Serotonin Receptor Sensitivity Research Articles

Роль генов серотонинергической медиаторной системы в формировании регуляторно-адаптивных возможностей человека

The purpose of this article was to establish the role of polymorphisms of genes regulating serotonin metabolism in the formation of human regulatory and adaptive capabilities. Materials and methods. The research involved 89 students of Kuban State Medical University. Their adaptation level was assessed at the end of the academic year according to the index of regulatory and adaptive status (IRAS) using the cardiorespiratory synchronism test (V.M. Pokrovskiy) on the VNS-Mikro device (Neurosoft, Russia). In addition, a molecular genetic analysis was performed (by DNA isolation from the peripheral blood using the standard phenol–chloroform extraction method) to identify polymorphisms of genes involved in serotonin biosynthesis (tryptophan hydroxylase genes TPH1 and TPH2) and genes encoding serotonin receptors (HTR2C and HTR2A). Results. The subjects were divided into three groups: with high (52.8 % of students), satisfactory (34.8 %) and low (12.4 %) regulatory and adaptive capabilities. In the group with high regulatory and adaptive capabilities, the most common alleles and genotypes were the following: *C allele for the ТРН1 gene; *G allele and *G/*T genotype for the ТРН2 gene, *G allele and *G/*G genotype for the HTR2С gene, and *A/*G genotype for the HTR2A gene. Statistically significant differences in the frequency of the *A/*G heterozygous genotype for the G1438A marker of the HTR2А gene were found between the groups with high and satisfactory regulatory and adaptive capabilities as well as in the groups with high and low regulatory and adaptive capabilities. In both cases, the *A/*G heterozygous genotype prevailed in individuals with high regulatory and adaptive capabilities, whereas the *G/*G heterozygous genotype was only identified in the group with low regulatory and adaptive capabilities. Thus, medical students with high regulatory and adaptive capabilities had alleles and genotypes that provide high sensitivity of serotonin receptors and sufficient activity of its biosynthesis enzymes. The obtained data revealed a dependence between the regulatory and adaptive capabilities and the polymorphisms of genes involved in both biosynthesis and reception of serotonin in humans.

Neurotransmitter Dysfunction in Irritable Bowel Syndrome: Emerging Approaches for Management.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose aetiology is still unknown. Most hypotheses point out the gut-brain axis as a key factor for IBS. The axis is composed of different anatomic and functional structures intercommunicated through neurotransmitters. However, the implications of key neurotransmitters such as norepinephrine, serotonin, glutamate, GABA or acetylcholine in IBS are poorly studied. The aim of this review is to evaluate the current evidence about neurotransmitter dysfunction in IBS and explore the potential therapeutic approaches. IBS patients with altered colorectal motility show augmented norepinephrine and acetylcholine levels in plasma and an increased sensitivity of central serotonin receptors. A decrease of colonic mucosal serotonin transporter and a downregulation of α2 adrenoceptors are also correlated with visceral hypersensitivity and an increase of 5-hydroxyindole acetic acid levels, enhanced expression of high affinity choline transporter and lower levels of GABA. Given these neurotransmitter dysfunctions, novel pharmacological approaches such as 5-HT3 receptor antagonists and 5-HT4 receptor agonists are being explored for IBS management, for their antiemetic and prokinetic effects. GABA-analogous medications are being considered to reduce visceral pain. Moreover, agonists and antagonists of muscarinic receptors are under clinical trials. Targeting neurotransmitter dysfunction could provide promising new approaches for IBS management.

