Stimulatory role for brain serotoninergic system on prolactin secretion in the male rat.

Systemic administration of parachlorophenylalanine (PCPA, 100 mg/kg sc on alternate days X two times), a blocker of serotonin (5-HT) synthesis, considerably decreased brain 5-HT and plasma prolactin (PRL) levels in young male rats. Intraventricular (IVT) administration of 5,7-dihydroxytryptamine (5,7-DHT, 200 mug/20 mul), a neurotoxic drug which destroys 5-HT nerve terminals, induced, 3, 12, and 30 days after treatment, a marked depletion of brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and considerably reduced plasma PRL levels at each time interval. Feeding of rat for up to 4 days with a tryptophan (TP)-deficient diet, caused a depletion of brain 5-HT and 5-HIAA contents and did not modify plasma PRL levels. Addition of TP (2 g/kg of diet) to the TP-deficient diet resulted in increased brain 5-HT and 5-HIAA contents and significantly increased PRL levels. These data provide evidence for the role of the 5-HT system in the maintenance of tonic PRL secretion.     

Injected tryptophan increases brain but not plasma tryptophan levels more in ethanol treated rats

In previous studies, long term treatment with ethanol has been shown to enhance brain 5-hydroxytryptamine 5-(HT) metabolism by increasing the activity of the regulatory enzyme tryptophan hydroxylase and or availability of circulating tryptophan secondarily to an inhibition of hepatic tryptophan pyrrolase. In the present study ethanol treatment given for two weeks decreased hepatic apo-tryptophan pyrrolase but not total tryptophan pyrrolase activity in rats. Tryptophan levels in plasma and brain did not increase significantly. But there was a marked increase of 5-HT but not 5-hydroxyindoleacetic acid (5-HIAA) concentration in brain, suggesting a possible increase in the activity of tryptophan hydroxylase. The effect of a tryptophan load on brain 5-HT metabolism was therefore compared in controls and ethanol treated rats. One hour after tryptophan injection (50 mg/kg i.p.) plasma concentrations of total and free tryptophan were identical in controls and ethanol treated rats, but the increases of brain tryptophan 5-HT and 5-HIAA were considerably greater in the latter group. The results are consistent with long term ethanol treatment enhancing brain serotonin metabolism and show that brain uptake/utilization of exogenous tryptophan is increased in ethanol treated rats and may be useful to understand the role and possible mechanism of tryptophan/serotonin involvement in mood regulation.     

Injected tryptophan increases brain but not plasma tryptophan levels more in ethanol treated rats

In previous studies, long term treatment with ethanol has been shown to enhance brain 5-hydroxytryptamine 5-(HT) metabolism by increasing the activity of the regulatory enzyme tryptophan hydroxylase and or availability of circulating tryptophan secondarily to an inhibition of hepatic tryptophan pyrrolase. In the present study ethanol treatment given for two weeks decreased hepatic apo-tryptophan pyrrolase but not total tryptophan pyrrolase activity in rats. Tryptophan levels in plasma and brain did not increase significantly. But there was a marked increase of 5-HT but not 5-hydroxyindoleacetic acid (5-HIAA) concentration in brain, suggesting a possible increase in the activity of tryptophan hydroxylase. The effect of a tryptophan load on brain 5-HT metabolism was therefore compared in controls and ethanol treated rats. One hour after tryptophan injection (50 mg/kg i.p.) plasma concentrations of total and free tryptophan were identical in controls and ethanol treated rats, but the increases of brain tryptophan 5-HT and 5-HIAA were considerably greater in the latter group. The results are consistent with long term ethanol treatment enhancing brain serotonin metabolism and show that brain uptake/utilization of exogenous tryptophan is increased in ethanol treated rats and may be useful to understand the role and possible mechanism of tryptophan/serotonin involvement in mood regulation.     

