for the pure substance hyperforin. Over the past year a number of good clinical studies have been carried out which confirm the efficacy and tolerability of St. John's wort extracts in mild depressive disorders, even if the therapeutic efficacy has recently been questioned by an American study. All studies have confirmed the good tolerability of St. John's wort extract and the very low frequency of adverse events. However, some drug interactions have been found to occur with St. John's wort extract, a number of which are of clinical relevance. In summary, pharmacological activity and therapeutic efficacy of St. John's wort extract as an antidepressant are supported by a large number of scientific publications. Within the wide range of components in St. John's wort extract, hyperforin plays an important, if not an outstanding role.
Munarriz, R., S. W. Kim, et al. (2003). "A review of the physiology and pharmacology of peripheral (vaginal and clitoral) female genital arousal in the animal model." J Urol 170(2 Pt 2): S40-4; discussion S44-5.
PURPOSE: We review contemporary scientific data concerning the physiology and pharmacology of peripheral female genital arousal responses in the animal (rabbit and rat) model. MATERIALS AND METHODS: We reviewed the contemporary literature and our research studies concerning physiology and pharmacology of peripheral genital arousal from 3 experimental animal models, including genital smooth muscle cell culture, genital strip organ bath and in vivo animal model studies. RESULTS: Nitric oxide (NO) appears to be a key pathway mediating clitoral smooth muscle relaxation. In the vagina NO appeared to have a more controversial role in mediating vaginal muscularis smooth muscle relaxation. Vasoactive intestinal polypeptide induced vaginal smooth muscle relaxation. Functional alpha-adrenergic receptors were expressed in the clitoris and vagina, and mediated norepinephrine induced genital smooth muscle contraction. Androgens and estrogens modulated distinct physiological responses in vagina, and androgens facilitated vaginal smooth muscle relaxation. Papaverine hydrochloride, a smooth muscle relaxant, and phentolamine mesylate, an alpha-blocker, administered into the vaginal spongy muscularis layer increased vaginal wall pressure and vaginal blood flow. Sildenafil caused significant increases in genital (clitoral and vaginal) blood flow and vaginal lubrication in intact and ovariectomized animals. This response was more pronounced in animals treated with estradiol, suggesting that the NO cyclic guanosine monophosphate pathway is involved in the physiological mechanism of female genital arousal and that sildenafil facilitates this response in an in vivo animal model. CONCLUSIONS: To achieve improved understanding of the biological aspects of female sexual function, further research is needed in the physiology and pharmacology of peripheral (clitoral and vaginal) genital arousal in the animal model.
Myhrer, T. (2003). "Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks." Brain Res Brain Res Rev 41(2-3): 268-87.
From previous literature, it appears that most classical neurotransmitter systems can in some way influence learning and memory in the rat. A matter of crucial interest is, however, whether the chemical systems contribute in a similar manner or whether they have different abilities to support cognitive processes. The purpose of the present study was to investigate this issue. The investigation was carried out by reviewing relevant studies of neurochemistry and cognition. Inclusion criteria were set for selection of behavioral tasks to be elucidated and for studies employing acceptable tasks. Morris water maze, radial maze, passive avoidance, and spontaneous alternation met the criteria for inclusion, and a table for each of these tests summarizes the neurochemical results of the studies accepted for inclusion. In this way, a reliable comparability of results from relevant studies was obtained. The comparisons revealed that for both systemic and targeted infusions of agents the neurochemical systems possess different abilities to influence learning and memory. Calculation of impact factors (percentage of significant effects of chemical agents like agonists, antagonists, neurotoxins) showed that glutamate was ranking highest (93), followed by GABA (81), dopamine (81), acetylcholine (81), serotonin (55), and norepinephrine (48). No task specific roles were observed for the transmitter systems. The highest sensitivity (percentage of significant effects) to interference with neurochemical systems was found for the spontaneous alternation task (86), followed by water maze (76), passive avoidance (72), and radial maze (58). The multiple memory systems in the rat brain can hardly be related to specific transmitter systems, because of the great extent of interactions between the systems.