Serotonergic mechanisms of regulation of the systemic circulation vessels lumen

Review is devoted to the assessment of the serotonergic mechanisms role in the hemodynamics regulation. The special attention is given to the role of various serotonin receptors involved in the gastrointestinal tract motility regulation, in particular located in the digestive system vessel walls. It is known that serotonin has a dual effect on the vessel lumen, due to the heterogeneity of serotonin receptors, which are part of the vascular wall, and different sensitivity of serotonin receptors. Mechanisms at various levels, from central to local, are able to participate in the serotonergic regulation of the vascular lumen, as well as in motility control. According to our data, in the regulation of the upper gastrointestinal tract motor activity participate 5-HT1B- and 5-HT3-receptors located in the stomach and intestines autonomic ganglia, 5-HT2B-receptors localized on stomach plexus neurons and on small and large intestine smooth muscles; 5-HT4-receptors located on stomach wall smooth muscles and intraorgan intestinal plexus neurons. According to the literature, vascular wall 5-HT2B- and 5-HT7-receptors provide vasodilation, whereas the 5-HT1B/1D-, 5-HT2A- and 5-HT2B-receptors - vasoconstriction. Significance of plasma free serotonin level for hemodynamic, serotonergic mechanisms for the different types vessels diameter changing, the interaction of serotonin receptors with sympathetic nervous system and their possible role in the vascular tone regulation are described, particularly the role of presynaptic 5-HT1B/1D-receptors, which prevent the catecholamines release by vegetative nerves endings, is established. Different points of view on the serotoninergic regulation issue, existing contradictions, as well as areas for further fundamental and practical research are presented.

Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice

BackgroundPreviously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes.MethodsTo explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity.ResultsOne consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior.ConclusionsOur findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.

Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence

The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory 5-HT transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging SNPs across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain of function Ser129 allele predicted alcohol dependence (p = 0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (p = 0.01). Both the HTR3B Ser129 allele (p = 0.014, OR = 1.7 [1.1–2.6]) and low 5-HTTLPR activity (p = 0.011, OR = 2.5 [1.3–4.6]) were more common in men with alcohol + drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol + drug dependence (OR = 6.0 [2.1–16.6]) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron.

Strain‐dependent serotonin neuron feedback control: role of serotonin2C receptors

We investigated the role of serotonin(2C) receptor-mediated feedback mechanisms in the response to citalopram in C57BL/6 and DBA/2 mice, which are respectively responders and non-responders to selective serotonin reuptake inhibitors in the forced swimming test. The microdialysis technique was used to assess changes in extracellular serotonin and GABA in the mouse dorsal raphé (DR). Citalopram (1.25-20 mg/kg) raised extracellular serotonin and GABA in the DR of both mouse strains. These effects were abolished by depleting brain serotonin with p-chlorophenylalanine (300 mg/kg × 3). Systemic and/or intra-DR infusion of the serotonin(2C) receptor antagonist 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (1 mg/kg and 0.1 μM, respectively) enhanced citalopram's effect on extracellular serotonin in the DR and medial prefrontal cortex and abolished the rise of GABA in the DR of DBA/2 mice but had no effect in C57BL/6 mice. The serotonin(2C) receptor agonist Ro60-0175 (0.03-3.0 mg/kg) reduced extracellular serotonin and raised GABA in the DR of DBA/2 mice but had much less effect in C57BL/6 mice. These findings show that the sensitivity of serotonin(2C) receptors determines the efficacy of augmentation strategies aimed at enhancing the effect of serotonin reuptake inhibitors on extracellular serotonin through the suppression of serotonin(2C) receptor-mediated feedback control of serotonin neurons.

Restricted and disrupted sleep: Effects on autonomic function, neuroendocrine stress systems and stress responsivity

Frequently disrupted and restricted sleep is a common problem for many people in our modern around-the-clock society. In this context, it is an important question how sleep loss affects the stress systems in our bodies since these systems enable us to deal with everyday challenges. Altered activity and reactivity of these systems following insufficient sleep might have serious repercussions for health and well-being. Studies on both humans and rodents have shown that sleep deprivation and sleep restriction are conditions often associated with mild, temporary increases in the activity of the major neuroendocrine stress systems, i.e., the autonomic sympatho-adrenal system and the hypothalamic-pituitary-adrenal axis. Sleep deprivation may not only have a direct activating effect by itself but, in the long run, it may also affect the reactivity of these systems to other stressors and challenges. Although the first signs of alterations in the way people deal with challenges under conditions of restricted sleep appear to be on the level of emotional perception, chronic sleep restriction may ultimately change the fundamental properties of neuroendocrine stress systems as well. Understandably, few controlled studies in humans have been devoted to this topic. Yet, experimental studies in rodents show that chronic sleep restriction may gradually alter neuroendocrine stress responses as well as the central mechanisms involved in the regulation of these responses. Importantly, the available data from studies in laboratory animals suggest that sleep restriction may gradually change certain brain systems and neuroendocrine systems in a manner that is similar to what is seen in stress-related disorders such as depression (e.g., reduced serotonin receptor sensitivity and altered regulation of the hypothalamic-pituitary-adrenal axis). Such data support the view that insufficient sleep, by acting on stress systems, may sensitize individuals to stress-related disorders. Indeed, epidemiological studies suggest that sleep complaints and sleep restriction may be important risk factors for a variety of diseases that are often linked to stress, including cardiovascular diseases and mood disorders.

