Showing papers on "Serotonin published in 1990"

Serotonin Function and the Mechanism of Antidepressant Action: Reversal of Antidepressant-Induced Remission by Rapid Depletion of Plasma Tryptophan

Abstract: Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.

Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid.

Abstract: Recent evidence suggests that there may be overactivation of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors in Huntington's disease (HD). Tryptophan metabolism by the kynurenine pathway produces both quinolinic acid, an NMDA receptor agonist, and kynurenic acid, an NMDA receptor antagonist. In the present study, multiple components of the tyrosine and tryptophan metabolic pathways were quantified in postmortem putamen of 35 control and 30 HD patients, using HPLC with 16-sensor electrochemical detection. Consistent with previous reports in HD putamen, there were significant increases in 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, and serotonin concentrations. Within the kynurenine pathway, the ratio of kynurenine to kynurenic acid was significantly (p less than 0.01) increased twofold in HD patients as compared with controls, consistent with reduced formation of kynurenic acid in HD. CSF concentrations of kynurenic acid were significantly reduced in HD patients as compared with controls and patients with other neurologic diseases. Because kynurenic acid is an endogenous inhibitor of excitatory neurotransmission and can block excitotoxic degeneration in vivo, a relative deficiency of this compound could directly contribute to neuronal degeneration in HD.

Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex

Abstract: Quantitative in vitro autoradiography was used to determine and compare the areal and laminar distribution of the major dopaminergic, adrenergic, and serotonergic neurotransmitter receptors in 4 cytoarchitectonic regions of the prefrontal cortex (Walker's areas 12, 46, 9, and 25) in adult rhesus monkeys. The selective ligands, 3H-SCH- 23390, 3H-raclopride, 3H-prazosin, and 3H-clonidine were used to label the D1 and D2 dopamine receptor subtypes and the alpha 1- and alpha 2- adrenergic receptors, respectively, while 125I-iodopindolol was used to detect beta-adrenergic receptors. The radioligands, 3H-5- hydroxytryptamine and 3H-ketanserin labeled, respectively, the 5-HT1 and 5-HT2 receptors. Densitometry was performed on all cortical layers and sublayers for each of the 7 ligands to allow quantitative as well as qualitative comparison among them in each cytoarchitectonic area. Although each monoamine receptor was distributed in a distinctive laminar-specific pattern that was remarkably similar from area to area, there was considerable overlap among the dopaminergic, adrenergic, and serotoninergic receptors, while subtypes of the same receptor class tended to have complementary laminar profiles and different concentrations. Thus, the D1 dopamine, the alpha 1- and alpha 2- adrenergic, and the 5-HT1 receptors were present in highest relative concentration in superficial layers I, II, and IIIa (the “S” group). In contrast, the beta 1- and beta 2-adrenergic subtypes and the 5-HT2 receptor had their highest concentrations in the intermediate layers, IIIb and IV (the “I” group), while the D2 receptor was distinguished by relatively high concentrations in the deep layer V compared to all other layers (the “D” class). Consequently, clear laminar differences were observed in the D1 vs D2 dopaminergic, the alpha- vs beta- adrenergic, and the 5-HT1 vs 5-HT2 serotoninergic receptor subtypes in all 4 areas examined. The anatomical overlap of different monoaminergic receptors in the same cortical strata suggests that there may be families of receptors linked by localization on common targets, while the complementary laminar distribution of the D1 vs D2, the 5-HT1 vs 5- HT2 and the alpha- vs beta-adrenergic receptors raises the possibility that different subtypes within a given class may have distinctive actions in cortex by virtue of their localization on different cells or possibly different portions of the same cell. Understanding the anatomical arrangement of receptors within the cortical layers may aid in the analysis of monoaminergic modulation of higher cortical function.