Norbury, R., W. J. Cutter, et al. (2003). "The neuroprotective effects of estrogen on the aging brain." Exp Gerontol 38(1-2): 109-17.
The population of the western world is ageing. This increase in the elderly population will inevitably mean a rise in the prevalence of age-related cognitive decline and late-onset neuropsychiatric disorder, such as Alzheimer's disease (AD). There are sex differences in the incidence and age of onset of these disorders. Sex steroids and sex chromosomes are therefore implicated in their pathophysiology. We have identified relevant past and current literature using a Medline search and from the references of relevant papers. These were then reviewed and relevant articles have been summarized and included in the review. Evidence is presented for the wide-ranging actions of estrogen in the brain at the cellular, metabolic and neurotransmitter levels as well as from the cognitive, AD, depression and cerebrovascular perspectives. The authors conclude that it is unlikely that estrogen will become a stand-alone treatment for any of these disorders, although there may still be a role as an adjunctive treatment and as a prophylactic measure.
Otani, T. and T. Kato (2003). "[Posttraumatic stress disorder]." Ryoikibetsu Shokogun Shirizu(38): 481-6.
Pagel, J. F. and P. Helfter (2003). "Drug induced nightmares--an etiology based review." Hum Psychopharmacol 18(1): 59-67.
OBJECTIVE: Recent clinical trials have included patient complaints of nightmares as a category of reportable medication side effects. This study integrates that data into current experimental and theoretical research of drug effects that may alter dreaming and nightmares. The objective is to provide a clinical and theoretical framework useful in categorizing the potential and reported drug effects on nightmares. METHODOLOGY: This study reviews case reports and clinical trials that have reported nightmares or alterations in dreaming occurring secondary to medication usage. These data are analysed as to the probability of the drug/nightmare association, and integrated into current electrophysiological and neurochemical theories of dreaming and nightmares. RESULTS: Pharmacological agents affecting the neurotransmitters norepinephrine, serotonin and dopamine are clearly associated with patient reports of nightmares. Agents affecting immunological response to infectious disease are likely to induce nightmares in some patients. A possible association exists between reports of nightmares and agents affecting the neurotransmitters acetylcholine, GABA and histamine, as well as for some anesthetics, antipsychotics and antiepileptic agents. CONCLUSION: By utilizing our current experimental and theoretical knowledge base, the potential etiology of a majority of reported drug effects on nightmares can be classified. These data support current neurochemical theories of dreaming, as well as suggesting that the biochemical basis for dreaming and nightmare induction may be more complex than generally suggested.
Pary, R., P. R. Matuschka, et al. (2003). "Generalized anxiety disorder." South Med J 96(6): 581-6.
Anxiety is a part of daily life. While mild levels of anxiety can be positive, moderate to severe levels can cause intense distress. When anxiety interferes with a person's ability to function, it warrants treatment. Generalized anxiety disorder (GAD) is a chronic disabling condition characterized by at least 6 months of frequent worries and three of the following symptoms: fatigue, restlessness, poor concentration, irritability, muscle tension, and unsatisfying sleep. The primary treatment for anxiety is pharmacotherapy. Medication prescribed for anxiety has shifted from exclusive benzodiazepine therapy to a combination of benzodiazepine and antidepressant drugs. The principal disadvantages of benzodiazepines are their long-term use with associated physical dependence, tolerance, and withdrawal symptoms. Several reports support the serotonin reuptake inhibitors and the serotonin norepinephrine reuptake inhibitors for the treatment of anxiety disorders.
Pliszka, S. R. (2003). "Non-stimulant treatment of attention-deficit/hyperactivity disorder." CNS Spectr 8(4): 253-8.