The effect of tryptophan depletion on brain activation measured by functional magnetic resonance imaging during the Stroop test in healthy subjects

We investigated the role of serotonin in cognitive activation of the frontal cortex. The serotonergic system was affected by the administration of an amino acids mixture without tryptophan (tryptophan depletion). In a placebo-controlled double-blind cross-over study with 20 healthy volunteers, we tested the hypothesis that a tryptophan (serotonin) decrease affects the activation of prefrontal cortex by the Stroop test. Cognitive brain activation was evaluated by functional magnetic resonance imaging (fMRI). Tryptophan depletion decreased the plasma tryptophan level up to 90 % for five hours after the tryptophan-free drink had been consumed when compared with the same mixture with tryptophan (p?0.0001). Tryptophan depletion did not affect the Stroop test performance. We compared fMRI activation in both conditions (tryptophan depletion and placebo) with plasma tryptophan levels as the covariates. The tryptophan depletion increased the activation (fMRI signal) in the bilateral mediofrontal cortex, anterior cingulate and left dorsolateral prefrontal cortex. The present findings allow the postulate that serotonergic medial forebrain and cingulum bundle pathways play a role in the activity of cortical structures involved in Stroop test processing.     

Increased central serotonergic activity associated with nocturnal anorexia induced by Walker 256 carcinoma

The role of brain serotonin levels in Walker 256 tumor induced anorexia was investigated. Total and free plasma tryptophan, regional brain serotonin and 5-hydroxyindoleacetic acid were determined at night, and their relationship to nocturnal anorexia assessed by linear regression analysis. No significant difference in tryptophan, serotonin, or 5-hydroxyindoleacetic acid levels was detected between pair fed and tumor bearing rats exhibiting a 20% reduction of nighttime food intake. Tumor bearing rats with a 40% reduction in food intake had higher nighttime plasma free tryptophan and regional 5-hydroxyindoleacetic acid levels than their pair fed malnourished controls. These results indicate that increased plasma free tryptophan and elevated serotonin metabolism may not be the initial dysfunction responsible for nocturnal anorexia. However, it may contribute to the decreasing nocturnal food intake in severely anorexic tumor rats.     

Brain Tryptophan Hydroxylation in the Portacaval Shunted Rat: A Hypothesis for the Regulation of Serotonin Turnover In Vivo

Regional and whole-brain tryptophan-hydroxylating activity and serotonin turnover were investigated in portacaval shunted (PCS) rats using an in vivo decarboxylase inhibition assay. To saturate tryptophan hydroxylation with amino acid substrate, rats were administered a high dose of tryptophan 1 h prior to analysis of brain tryptophan, 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid. The analysis revealed, as expected, higher brain concentrations of tryptophan and 5-hydroxyindoles and increased serotonin synthesis rate in PCS rats as compared with shamoperated controls. Saturating levels of brain tryptophan were achieved in both PCS and sham animals after exogenous tryptophan administration. The tryptophan load resulted in increased brain serotonin turnover in all regions and in whole brain compared with rats that did not receive a tryptophan load. Tryptophan-loaded PCS rats showed increased brain serotonin turnover compared with tryptophan-loaded sham rats. Regionally, this supranormal tryptophan-hydroxylating activity was most pronounced in the mesencephalon-pons followed by the cortex. It is concluded that, at least in the PCS rat, brain tryptophan hydroxylation is an inducible process. Since it is known that brain tissue from PCS rats undergoes a redox shift toward a reduced state and that the essential cofactor tetrahydrobiopterin is active in tryptophan hydroxylation only when present in its reduced form, it is hypothesized that this is the reason for the supranormal tryptophan-hydroxylating activity displayed by the PCS rats. The hypothesis further suggests that alterations in tetrahydrobiopterin availability may serve as a mechanism by which brain tryptophan hydroxylation, and therefore serotonin turnover, can be regulated with high sensitivity in vivo.     

Low tryptophan diet increases stress-sensitivity, but does not affect habituation in rats