Specificity of Serotonin Reuptake Inhibitors in the Treatment of Obsessive-Compulsive Disorder: Comparison of Fluvoxamine and Desipramine

Abstract: • To evaluate whether serotonin reuptake inhibition is critical to the treatment of obsessive-compulsive disorder, 40 outpatients with a principal diagnosis of obsessive-compulsive disorder were randomized in a double-blind fashion to 8 weeks of treatment with either the serotonin reuptake inhibitor fluvoxamine maleate (n = 21) or the norepinephrine reuptake inhibitor desipramine hydrochloride (n =19). Fluvoxamine was significantly better than desipramine in reducing the severity of obsessive-compulsive symptoms, as measured by the Yale-Brown Obsessive Compulsive Scale and by the global response rate ("responder" equaling "much improved"). Eleven of 21 patients were responders with fluvoxamine compared with 2 of 19 patients with desipramine. Fluvoxamine, but not desipramine, was also effective in reducing the severity of "secondary" depression. Fluvoxamine-induced improvement in symptoms of obsessive-compulsive disorder was not correlated with the severity of baseline depressive symptoms. This study provides additional evidence that the acute serotonin reuptake properties of a drug are predictive of its anti—obsessive-compulsive efficacy. It is hypothesized that the mechanism of action of serotonin reuptake inhibitors in obsessive-compulsive disorder may be related to chronic treatment-induced adaptive changes in presynaptic serotonin receptor function (eg, autoreceptor desensitization) and/ or indirect influences on dopaminergic function (eg, in the basal ganglia).

A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence.

Abstract: The electrophysiologic assessment of the action of different types of antidepressant treatments on the serotonin (5-hydroxytryptamine [5-HT]) system revealed as a common effect an enhancement of 5-HT neurotransmission, albeit each treatment achieved this result via a different mechanism. Tricyclic antidepressant drugs and electroconvulsive shock treatment sensitize postsynaptic neurons to 5-HT. Monoamine oxidase inhibitors enhance the availability of releasable 5-HT. Serotonin reuptake blockers increase the efficacy of 5-HT neurons by desensitizing 5-HT autoreceptors located on 5-HT nerve terminals. Serotonin1A receptor agonists would enhance the tonic activation of postsynaptic 5-HT1A receptors. Such results suggest that this effect of antidepressant treatments on the 5-HT system might be intimately related to their therapeutic effect in major depression.

Role of serotonin in depression.

Abstract: There is extensive evidence that serotonin (5-HT) may play an important role in making persons vulnerable to depression or mania, in the precipitation of an episode of depression or mania, or in the mechanism of action of drugs which have an antidepressant, antimanic or mood stabilizing effect.’.’Some of the evidence for these conclusions will be critically reviewed and some new data from our laboratory will be presented.

Cardiovascular effects of serotonin agonists and antagonists.

Abstract: The effects of serotonin (5-hydroxytryptamine; 5-HT) on the cardiovascular system are complex. These effects, consisting of bradycardia or tachycardia, hypotension or hypertension, and vasodilation or vasoconstriction are mediated by three main sets of receptors called 5-HT1-like, 5-HT2, and 5-HT3. In addition, recent findings suggest the participation of a putative 5-HT4 receptor. Though selective 5-HT1A receptor agonists can lower heart rate (and arterial blood pressure), 5-HT usually lowers heart rate by eliciting an initial short-lasting hypotension due to bradycardia (von Bezold-Jarisch-like reflex) via 5-HT3 receptors located on sensory vagal nerve endings in the heart. Once this bradycardia reflex is suppressed--for example, during deep anesthesia, vagotomy, or spinal section--5-HT can increase heart rate in different species by a variety of mechanisms. Myocardial 5-HT1-like, 5-HT2, and 5-HT4 receptors appear to be involved in the cat, rat, and pig, respectively. 5-HT-induced tachycardia in the dog and rabbit is due mainly to release of catecholamines and involves 5-HT2 receptors on the adrenal medulla and 5-HT3 receptors on postganglionic cardiac sympathetic nerve fibers. Recently, 5-HT3 receptors also have been implicated in the 5-HT-induced tachycardia in the conscious dog. The blood pressure response to 5-HT is usually triphasic and consists of a von Bezold-Jarisch-like reflex, a middle pressor phase, and a longer-lasting hypotension. The pressor response is a consequence of vasoconstriction mediated via 5-HT2 receptors; however, vasoconstriction in the dog saphenous vein and cephalic arteries and arteriovenous anastomoses is due to stimulation of 5-HT1-like receptors. The depressor response exclusively involves 5-HT1-like receptors located at four different sites: (a) central nervous system (decrease in sympathetic and increase in vagal nervous activity), (b) sympathetic nerve terminals (reduction of transmitter release), (c) vascular smooth muscle (vasodilatation), and (d) vascular endothelium (release of a relaxant factor, probably nitric oxide). Arteriolar dilatation, together with the constriction of arteriovenous anastomoses, leads to an increase in nutrient (tissue; capillary) blood flow. The 5-HT1-like receptors are heterogeneous in nature; however, apart from the resemblance of the central nervous system 5-HT1-like receptor causing hypotension and bradycardia to the 5-HT1A binding subtype, the relationship of the other 5-HT1-like receptors to 5-HT1 binding subtypes is still debatable.(ABSTRACT TRUNCATED AT 400 WORDS)

