Neuroendocrine responses to serotonergic agents in alcoholics.

Previous studies have suggested a possible deficit in serotonergic function in alcoholism. In order to further assess the serotonergic system in alcoholism, the plasma cortisol and prolactin (PRL) responses following 6-chloro-2-[1-piperazinyl]pyrazine (MK-212), a direct-acting serotonin2 (5-HT2)/5-HT1c receptor agonist, L-5-hydroxytryptophan (L-5-HTP), a precursor of 5-HT, and placebo were compared in male alcoholics and normal controls. The increase in plasma cortisol following L-5-HTP was significantly lower in the alcoholic subjects compared with the normal controls. The plasma PRL, but not the plasma cortisol response, following MK-212 was also significantly lower in the alcoholics. L-5-HTP had no significant effect on plasma PRL levels in either group. The basal plasma cortisol and PRL concentrations of the alcoholics and normal controls were not significantly different. These data are consistent with previous reports of a serotonergic abnormality in alcoholism.     

Effect of cocaine injections on the neuroendocrine response to the serotonin agonist MK-212.

This study was undertaken to examine whether several of the hormones that can be released by activation of serotonin receptors will be affected by long-term cocaine administration. Male rats received cocaine injections (15 mg/kg, IP) twice daily for 7 days. Forty-two hr after the last cocaine injection, the rats were challenged with increasing doses (0, 1, 5, 10 mg/kg, IP) of the 5-HT1/5-HT2 agonist MK-212 (6-chloro-2-[1-piper-azinyl]-pyrazine). The following observations were made: (1) cocaine reduced the rate of body weight gain; (2) cocaine inhibited the stimulatory effect of MK-212 on plasma vasopressin, oxytocin, and prolactin concentrations and on plasma renin activity and concentration; (3) cocaine did not inhibit the stimulatory effect of MK-212 on plasma ACTH or corticosterone concentrations. The data indicate that a wide-spectrum 5-HT (serotonin) agonist such as MK-212 can reveal differential neuroendocrine responses. This effect could be related to cocaine-induced changes in the different 5-HT receptor subtypes that regulate the secretion of these hormones.     

Pindolol does not augment cortisol and prolactin responses to paroxetine in healthy subjects

OBJECTIVE: Animal studies have shown that pindolol augmentation of selective serotonin re-uptake inhibitors (SSRIs) may act through inhibition of 5-HT(1A) autoreceptors in the raphe. The combination of pindolol plus a SSRI produces increased synaptic 5-HT levels that are greater than those achieved with a SSRI alone. However, it is unclear whether this actually occurs in humans, and clinical studies of pindolol augmentation have produced inconsistent results. Since the release of cortisol and prolactin is under serotonergic control, we hypothesized that pindolol augmentation of synaptic 5-HT concentrations produced by an SSRI in humans should lead to enhanced SSRI-induced cortisol and prolactin responses. METHODS: Cortisol and prolactin responses were measured after challenge tests with paroxetine (20-40 mg) plus pindolol (5 mg) and after paroxetine plus placebo in six non-depressed, healthy control subjects. RESULTS: No differences were observed in the cortisol or prolactin responses between either neuroendocrine challenge test. CONCLUSIONS: These results suggest that SSRI augmentation with usual clinical doses of pindolol does not increase central synaptic 5-HT neurotransmission sufficient to induce an enhanced neuroendocrine response.     

Prolactin and cortisol responses to MK-212, a serotonin agonist, in obsessive-compulsive disorder

To examine further the serotoninergic system in obsessive-compulsive disorder (OCD), the plasma concentrations of cortisol and prolactin and the behavioral responses after oral administration of MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine), a serotonin agonist, and placebo were studied in 17 patients with OCD and nine normal controls. The two groups did not differ significantly in basal plasma prolactin or cortisol levels. Nevertheless, both the prolactin and cortisol response to oral administration of MK-212 (20 mg) were significantly blunted in the patients with OCD compared with those of the normal controls. MK-212 did not affect the intensity of OCD symptoms. However, MK-212, as compared with placebo, produced slight but statistically significant increases in self-ratings of nausea, dizziness, anxiety, feeling strange, and mixed feelings of calmness and restlessness, as well as depression and feeling high. These behavioral ratings were not significantly different in patients and normal controls. These findings are consistent with previous reports of diminished serotoninergic responsivity in OCD and raise the possibility of subsensitivity of at least some serotonin receptors in this disorder.     