Cerebral dysfunction of 5-HT (serotonin) has been associated with stress response and with affective disorders. Stress alone is insufficient to induce depression, since only a minor proportion of subjects that have experienced stressful life events develop depressive episodes. We investigated whether long-term brain 5-HT depletion induced in rats by a diet with low content of its precursor tryptophan affects stress-responsiveness in rats. Stress-sensitivity was measured through various physiological parameters and by measuring the rats' response to acoustic stimuli. One group of rats was subjected to daily acoustic stimulus sessions for 5 days. Other groups received both immobilization stress and acoustic stimulus sessions daily for either 9 days (chronic experiment) or 1 day (acute experiment). A low tryptophan diet led to decreases in plasma tryptophan levels, low ratio of tryptophan/large neutral amino acid, whole blood 5-HT, and neuronal 5-HT content in the Dorsal and Median Raphe Nuclei, as well as altered c-fos expression in the brain. Without concomitant immobilization, the diet alone did not affect reactivity and habituation to acoustic stimuli, although plasma corticosterone levels, but not the adrenal weights, were increased on day 5. Low tryptophan and chronic immobilization stress together with the acoustic testing procedure increased adrenal weight, plasma corticosterone levels and reactivity to the acoustic stimuli, but not the rate of habituation to acoustic stimuli. These results show that cerebral dysfunction of serotonin achieved through a low tryptophan diet, increases the sensitivity of rats to external and stressful stimuli, but does not impair the capacity to adapt to these stimuli. Accordingly, brain-serotonin modulates reactivity to stress, but not stress coping.     

Brain serotonin and blood pressure regulation: studies using in vivo electrochemistry and direct tissue assay

Hypotensive responses to tryptophan and 5-hydroxytryptophan infusions were studied in normotensive male Sprague-Dawley rats. Results showed that 5-hydroxytryptophan but not tryptophan lowered pressure in a dose dependent way in direct relation to the production of brain serotonin and 5-HIAA. Intrinsic release of serotonin from brain was also studied during periods of induced hypertension and hypotension. Brain monoamine responses to blood pressure changes induced by intravenous phenylephrine and nitroprusside were measured in dorsal raphe nucleus and nucleus tractus solitarius by in vivo electrochemistry. Results showed that 5-HIAA was increased during drug induced hypertension and during reflex hypertension which followed a period of hypotension. These changes were blocked by sinoaortic denervation indicating that these central serotonergic neurons are responding to increased pressure sensed by baroreceptors. Therefore, serotonin has a role in blood pressure regulation as a pharmacologic agent and as a neurotransmitter in homeostatic control of pressure.     

Fetal brain serotonin synthesis and catabolism is under control by mother intake of tryptophan.

Previous morphological studies reported that serotonergic neurons appear in rats in the second half of prenatal life. Initially the biochemical differentiation of these neurons before birth was studied. Both serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) was detected in the fetal brain on day 15 of gestation. During prenatal development an increase was detected in the brain levels of 5-HT (200% higher on day 19 than on day 15) and 5-HIAA (700% higher on day 19 than on day 15). Oral administration of tryptophan to pregnant rats induced a dose-related increase of tryptophan concentration in different fetal tissues, including brain. The increase in tryptophan tissue concentration was detected for low doses (50 mg/kg) and remained unsaturated after administration of high doses (1000 mg/kg). This observation suggests that the placental barrier is not effective to block the influx of high levels of tryptophan to the fetus. Tryptophan concentration in the brain is 300% higher than in the carcass and 600% higher than in the placenta. These data suggest a mechanism to assume a role in concentrating of tryptophan in the brain. Finally, it was found that an increase in brain tryptophan induced changes in both serotonin and 5-HIAA brain levels, but did not modify tyrosine, dopamine or norepinephrine levels. Thus, under physiological conditions, tryptophan hydroxylase activity in prenatal brain is probably not saturated by its substrate tryptophan.     

Effects of thyrotropin releasing hormone and its analogue, DN 1417, on biopterin concentration and tryptophan hydroxylation in rat raphe slices

The effects of subchronic administration of thyrotropin releasing hormone (TRH) and its analogue, gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN 1417), on serotonin biosynthesis in situ were investigated in tissue slices of the midbrain raphe of rats. TRH or DN 1417 (10 mg/kg per day intraperitoneally) were administered to male Wistar rats for ten days. At twenty four hr after the last injection, tissue slices of the midbrain raphe were prepared and the rate of serotonin biosynthesis was estimated by measuring formation of 5-hydroxytryptophan (5-HTP) from tryptophan during inhibition of aromatic L-amino acid decarboxylase using high-performance liquid chromatography with fluorescence detection. Total biopterin content was determined by a specific radioimmunoassay. 5-HTP formation was decreased 22% and 29%, and total biopterin content 69% and 72%, in TRH- and DN 1417-treated rats, respectively. However, tryptophan concentration in raphe slices did not change. In contrast, the Vmax of tryptophan hydroxylase in the homogenate of the raphe nucleus in the presence of a saturating concentration of (6R)-L-erythro-tetrahydrobiopterin, the naturally occurring pterin cofactor, was significantly increased after repeated administration of TRH or DN 1417. These results indicate that reduction of in situ serotonin biosynthesis in tissue slices from the rats treated with TRH or DN 1417 subchronically contray to the increase in in vitro tryptophan hydroxylase may result from the decrease of the biopterin cofactor, and that changes in concentrations of the biopterin cofactor may play a regulatory role in serotonin biosynthesis in vivo under certain conditions.     