Serotonin and Appetite

Abstract: Feeding or food withdrawal can affect the supply of tryptophan to the brain and hence (in some circumstances) 5-HT synthesis therein. Also fenfluramine which releases 5-HT to postsynaptic receptors suppresses appetite, and there are reports that tryptophan can have a similar effect. Furthermore, feeding is reported to release hypothalamic 5-HT. Therefore 5-HT could have a role in the normal termination of feeding and perhaps also in disorders of appetite. The recognition of various 5-HT receptor subtypes has stimulated research in this area. We have now investigated the involvement of the subtypes in the pharmacological control of feeding. Thus, 5-HT1A agonists (8-OHDPAT, buspirone, gepirone, etc.) stimulate intake in freely feeding rats, probably by activating autoreceptors on the cell bodies of 5-HT neurons so that 5-HT release at terminals is decreased. The hyperphagia is not explicable by increased activity or gnawing and is strikingly manifest against carbohydrate in carbohydrate vs. protein choice experiments. Feeding in previously food-deprived rats is decreased by the 5-HT agonists RU 24969, 1-(3-chlorophenyl) piperazine (mCPP) and 1-(3-trifluoromethyl) phenyl) piperazine (TFMPP). Effects of antagonists on these properties suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors only, while mCPP and TFMPP induce hypophagia at 5-HT1C sites, though this effect also requires 5-HT1B receptors for its expression. Responsible sites occur in the paraventricular nucleus of the hypothalamus as infusing either RU 24969 or TFMPP therein causes hypophagia. On systemic injection, the hypophagic drugs are particularly active in female rats, an effect of conceivable relevance to human anorexic illness.

Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis

Abstract: Serotonin (5-HT) stimulated the release of arachidonic acid in hippocampal neurons cocultured with glial cells but not in glial cultures alone. Similar results were observed for the 5-HT-stimulated release of inositol phosphates. These results suggest a neural but not glial origin of both responses. Pharmacological studies suggested that release of arachidonic acid and inositol phosphates was mediated by a type 2 5-HT (5-HT2) receptor. 5-HT-stimulated release of arachidonic acid was also detected in cortical neurons, which contain high levels of 5-HT2 receptors, but not striatum, spinal cord, or cerebellar granule cells, which have very low levels or are devoid of 5-HT2 receptors. The phorbol ester phorbol 12-myristate 13-acetate augmented the 5-HT-stimulated release of arachidonic acid but inhibited the 5-HT-stimulated release of inositol phosphates. 5-HT-stimulated release of arachidonic acid, but not inositol phosphates, was dependent on extracellular calcium. 5-HT stimulated the release of [3H]lysophosphatidylcholine from [3H]choline-labeled cells with no increase in the release of [3H]choline or phospho[3H]choline. These data suggest that 5-HT stimulated the release of arachidonic acid in hippocampal neurons through the activation of phospholipase A2, independent of the activation of phospholipase C.

Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives.

Abstract: Adult guinea pig hippocampal membranes contain two 5-hydroxytryptamine (5-HT) receptors positively coupled with an adenylate cyclase. One is a typical 5-HT1A receptor and the second is a nonclassical 5-HT receptor that we previously proposed to call 5-HT4. Here, we show that 4-amino-5-chlor-2-methoxy-benzamide derivatives are agonists of 5-HT4 receptors in guinea pig hippocampal membranes. Their effects on the adenylate cyclase of these membranes are not additive with those of 5-HT but are additive with those of RU 24969, a typical 5-HT1 agonist. The effects of benzamides, as well as those of 5-HT, on 5-HT4 receptors are not blocked by 5-HT1, 5-HT2, or 5-HT3 antagonists except ICS 205 903, which does so with a low affinity (1 microM). The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons.