Stimulants are a highly efficacious and safe treatment for attention-deficit/hyperactivity disorder (ADHD), with 75% to 90% of patients responding well if two different stimulants (amphetamine and methylphenidate) are used. Nonetheless, a subset of ADHD patients will either fail to respond to stimulants or have side effects that preclude their use (tics, severe loss of appetite, marked insomnia). For such patients, there are a number of non-stimulant agents that serve as second-line treatments. Tricyclic antidepressants (TCAs) are the most studied of these drugs. They are superior to placebo in the treatment of ADHD and may reduce abnormal movements in patients with ADHD/tic disorder. TCAs often produce side effects of sedation, dry mouth, and constipation. Bupropion is superior to placebo in the treatment of ADHD and has a more favorable side-effect profile than the TCAs. A new selective norepinephrine reuptake inhibitor, atomoxetine, has been shown to be efficacious in the treatment of ADHD and has recently received an approvable letter from the Food and Drug Administration. The a-agonists clonidine and guanfacine have also been used as alternative agents in ADHD, though the controlled data are more limited. A recent controlled clinical trial suggests a combination of methylphenidate and clonidine has advantages in the treatment of comorbid ADHD and tics over either medication alone. Clinical guidelines for each of these agents, as well as their use in combination with stimulants in comorbid conditions, will be discussed.
Rajput, A. and M. Rajput (2003). "Essential tremor and parkinsonism." Adv Neurol 91: 397-9.
Richmond, R. and N. Zwar (2003). "Review of bupropion for smoking cessation." Drug Alcohol Rev 22(2): 203-20.
The advent of bupropion hydrochloride sustained release (Zyban) has heralded a major change in the options available for smoking cessation pharmacotherapy. Bupropion is a selective re-uptake inhibitor of dopamine and noradrenalin which prevents or reduces cravings and other features of nicotine withdrawal. Bupropion is a useful oral and non-nicotine form of pharmacotherapy for smoking cessation. For this review a total of 221 papers were reviewed plus poster presentations. This review examines in detail original clinical trials on efficacy, categorised according to whether they were acute treatment trials in healthy smokers; studies in specific populations such as people with depression, chronic obstructive pulmonary disease (COPD) or cardiovascular disease; or relapse prevention studies. Overall, these studies in varying populations comprising over four thousand subjects, showed bupropion consistently produces a positive effect on smoking cessation outcomes. The evidence highlights the major public health role that bupropion has in smoking cessation. The methodological issues of published clinical trials reporting one year outcomes were examined in detail including: completeness of follow-up; loss to follow-up; intention to treat analysis; blindness of assessment; and validation of smoking status. The review discusses contraindications, adverse effects, dose and overdose, addictive potential, and the role of bupropion in reducing cessation-related weight gain. Bupropion combined with or compared to other pharmacotherapies (nicotine patch; nortriptyline) is considered. Impressive evidence exists for the use of bupropion in smoking cessation among difficult patients who are hard-core smokers such as those with cardiovascular disease, chronic obstructive pulmonary disease (COPD) and depression. Bupropion reduces withdrawal symptoms as well as weight gain and is effective for smoking cessation for people with and without a history of depression or alcoholism. Serious side effects of bupropion use are rare. The major safety issue with bupropion is risk of seizures (estimated at approximately 0.1%) and it should not be prescribed to patients with a current seizure disorder or any history of seizures. In clinical trials of bupropion for smoking cessation no seizures were reported. Allergic reactions occur at a rate of approximately 3% and minor adverse effects are common including dry mouth and insomnia.
Ryan, N. D. (2003). "Child and adolescent depression: short-term treatment effectiveness and long-term opportunities." Int J Methods Psychiatr Res 12(1): 44-53.
As with adult major depressive disorder (MDD), child and adolescent MDD is characterized as a common, chronic and recurrent disorder. It is also associated with short- and long-term functional impairment, morbidity, and mortality. Effective treatments, both psychotherapeutic and pharmacotherapeutic, are available for the short-term treatment and management of youth with MDD. However, to date, there are no data on the long-term treatment and management of children and adolescents with MDD and how long-term treatment may affect the outcomes of either high-risk or already affected youth. Understanding the long-term consequences of MDD during youth is as important as understanding how to treat a single episode of depression. Available data on the pharmacotherapeutic and psychotherapeutic options are discussed. In general, tricyclic antidepressants (TCAs) are not as effective for the treatment of youth with MDD as adults with MDD. The selective serotonin reuptake inhibitors (SSRIs) have been shown to be effective in children and adolescents with MDD and non-obsessive compulsive anxiety disorders. The serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine XR, has been shown to be effective for the treatment of generalized anxiety disorder in children and adolescents. Understanding the long-term clinical consequences of depressive disorders in youth may provide opportunities for better intervention across the clinical course of illness. Early recognition, diagnosis and adequate treatment of 'high-risk' youth with subsyndromal depressive symptoms, treatment of acute episodes of depression to prevent 'kindling', and aggressive prophylaxis have the potential to improve the mental health of youth throughout their lives.