Brain microdialysis of isolation-reared mice under freely-moving conditions

Brain microdialysis has become a well established and a widely-used technique for in vivo measurement of extracellular levels of neurotransmitters. However, a single neurotransmitter in the perfusates has been measured in most studies. The present paper describes a simultaneous measurement of serotonin and dopamine release in the prefrontal cortex of mice. Using this technique, we examined the modulation by serotonin(1A) receptors of serotonin, dopamine, and noradrenaline release in the cortex of isolation-reared mice. The isolation-reared mouse is a useful model of complicated mood disorders including phenotypes of anxiety, depression, and aggression. The study shows that isolation rearing selectively decreases the sensitivity of serotonin(1A) receptors to increase dopamine release.

Supersensitivity of 5-HT1A autoreceptors and alpha2-adrenoceptors regulating monoamine synthesis in the brain of morphine-dependent rats.

The sensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) modulating brain monoamine synthesis was investigated in rats during morphine treatment and after naloxone-precipitated withdrawal. The accumulation of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in vivo. Acute morphine (3-100 mg/kg, 1 h) increased the synthesis of 5-HTP/5-HT in various brain regions (15%-35%) and that of DOPA/dopamine (DA) in striatum (28%-63%), but decreased the synthesis of DOPA/noradrenaline (NA) in hippocampus and cortex (20%-33%). Naloxone (2-60 mg/kg, 1 h) did not alter the synthesis of 5-HTP or DOPA in brain. Tolerance to the inhibitory effect of morphine on DOPA/NA synthesis and a sensitization to its stimulatory effects on DOPA/DA and 5-HTP/5-HT synthesis were observed after chronic morphine and/or in morphine-withdrawn rats. In morphine-dependent rats (tolerant and withdrawn states) the inhibitory effects of the 5-HT1A agonists 8-OH-DPAT and buspirone (0.1 mg/kg, 1 h), and that of the alpha2-adrenoceptor agonist clonidine (0.1 mg/kg, 1 h), on the synthesis of 5-HTP/5-HT were potentiated (25%-50%). Moreover, the effect of 8-OH-DPAT was antagonized by WAY 100135, a selective 5-HT1A antagonist. In morphine-dependent rats (tolerant state), the inhibitory effects of clonidine on the synthesis of DOPA/NA (hippocampus, hypothalamus) and DOPA/DA (striatum) also were potentiated (35%-55%). In summary, we conclude that morphine addiction is associated with supersensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) that modulate the synthesis of monoamines in brain.

Endurance training in Wistar rats decreases receptor sensitivity to a serotonin agonist

There is mounting evidence that increased brain serotonin during exercise is associated with the onset of CNS-mediated fatigue. Serotonin receptor sensitivity is likely to be an important determinant of this fatigue. Alterations in brain serotonin receptor sensitivity were examined in Wistar rats throughout 6 weeks of endurance training, running on a treadmill four times a week with two exercise tests per week to exhaustion. Receptor sensitivity was determined indirectly as the reduction in exercise time in response to a dose of a serotonin (1A) agonist, m-chlorophenylpiperazine (m-CPP). The two groups of controls were used to examine (i) the effect of the injection per se on exercise performance and (ii) changes in serotonin receptor sensitivity associated with maturation. In the test group, undrugged exercise performance significantly improved by 47% after 6 weeks of training (4518 +/- 729 to 6640 +/- 903 s, P=0.01). Drugged exercise performance also increased significantly from week 1 to week 6 (306 +/- 69-712 +/- 192 s, P = 0.04). Control group results indicated that the dose of m-CPP alone caused fatigue during exercise tests and that maturation was not responsible for any decrease in receptor sensitivity. Improved resistance to the fatiguing effects of the serotonin agonist suggests desensitization of central serotonin receptors, probably the 5-HT1A receptors. Endurance training appears to stimulate an adaptive response to the fatiguing effects of increased brain serotonin, which may enhance endurance exercise performance.