Serotonin release contributes to the locomotor stimulant effects of 3,4-methylenedioxymethamphetamine in rats.

Abstract: Methylenedioxymethamphetamine (MDMA) is a phenylethylamine with novel mood-altering properties in humans. MDMA shares the dopamine-releasing properties of amphetamine but has been found to be a more potent releaser of serotonin (5-HT). The present study undertook to determine the relative roles of dopamine and 5-HT release in MDMA-induced locomotor hyperactivity. S-(+)MDMA produced dose-dependent increases of rat locomotion. Investigatory behaviors such as holepokes and rearings were suppressed by (+)MDMA. Pretreatment with the selective 5-HT uptake inhibitors fluoxetine, sertraline and zimelidine inhibited (+)MDMA-induced locomotor hyperactivity but failed to antagonize the reduction of holepokes and rearings. Because 5-HT uptake inhibitors have been found previously to block the MDMA-induced release of 5-HT in vitro, and because fluoxetine was found to have no effect on (+)amphetamine-induced hyperactivity, the present results suggest that (+) MDMA-induced locomotor hyperactivity is dependent on release of endogenous 5-HT. Additionally, prior depletion of central 5-HT with p-chlorophenylalanine partially antagonized the (+)MDMA-induced hyperactivity, although catecholamine synthesis inhibition with alpha-methyl-p-tyrosine did not block the effects of (+)MDMA. Taken together, these studies suggest that (+)MDMA increases locomotor activity via mechanisms that are dependent on the release of central 5-HT and that are qualitatively different from the mechanism of action of (+)amphetamine.

Distribution of Serotonin Receptors

Abstract: During the last decade our knowledge of serotonin (5-hydroxytryptamine, 5-HT) receptors has undergone a dramatic change. The main reasons for this can be found in the introduction of radioligand binding techniques, the development of compounds acting selectively on receptor sub-populations and the utilization of anatomical techniques for identifying regions enriched in receptors subtypes. More recently, the application of molecular biology techniques has provided detailed insights into the protein structure of some 5-HT receptors.' While a t the presynaptic level histofluorescence, autoradiography and immunohistochemistry have been the tools used to establish serotoninergic pathways,2 autoradiography has been the exclusive way to visualize preand postsynaptic receptor sites for 5-HT until now. ['HILSD and ['HIS-HT were the first serotoninergic ligands introduced. After the discovery of the serotoninergic component of several neuroleptics, ['Hlspiperone was also found to be a ligand for 5-HT receptors. The seminal work of Peroutka and Snyder let to the definition of 5-HT, and 5HT2 receptors and the use of [3H]5-HT, ['HILSD and [ 'Hlspiperone for the selective labeling of these receptors.' Since then, many other ligands have been introduced for labeling more or less selectively 5-HT receptors subtypes. In the present paper we would like to review the results obtained with autoradiographic techniques in the analysis of 5-HT receptors in the brain and their contribution to our understanding of the multiplicity of receptors where 5-HT acts to produce its diverse effects.

A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model.

Abstract: We describe here an autoradiographic method to measure the in vivo rate of serotonin synthesis in rat brain. The method is based on the use of the l-tryptophan analogue a-methyl-l-tryptophan (a-MTrp), which is converted in vivo into a-methylserotonin (a-M5HT). Since a-M5HT is not a substrate for monoamine oxidase, it is accumulated in the brain tissue. Data are presented to confirm time-dependent conversion of a-MTrp into a-M5HT in the dorsal raphe nucleus and also in the pineal body, an organ outside the blood–brain barrier. It has also been shown that washing brain slices in 10% trichloroacetic acid results in <3% incorporation of a-MTrp into brain proteins. The rates of synthesis are calculated in several grossly dissected brain structures by using tracer kinetics and a three-compartment biological model. The half-life of the precursor pool is estimated to be ∼20 min. The rate of serotonin synthesis is highest in the pineal body.