Effects of oral racemic citalopram on neuroendocrine responses

Citalopram, a selective serotonin reuptake inhibitor (SSRI), has been used as a neuroendocrine probe to assess serotonin (5-HT) function in human subjects. In an effort to characterize the oral citalopram challenge, we hypothesized that oral racemic citalopram would increase plasma cortisol, prolactin and adrenocorticotropic hormone (ACTH) concentrations; ACTH had not been measured in previous studies on the neuroendocrine effects of citalopram. Nine healthy male subjects initially received 20 mg of citalopram in an open-label study, and subsequently received placebo and 40 mg of citalopram in a single-blind, randomized, cross-over study. The administration of citalopram 20 mg failed to produce a significant neuroendocrine response but 40 mg resulted in reliably increased plasma cortisol concentrations. The 40 mg dose, however, did not reliably influence the levels of plasma prolactin or plasma ACTH. The results of this study indicate that caution should be used in accepting oral racemic citalopram as a potential presynaptic serotonergic challenge agent. Further studies are needed to fully determine the validity of racemic citalopram and the active enantiomer, escitalopram, as 5-HT probes.     

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. III. Effect of antidepressants and lithium carbonate

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.     

Evidence that the medial and dorsal raphe nuclei mediate serotonergically-induced increases in prolactin release from the pituitary

Electrolytic lesions of the medial (MR) or dorsal (DR) raphe nucleus significantly antagonized serum prolactin elevations produced by 5-hydroxytryptophan (5-HTP) in rats pretreated with fluoxetine or citalopram, (serotonin (5-HT) uptake blockers). Lesioned animals in which total blockade of serum prolactin elevations was observed also had total blockade of 5-HT accumulation in the median eminence. However, the increase in serum prolactin levels produced by 5-HTP plus 5-HT reuptake blockade in lesioned rats was not significantly different from sham-operated rats if as little as 15–20% of control median eminence accumulation was present. Serum prolactin elevations produced by quipazine, a direct acting 5-HT agonist, were not significantly affected by MR lesions. On the basis of these results, we suggest that: (1) serum prolactin elevations following 5-HT reuptake blockade plus 5-HTP are correlated with 5-HT concentration in the median eminence; (2) lesion-induced antagonism of 5-HTP-induced prolactin elevation is critically dependent upon complete blockade of median eminence 5-HT accumulation; and (3) 5-HT neurons arising from cell bodies located in the MR and DR are necessary for endogenous serotonergically mediated effects on prolactin secretion in the rat.     

Cortisol and growth hormone responses to the 5-HT1A agonist gepirone in depressed patients

The 5-HT1A agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 min after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Serum cortisol levels were significantly higher 90 min after gepirone compared to placebo (p less than 0.05). Baseline Hamilton depression ratings were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p less than 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p less than 0.02) attenuated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may correlate with depression severity. Furthermore, a desensitization to gepirone's effects on cortisol may occur after chronic gepirone administration.     

Changes in Learning and Memory, Acetylcholinesterase Activity and Monoamines in Brain After Chronic Carbamazepine Administration in Rats

Summary Groups of adult male Wistar rats were administered carbamazepine (CBZ) in doses of 5, 10, 20, 40, or 80 mg/kg/day intraperitoneally (i.p.) for 21 days. The learning and memory of the rats were assessed by the T-maze and passive avoidance tests. The CBZ plasma levels, the activity of acetylcholinesterase (AChE) in different brain regions, and the levels of monoamines in the hippocampus were also measured. None of the administered doses of CBZ impaired learning and memory. Rats with CBZ plasma levels of 2.5 and 4.5 μg/ml corresponding to the doses of 20 and 40 mg/kg, learned significantly better than controls. AChE activity was decreased in hippocampus and pyriform cortex (19%) in these groups. Simultaneously, an increase in the serotonin (5-HT) (36%) and dopamine (137%) levels in the hippocampus was noted in the 20-mg/kg CBZ group. 5–Hydroxyindole acetic acid (5-HIAA) and homovanillic acid (HVA) levels were increased at 10-, 20-, and 40-mg/kg CBZ doses. However, a dose of 80-mg/kg caused no change in learning performance as compared with that of controls. Correspondingly, no changes were evident in the AChE activity or monoamine levels. We postulated that the decreased AChE activity caused by CBZ in the therapeutic range may lead to increased ACh levels in brain, thus producing improvement in learning and memory. The increased turnover of 5-HT and dopamine (DA) in the hippocampus may play a role in long-term potentiation and improvement in memory.     

The effects of paroxetine and tianeptine on peripheral biochemical markers in major depression