Endurance training in Wistar rats decreases receptor sensitivity to a serotonin agonist

There is mounting evidence that increased brain serotonin during exercise is associated with the onset of CNS‐mediated fatigue. Serotonin receptor sensitivity is likely to be an important determinant of this fatigue. Alterations in brain serotonin receptor sensitivity were examined in Wistar rats throughout 6 weeks of endurance training, running on a treadmill four times a week with two exercise tests per week to exhaustion. Receptor sensitivity was determined indirectly as the reduction in exercise time in response to a dose of a serotonin (1A) agonist, m‐chlorophenylpiperazine (m‐CPP). The two groups of controls were used to examine (i) the effect of the injection per se on exercise performance and (ii) changes in serotonin receptor sensitivity associated with maturation. In the test group, undrugged exercise performance significantly improved by 47% after 6 weeks of training (4518 ± 729 to 6640 ± 903 s, P=0.01). Drugged exercise performance also increased significantly from week 1 to week 6 (306 ± 69–712 ± 192 s, P = 0.04). Control group results indicated that the dose of m‐CPP alone caused fatigue during exercise tests and that maturation was not responsible for any decrease in receptor sensitivity. Improved resistance to the fatiguing effects of the serotonin agonist suggests desensitization of central serotonin receptors, probably the 5‐HT1A receptors. Endurance training appears to stimulate an adaptive response to the fatiguing effects of increased brain serotonin, which may enhance endurance exercise performance.

The neurobiology of antidepressants.

Raising neurotransmitter levels is only one means by which antidepressants act. The activity of modern drugs appears to readjust the balance between serotonin and noradrenaline by more fundamental means. Likely mechanisms include correction of the diminished sensitivity and numbers of specific serotonin and noradrenaline receptors found in depression. Also responsible may be changes in the normal pattern of movements of these transmitters across the synaptic membranes within the diffuse modulatory systems. It is possible that by increasing the serotonin levels these drugs may increase neurogenesis, suggesting that neuronal losses may be a fundamental cause of the symptoms.

Biological markers of serotonin receptors in depression and animal models of depression

SummaryThe mechanism of action of antidepressant drugs is postulated to be linked in part to alterations which these drugs cause in the availability of serotonin, and in the sensitivity of serotonin receptors. Studying biological markers of serotonin receptors in animal models of depression as well as in patients with depression can expand our understanding of how antidepressants work. This article reviews the actions of various known antidepressants on serotonin systems in animal models of depression, and how these actions are linked to the therapeutic mechanism of antidepressants in patients with major depressive disorder.

Serotonin receptor sensitivity and aggression

This study investigated the relationship between increased serotonin (5-hydroxytryptamine, 5HT) receptor sensitivity and human aggression. A low oral dose of meta-chlorophenylpiperazine (MCPP), a postsynaptics 5HT receptor agonist, was administered in a placebo-controlled design to depressed ( n = 22) and panic disorder ( n = 20) patients classified with or wothout signs of outwardly directed aggression, patients with a history of suicide attemps (inwardly directed aggression) ( n = 11), and normal controls ( n = 19). Hormones under 5HT control were measured at 30-min intervals. Results were as follows: (1) MCPP did not induce or reduce anger, (2) patients with outwardly directed aggression did not have significantly greater MCPP-induced cortisol or prolactin release than did patients without signs of outwardly directed aggression, (3) patients with a history of suicide attemps did not have significantly greater MCPP-induced cortisol or prolactin release than did normal controls, and (4) MCPP-induced hormone release was unrelated to measures of aggression.