Serotonin uptake and serotonin uptake inhibition.

Abstract: Serotonin uptake carriers occur on serotonin neurons, on glial cells and on blood platelets. The uptake carrier on serotonin neurons inactivates serotonin that has been released into the synaptic cleft by transporting it back into the nerve terminal. The serotonin uptake carrier is the means by which blood platelets acquire serotonin, since they do not synthesize it. The function of the serotonin uptake carrier on glial cells is poorly understood. Selective inhibitors of serotonin uptake enhance neurotransmission via serotonergic neurons and have been useful pharmacologic tools for studying physiologic roles of serotonin neurons. Some serotonin uptake inhibitors are finding therapeutic uses in mental depression and other psychiatric disorders and in treating obesity and bulimia; other therapeutic applications continue to be evaluated.

Autoradiographic characterization of (+-)-1-(2,5-dimethoxy-4-[125I] iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1c receptors in rat brain.

Abstract: The 5-HT2 (serotonin) receptor has traditionally been labeled with antagonist radioligands such as [3H]ketanserin and [3H]spiperone, which label both agonist high-affinity (guanyl nucleotide-sensitive) and agonist low-affinity (guanyl nucleotide-insensitive) states of this receptor. The hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is an agonist which labels the high-affinity guanyl nucleotide-sensitive state of brain 5-HT2 receptors selectively. In the present study, conditions for autoradiographic visualization of (+/-)-[125I]DOI-labeled 5-HT2 receptors were optimized and binding to slide-mounted sections was characterized with respect to pharmacology, guanyl nucleotide sensitivity and anatomical distribution. In slide-mounted rat brain sections (+/-)-[125I]DOI binding was saturable, of high affinity (KD approximately 4 nM) and displayed a pharmacologic profile typical of 5-HT2 receptors. Consistent with coupling of 5-HT2 receptors in the high-affinity state to a guanyl nucleotide regulatory protein, [125I]DOI binding was inhibited by guanyl nucleotides but not by adenosine triphosphate. Patterns of autoradiographic distribution of [125I]DOI binding to 5-HT2 receptors were similar to those seen with [3H]ketanserin- and [125I]-lysergic acid diethylamide-labeled 5-HT2 receptors. However, the density of 5-HT2 receptors labeled by the agonist [125I]DOI was markedly lower (30-50%) than that labeled by the antagonist [3H]ketanserin. High densities of [125I]DOI labeling were present in olfactory bulb, anterior regions of cerebral cortex (layer IV), claustrum, caudate putamen, globus pallidus, ventral pallidum, islands of Calleja, mammillary nuclei and inferior olive. Binding in hippocampus, thalamus and hypothalamus was generally sparse. Of note, choroid plexus, a site rich in 5-HT1c receptors had a high density of [125I]DOI binding sites but [3H]ketanserin binding in this region was low. Studies in which [125I]DOI binding to 5-HT2 receptors was blocked with spiperone revealed persisting robust [125I]DOI binding in choroid plexus, which was guanyl nucleotide-sensitive and displayed a pharmacologic profile consistent with its binding to 5-HT1c receptors. These studies suggest that [125I]DOI may be useful as a radiolabel for visualizing the agonist high-affinity state of 5-HT2 receptors and for visualizing 5-HT1c receptors.

The role of serotonin in eating disorders.