Simonneaux, V. and C. Ribelayga (2003). "Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters." Pharmacol Rev 55(2): 325-95.
Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.
Simpson, D. and C. M. Perry (2003). "Atomoxetine." Paediatr Drugs 5(6): 407-15; discussion 416-7.
Atomoxetine, formerly tomoxetine, is a selective norepinephrine reuptake inhibitor and a new, nonstimulant treatment for attention deficit hyperactivity disorder (ADHD). In vitro, ex vivo and in vivo studies have shown that atomoxetine is a highly selective antagonist of the presynaptic norepinephrine transporter with little or no affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. In four randomized, placebo-controlled clinical trials conducted over 6-9 weeks in children and adolescents with ADHD, atomoxetine (total daily dose 1-1.8 mg/kg administered in one or two doses daily) reduced symptoms (hyperactivity, impulsiveness and inattention) as determined by the reduction in ADHD total score (34-38% with atomoxetine versus 13-15.7% with placebo [p < 0.05]). Atomoxetine also significantly improved ADHD subscale rating scores (p < 0.05 and p < 0.001), psychosocial well-being (p < 0.05) and ADHD-related problem behavior according to parent and teacher ratings (p < 0.05). Atomoxetine was well tolerated in clinical trials and discontinuation rates due to adverse events were low (<5%). The most common treatment-related adverse event was decreased appetite. Atomoxetine shows no abuse potential and is not a controlled substance in the US.
Small, K. M., D. W. McGraw, et al. (2003). "Pharmacology and physiology of human adrenergic receptor polymorphisms." Annu Rev Pharmacol Toxicol 43: 381-411.
Adrenergic receptors are expressed on virtually every cell type in the body and are the receptors for epinephrine and norepinephrine within the sympathetic nervous system. They serve critical roles in maintaining homeostasis in normal physiologic settings as well as pathologic states. These receptors are also targets for therapeutically administered agonists and antagonists. Recent studies have shown that at least seven adrenergic receptor subtypes display variation in amino acid sequence in the human population due to common genetic polymorphisms. Variations in potential regulatory domains in noncoding sequence are also present. Here, we review the consequences of these polymorphisms in terms of signaling, human physiology and disease, and response to therapy.
Stefano, G. B., T. Esch, et al. (2003). "Endocannabinoids as autoregulatory signaling molecules: coupling to nitric oxide and a possible association with the relaxation response." Med Sci Monit 9(4): RA63-75.
Endocannabinoid signaling processes are present in diverse organisms and in organisms 500 million years divergent in evolution. Cannabinoid receptor-1 expression (CB1), anandamide, and anandamide amidase have been found in invertebrates. Furthermore, this signaling system is coupled to constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO) release in both vertebrates and invertebrates, thereby regulating neural, immune, and vascular-like functions in these divergent organisms. In human endothelial cells from various blood vessels, CB1 immunoreactive components are present as is its coupling to anandamide-stimulated cNOS-derived NO production, which exerts an autoregulatory role on cNOS release. The modulation of vascular diameter and vascular tone represents a crucial point of interest in these pathways, and interactions between NO and the sympathetic nerve system are of importance, i.e, norepinephrine. Here, a possible association of NO and endocannabinoid signaling with the relaxation response, a physiological counterpart of the stress response, may exist.
Stewart, J. (2003). "Stress and relapse to drug seeking: studies in laboratory animals shed light on mechanisms and sources of long-term vulnerability." Am J Addict 12(1): 1-17.
Relapse is a major characteristic of drug addiction disorders and remains the primary problem for treatment. Recently, there has been hope that these disorders may be amenable to pharmacological treatments that have successfully treated other psychopathological disorders. Pharmacological approaches to drug abuse have tended to be guided by the primary drug used by the individual, though sub