An fMRI study on the role of serotonin in reactive aggression

Reactive aggression after interpersonal provocation is a common behavior in humans. Little is known, however, about brain regions and neurotransmitters critical for the decision-making and affective processes involved in aggressive interactions. With the present fMRI study, we wanted to examine the role of serotonin in reactive aggression by means of an acute tryptophan depletion (ATD). Participants performed in a competitive reaction time task (Taylor Aggression Paradigm, TAP) which entitled the winner to punish the loser. The TAP seeks to elicit aggression by provocation. The study followed a double-blind between-subject design including only male participants. Behavioral data showed an aggression diminishing effect of ATD in low trait-aggressive participants, whereas no ATD effect was detected in high trait-aggressive participants. ATD also led to reduced insula activity during the decision phase, independently of the level of provocation. Whereas previous reports have suggested an inverse relationship between serotonin level and aggressive behavior with low levels of serotonin leading to higher aggression and vice versa, such a simple relationship is inconsistent with the current data.     

Stimulatory effect of a maize diet on sexual behaviour of male rats

Feeding rats for 4 days with a diet of maize, a staple which is deficient in tryptophan (TP), caused a depletion of brain 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) without affectin noradrenaline and dopamine content.Addition of TP (2 g/kg of diet) to the TP deficient diet resulted in increased brain 5-HT and 5-HIAA content.Isolated male rats consuming the maize diet, when brought together, showed markedly increased mounting activity, while rats on the maize diet supplemented with TP did not display such a behaviour.These data provide further evidence for the role of the 5-HT system in regulating the sexual behaviour of male rats.     

Effects of chronically elevated intake of sweet solutions on sexual behavior of male rats

Three experiments were conducted on the sexual behavior of gonadally intact and castrated male Sabra rats. Half of the animals drank water during the course of the experiment and half were offered sweet solutions, the assumption being that sweet gustatory stimulation elevates the level of central endogenous opioid peptides in rats. The effects on sexual behavior of the following drugs were explored: the opiate receptor blocker naloxone (5 mg/kg, sc), the serotonin precursor 5-hydroxytryptophan (5-HTP) (20 mg/kg, sc), the serotonin antagonist methysergide (1 mg/kg, sc), and naloxone in combination with methysergide. Naloxone, whether administered alone or in combination with methysergide, impaired sexual performance in castrated male rats, and in gonadally intact rats maintained on sweet solutions. Methysergide elevated sexual behavior in all groups, whereas 5-HTP tended to suppress such behavior. The results support the hypothesis that endogenous opiates play a role in the expression of male sexual behavior in rats. While subtle in intact animals this role may become crucial following the disruption of sex hormone supply. Serotonergic influence on male sexual behavior is inhibitory.     

Cerebral serotonin and the hypothalamo-hypophyseal-adrenal system of the rat during aging]

The role of brain serotonin (5HT) on the hypothalamus-pituitary-adrenal system (HPAs) under basal condition and after injections of p-chlorophenylalanine (pCPA) and L-5-hydroxytryptophan (L-5HTP) has been studied in 6, 12 and 28 month old male Wistar rats. Four experimental groups were made for each age: control, saline, injected with pCPA (250 mg/kg i.p.) and L-5HTP (200 mg/kg i.p.), the effects being valued 2 hours after L-5HTP administration and 24 hours after pCPA injection. In all groups the plasmatic ACTH, the corticosterone levels as well as the simultaneous changes of the 5TH content tryptophan hydroxylase activity in whole brain were estimated two hours after the L-5HTP injection and 24 hours after that of pCPA. Significant changes are not found in the plasmatic ACTH and corticosterone values with respect to age under basal condition. Nevertheless, the response of HPAs differs with the age after pCPA or L-5HTP injection. The ACTH and corticosterone levels augment by L-5HTP and decrease by pCPA in all age groups, but this corresponding increase or decrease was less marked in the older rats. The 5HT content as tryptophan hydroxylase activity in brain decreased in old animals. pCPA and L-5HTP determine, respectively, high falls and rise of 5TH values, these changes being more intense for pCPA in old rats and for L-5HTP in young and mature animals. The tryptophan hydroxylase activity is decreased by pCPA as L-5HTP injections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Change in tryptophan hydroxylase activity in the brain of silver foxes and wild Norway rats in the course of selection according to behavior