Abstract: Recent pharmacological studies have more precisely characterised the nature of the inhibitory effect of brain serotonin (5-hydroxytryptamine) on feeding behaviour. Thus, the brain sites and receptors involved have been identified, and a possible physiological role of endogenous serotonin in controlling natural patterns of eating and nutrient selection has been defined. The medial hypothalamus is believed to be a critical location in the mediation of serotonin’s action. Specifically, the paraventricular and ventromedial nuclei are known to be involved in controlling energy balance, while the suprachiasmatic nucleus determines circadian patterns of eating. Serotonergic stimulation of these 3 nuclei with exogenous serotonin or drugs that release endogenous serotonin, preferentially reduces carbohydrate intake in naturally feeding animals through satiety mechanisms involved in the termination of feeding. This phenomenon is mediated by serotonin and possibly serotonin receptors, in contrast to serotonin autoreceptors which potentiate feeding possibly by inhibiting serotonin release. The activity of serotonergic function in the medial hypothalamus exhibits a circadian rhythm which is characterised by a peak at the beginning of the active cycle when the motivation to eat is strongest and is triggered by deficits in energy stores. At this time, carbohydrate is found to be the naturally preferred macronutrient, and it appears that serotonin becomes most activated under these conditions to terminate the carbohydrate-rich meal, possibly by activating satiety neurons localised in the medial hypothalamus. In this process, serotonin may interact antagonistically with noradrenaline (norepinephrine) and its α2-noradrenergic receptors that normally function to enhance carbohydrate intake at the onset of the natural feeding cycle. Moreover, while inducing satiety for carbohydrate, serotonin may also play a role in switching the animal’s preference towards protein. The regulation of this macronutrient is closely linked to that of carbohydrate, and it is normally preferred in the second meal of the natural feeding cycle. Most of the pharmacological evidence to date generally supports the hypothesis that disturbances in serotonin function occur in eating disorders. Decreases in plasma tryptophan, urinary 5-hydroxyindoleacetic acid (5-HIAA), platelet serotonin binding and basal cerebrospinal fluid 5-HIAA in anorexia nervosa normalise upon weight restoration and appear to be starvation effects. These alterations in serotonergic function may however perpetuate the symptomatology of anorexia nervosa once the illness is set in motion. Some drugs which in part affect serotonergic function facilitate weight gain in conjunction with an integrated psychotherapeutic and behavioural programme. Patients with bulimia nervosa, regardless of the presence of anorexia nervosa or major depression, who have been relatively weight stable and free of binge/vomit episodes for at least 3 weeks, have significantly blunted prolactin responses to the serotonin agonists. These findings indicate that post-synaptic responsiveness in hypothalamic-pituitary serotonergic pathways is reduced in bulimia. Similar alterations in other serotonin pathways at or above the level of the hypothalamus may contribute to binge eating and other behavioural symptoms in bulimic patients. The clinical response to several psychotropic agents known to potentiate serotonergic transmission further substantiates a serotonin dysregulation hypothesis of bulimia nervosa. Serotonergic function is subject to seasonal alterations and may also be implicated in changes of mood and eating behaviour which accompany the seasonal affective disorder. Serotonin agonists such as dexfenfluramine are effective in suppressing excessive caloric intake in carbohydrate cravers.

Dieting reduces plasma tryptophan and alters brain 5-ht function in women

Abstract: A three week low calorie diet significantly reduced both total plasma tryptophan and the ratio of tryptophan to competing amino acids in a group of 15 healthy volunteers. Despite a similar percentage weight loss the reduction in plasma tryptophan was greater in women than men. In addition, only in women was dieting associated with increased prolactin secretion following intravenous tryptophan, a measure of brain 5-hydroxytryptamine (5-HT) function. These results suggest that dieting reduces the availability of circulating tryptophan for brain 5-HT synthesis. Women appear more vulnerable than men both to this effect and to its consequences for brain 5-HT function. Altered brain 5-HT function may play a part in some of the psychological consequences of dieting, including the development of clinical eating disorders.

Fluoxetine and side effects.

Abstract: To the Editor.— Bouchard and colleagues1recently reported an increased risk of extrapyramidal signs and symptoms during treatment with fluoxetine or other potent and selective inhibitors of neuronal uptake of serotonin. Others have noted such symptoms when this new antidepressant was combined with a neuroleptic agent,2leading to the question of whether a pharmacodynamic effect or a pharmacokinetic drug interaction was at work, as may occur with increased plasma concentrations of tricyclic antidepressants.3Bouchard et al suggested that such reactions with fluoxetine or similar agentsalonemight arise through the ability of serotonin uptake blockers to potentiate putative inhibitory effects of serotonin on the metabolic production or release of dopamine by neurons of the basal ganglia. We tested this prediction in a laboratory model by measuring the accumulation of dopa after pretreating with a centrally active inhibitor of its decarboxylation (NSD-1015, 150 mg/kg intraperitoneally, 45 minutes before