Serotonin receptor sensitivity in major depression

Research on the role of serotonin (5-hydroxytryptamine, 5HT) in depression spans well over two decades. The most consistc~t finding is that the cerebrospinal fluid (CSF) concentration of the 5HT metabolite, 5-hydroxyindoleacetic acid (SHIAA) is lowered in about ,..10% of patients with major depression (MD) (review: Kalus et al. 1989). The fall of CSF 5HIAA levels suggests a decrease of 5HT metabolism in the CNS, which may be the result of, or lead to, increased 5HT receptor sensitivity. Studies examining 5HT receptor sensitivity, however, have provided conflirting results. One study reported increased 5HT receptor sensitivity in MD, using the 5HT precursor, 5-hy&'oxytryptophan (5HTP) as a 5HT challenger (Meltzer etal. 1984). However, Westenberg et al. (1982), using the same oral dose of 5HTP in combination with a decarboxylase inhibitor, found normal responses in depressed subjects..qty.!dies using tryptophan and fenfluramine as 5HT challenge agents found decreased (Heninger et al. 1984; Siever et al, 1984; Coctaro et al. 1989) or normal (Asnis et al. 1988) 5HT receptor sensitivity in depressed patients. The conflicting findings may be the result of the nonselectivity of these agents and their indirect stimuiation of 5HT receptors (van Praag et al. 1987). in contrast to the studies reviewed above, the

Activity-wheel stress and serotonergic hypersensitivity in rats

Adult male Wistar rats were subjected to activity wheel stress: unlimited access to an activity wheel for up to twelve days and food for 30 to 60 min each day. Each treated rat was paired with a control, the latter being housed in home cages and given sufficient food to maintain a weight similar to the stressed partner. All rats were previously trained on a variable interval schedule for milk reinforcement. When the activity of the stressed rat increased rapidly then decreased suddenly, the pair was decapitated for biochemical analysis. Levels of the serotonin metabolite, 5-hydroxyindoleacetic acid, decreased by 50%, and the Bmax for ketanserin binding increased by 19% in frontal cortical homogenates from the stressed rats when compared to controls. These data support the concept that stress increases the sensitivity of central serotonin receptors.

Changes in sensitivity of brain dopamine and serotonin receptors during long-term treatment with carbidine

The authors study the state of the dopamine and serotonin receptors of the brain during chronic administration of carbidine to animals. Parts of the brain from two rats were pooled and binding of tritium-spiperone and tritium-LSD was determined. Statistical analysis of the data for apomorphine sterotypy was carried out and the Student's test was used for analysis of the remaining data. It is shown that after discontinuation of carbidine binding of tritium-spiperone and tritium-LSD in the cortex was reduced.

Rat brain serotonin: Biochemical and functional evidence for a sex difference

Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the "5-HT behavioural syndrome" was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.

Effect of 5-Hydroxytryptophan on Serum Cortisol Levels in Major Affective Disorders

Serum cortisol levels were significantly increased following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, to patients with affective disorders. A three- to five-week period of treatment with lithium carbonate or monoamine oxidase (MAO) inhibitor augmented the mean 5-HTP-induced increase in serum cortisol concentration in manic or depressed patients, respectively: tricyclic antidepressant (TCA) and second-generation antidepressant treatment diminished the mean serum cortisol response in patients with major depression. These results are consistent with the hypothesis that lithium carbonate may enhance serotonin (5-HT) receptor sensitivity, whereas TCA and second-generation antidepressants diminish 5-HT receptor sensitivity. The enhancement of the cortisol response to 5-HTP by MAO inhibitors may be due to decreased metabolism of 5-HT. It is important to assess the effect of thymoleptic drug treatment on various responses to biogenic amine precursors or agonists in patients rather than laboratory animals.

Delayed emergence of antidepressant efficacy following withdrawal in olfactory bulbectomized rats

Repeated antidepressant treatment attenuates the step-down passive avoidance deficit which is induced by olfactory bulbectomy in rats. Using a shuttlebox passive avoidance procedure, the effects of antidepressants were investigated after various drug withdrawal intervals. Imipramine, amitriptyline, doxepin, bupropion and mianserin were effective at 48 and usually 72 hours after withdrawal, but no significant attenuation of the deficit was seen 4 hours after withdrawal from any antidepressant tested. At least 4 to 7 days of imipramine treatment were required for efficacy. A high dose of d-amphetamine (5 mg/kg) produced similar results while tranylcypromine and haloperidol were inactive at all withdrawal intervals tested. The olfactory bulbectomy syndrome may reflect functional derotonin deficiency, which would be ameliorated through antidepressant-induced alterations in serotonin receptor sensitivity.