The activity of tryptophan hydroxylase, the key enzyme of serotonin biosynthesis, was determined in the brain of silver foxes and wild rats selected, according to domestic or aggressive behavior, in respect to man. Significant increase of enzyme activity in midbrain of both domesticated rats and domesticated foxes was found, in comparison with that of aggressive animals. It was suggested that genetic mechanisms of the selection according to aggressive behavior, involve the changes of genes responsible for the synthesis of serotonin, the brain neurotransmitter which inhibits this type of behavior.     

Different influences of two types of diets commonly used for rats on a series of parameters related to the metabolism of central serotonin and noradrenaline

A commercial chow and a semipurified diet fed for 14 days to Sprague-Dawley male rats kept under standardized conditions of temperature, humidity, and light had different effects on a series of parameters related to the metabolism of central serotonin and noradrenaline. Rats fed the commercial chow had (1) a lower serum level of the six neutral amino acids (valine, isoleucine leucine, tyrosine, phenylalanine, and methionine) known to compete with tryptophan for its entry into the brain, (2) a higher ratio of tryptophan to the sum of the six neutral amino acids, (3) a lower ratio of tyrosine to the other five neutral amino acids, (4) a lower ratio of serotonin to 5-hydroxyindoleacetic acid in hypothalamus, (5) a higher tryptophan hydroxylase activity in raphe nuclei, and (6) a higher content of noradrenaline in hypothalamus. It is suggested that chow fed rats had a more active central serotonin metabolism in hypothalamus than rats fed the semipurified diet.     

Acute Tryptophan Depletion Reduces Nitric Oxide Synthase in the Rat Hippocampus

Acute tryptophan depletion (ATD) is extensively used to investigate the role of central serotonin (5-HT). However, several studies reported that ATD had no significant effect on central 5-HT concentration and some ATD-induced changes was independent of 5-HT in the rodent brain. Therefore, the potential mechanism of ATD might not be ascribed solely to changes in the central 5-HT system. In recent studies, evidence suggests that nitric oxide synthase (NOS) is closely associated with ATD-induced changes in modulation of cerebral blood flow and metabolism, cognitive, and locomotor activity. Thus, NOS is implicated to be an underlying factor contributing to ATD-induced changes. In the present study, the effect of ATD upon central NOS levels in the rat was evaluated. Male Sprague–Dawley (SD) rats were orally administered a tryptophan-free protein-carbohydrate mixture. Then, ATD effects upon affective behavior and spatial memory were assessed by the forced swimming test (FST) and Morris water maze test, respectively. Further, NOS activity and neuronal NOS (nNOS) protein levels in the hippocampus were measured after ATD. Our experimental results showed that ATD had no influence on affective behavior in the FST or spatial memory in SD rats. Interestingly, a significant reduction of both constitutive NOS activity and nNOS protein levels after ATD was found in the hippocampus. These findings demonstrate ATD does not influence affective behavior and spatial memory despite a direct effect on hippocampal NOS. Our study might provide a valuable clue for exploring earlier reported ATD-induced behavioral and neurochemical changes in rodents.     

L-tryptophan attenuation of the dopaminergic and behavioral responses to cocaine.

This study assessed the effects of acute intravenous L-tryptophan (neutral amino acid precursor for serotonin) administration on cocaine-induced dopaminergic responses. Male Sprague-Dawley rats were surgically implanted with guide cannulas in the nucleus accumbens 5 days prior to the study and with vascular catheters (carotid artery and jugular vein) on the day prior to the study. Using microdialysis, extracellular nucleus accumbens dopamine levels were measured in freely moving rats. Following a 2 h equilibration period, animals were randomized (n=7-8 per group) to receive either a constant intravenous (IV) infusion of L-tryptophan (200 mg/kg/h) or an equal volume (2 ml/h) of saline. Ninety minutes into the infusion, cocaine (20 mg/kg) was injected intra-peritoneally. Cocaine increased nucleus accumbens microdialysate dopamine levels (500% at 30 min). This was associated with marked hyperactivity. Tryptophan infusion elevated plasma tryptophan (8-fold), and blunted the cocaine-induced increase in nucleus accumbens microdialysate dopamine levels by approximately 60%. Furthermore, tryptophan attenuated the cocaine-induced locomotor activity. These neurochemical and behavioral effects of tryptophan were associated with a marked increase in brain tissue serotonin content. The results of these studies demonstrate the feasibility of acute dietary manipulation of neurochemical and behavioral responses to cocaine. The duration, adaptation and tolerance to these effects remain to be elucidated.     

Effect of tryptophan administration on serotonin and 5-hydroxyindoleacetic acid content in the brainstem of Lilly 110140-pretreated rats.

Adult male Sprague-Dawley rats were divided into 3 groups. One group was pretreated with Lilly 110140 (10 mg/kg) 27 hours and again 3 hours before sacrifice while a second group received Lilly 110140 only 3 hours before sacrifice. The third or control group received only equivalent volumes of saline. Animals from each group were administered 25 mg/kg L tryptophan intraperitoneally (i.p.) 0, 30, 60 or 90 minutes before sacrifice. Equivalent elevations in serum and also brainstem tryptophan content were observed in all three groups with the peak observed at 30 minutes. Brainstem serotonin content was significantly elevated in both groups of Lilly 110140-pretreated rats but not in the control group. Brainstem 5-hydroxyindoleacetic acid was significantly elevated after tryptophan administration in the control and the 3 hour and 27 hour, Lilly 110140-pretreated groups but not in the 3 hour Lilly 110140 pretreated group. The results indicate that neither 3 or 3 hours and 27 hours of Lilly 110140 pretreatment appreciably affects the increase in brainstem serotonin synthesis induced by the i.p. administration of 25 mg/kg of L tryptophan.     

Reduction of Serotonergic Function in Rat Brain by Tryptophan Depletion: Effects in Control and Fluvoxamine-Treated Rats

Abstract: The administration of tryptophan (Trp)-free amino acid mixtures to depressed patients responding to serotonin [5-hydroxytryptamine (5-HT)] uptake inhibitors (SSRIs) worsens their clinical state. This procedure reduces Trp availability to brain and thus impairs 5-HT synthesis. We have examined the influence of Trp depletion on extracellular 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the rat brain using in vivo microdialysis. The treatment with the SSRI fluvoxamine significantly increased 5-HT content in dialysates from frontal cortex, as compared with control rats (10.2 ± 2.7 vs. 3.1 ± 0.4 fmol per fraction), whereas 5-HIAA was unaffected. Food deprivation for 20 h reduced dialysate 5-HT content to almost control values in fluvoxamine-treated rats (10.2 ± 2.7 vs. 4.3 ± 0.6 fmol per fraction) but did not alter dialysate 5-HIAA content (7.8 ± 0.4 vs. 7.2 ± 0.5 pmol per fraction). The administration of Trp-free amino acid mixtures to fluvoxamine-treated rats significantly attenuated the release of 5-HT in frontal cortex (～50%) and, to a lesser extent, in the midbrain raphe nuclei. This effect was more marked in rats not deprived from food before the experiments (67% reduction of dialysate 5-HT content in frontal cortex) and was absent in control rats (treated with saline). In contrast, dialysate 5-HIAA was markedly affected by Trp depletion in all groups, including controls (65–75% reductions). These data show that the administration of an amino acid mixture with the same composition and dose (in milligrams per kilogram of body weight) as those inducing a severe mood impairment in depressed patients reduces 5-HT and 5-HIAA concentrations in brain dialysates. The reduction of 5-HT release, however, occurs only in animals previously treated with the antidepressant fluvoxamine for 2 weeks, which would be consistent with a marked reduction of 5-HT-mediated transmission in treated depressed patients but not in healthy controls.