Depression is related to the alterations of the central serotonergic system and some antidepressants achieve their therapeutic effects through alteration of serotonin (5-HT) (re)uptake. Peripheral biochemical markers, platelet and serum 5-HT concentrations, platelet monoamine oxidase (MAO) activity, plasma levels of cortisol and prolactin (PRL), were investigated in patients with major depression before and after 4 weeks of treatment with paroxetine (an inhibitor of 5-HT uptake) or tianeptine (a stimulator of 5-HT uptake). Study was open, single center and included female depressed patients, 21 treated with tianeptine (37.5 mg/day) and 15 treated with paroxetine (20 mg/day), and 11 drug-free healthy women (controls). Before treatment, depressed patients as a group had significantly higher serum 5-HT and cortisol concentrations than healthy controls. There were no differences in the other biochemical markers. Response to antidepressant treatment was estimated according to the 50% fall in the initial scores of Hamilton Depression Rating Scale (HAMD) after 4 weeks of treatment. Good therapeutic response was observed in 47% and 45% patients treated with paroxetine and tianeptine, respectively. Paroxetine treatment induced significant decrease in platelet 5-HT concentrations in both responders and nonresponders, while no alterations in platelet 5-HT values were found in tianeptine-treated patients. There was a subgroup of depressed patients in paroxetine-treated group with high pretreatment platelet 5-HT concentration and later poor therapeutic response to paroxetine treatment. Serum 5-HT values, platelet MAO activity or plasma cortisol or PRL levels were unchanged after both treatments. The results suggest that pretreatment platelet 5-HT levels, but not other peripheral biochemical markers, might predict therapeutic outcome at least in paroxetine-treated patients.     

Effect of serotonergic agents on neuroleptic induced catalepsy in rats

Three pharmacological tools namely zimelidine, danitracen and MK 212, were selected to examine the nature of involvement of serotonergic neurotransmission in catalepsy, an undesirable side effect following administration of neuroleptics in rats. Reserpine and haloperidol were chosen as cataleptogenic challenges. Zimelidine, a serotonin (5-HT) reuptake blocker, inhibited the manifestation of reserpine and haloperidol induced catalepsy. However, a dose dependent effect could not be demonstrated beyond 30 mumoles/kg. Danitracen, a 5-HT receptor blocker, prevented the occurrence of the symptoms that were observed following reserpine treatment but it could not elicit blockade of haloperidol response. MK 212, an S2 (5-HT2) receptor stimulant forestalled the occurrence of reserpine syndrome at lower doses but exhibited cataleptogenic effects at higher doses. Besides, MK 212 failed to influence catalepsy following administration of haloperidol. It appears that 5-HT exerts a homoeostatic control in the regulatory neuraxis in neuroleptic induced neurological side effects.     

Serotonergic responsivity in male young adults with autistic disorder. Results of a pilot study

Altered serotonergic function has been postulated to exist in autistic disorder. Central serotonergic responsivity was assessed with a neuroendocrine challenge test in seven male young adults with autistic disorder and in seven age- and gender-matched healthy controls. Binding indexes and physiologic responsivity of the platelet serotonin-2 (5-HT2) receptor complex were also measured, as was whole-blood serotonin content. Compared with controls, autistic subjects had substantially blunted prolactin release in response to a 60-mg oral dose of fenfluramine hydrochloride, an indirect serotonin agonist [corrected]. Furthermore, the magnitude of serotonin-amplified platelet aggregation, mediated by the platelet 5-HT2 receptor complex, was reduced in the autistic group, as was the mean number of platelet 5-HT2 receptor sites. Among autistic subjects, fenfluramine-induced prolactin release correlated positively with the serotonin-amplified platelet aggregation response and negatively with whole-blood serotonin content. The results of the present study are compatible with the hypothesis that central serotonergic responsivity is decreased in male autistic young adults. Correlations between central and peripheral serotonergic measures in autistic subjects suggest that systemic alterations in serotonergic function may occur in autism.     

Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat

This study examined whether the antinociception produced following the intrathecal (i.t.) administration of serotonin (5-hydroxytryptamine, 5-HT) and other 5-HT receptor agonists in a model of visceral pain that utilizes colorectal distension (CRD) as the noxious visceral stimulus is mediated through interaction with spinal 5-HT1, 5-HT2, or 5-HT3 receptor subtypes. CRD in conscious rats reliably elicits two pseudaffective reflexes: a vigorous pressor response and a visceromotor response. Antinociception is characterized by inhibition of both pseudaffective responses. The effects of 5-HT receptor agonists and antagonists on resting blood pressure were also examined. The i.t. administration of 5-HT resulted in a dose-dependent elevation of the visceromotor threshold and inhibition of the pressor response to CRD. The 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist RU-24969, the 5-HT2 receptor agonists DOI, MK-212 and alpha-methyl-5-HT and the 5-HT3 agonist 2-methyl-5-HT all dose-dependently inhibited the pressor response and dose-dependently elevated the visceromotor threshold to noxious CRD. The rank order of potency of these agonists was the same for both pseudaffective responses to CRD: DOI greater than or equal to 8-OH-DPAT greater than or equal to MK-212 = RU-24969 greater than or equal to alpha-methyl-5-HT = 2-methyl-5-HT much greater than 5-HT. The antinociceptive effects of 5-HT, RU-24969, alpha-methyl-5-HT and DOI were antagonized by i.t. pretreatment with methysergide. Intrathecal pretreatment with ketanserin antagonized the antinociceptive effects of MK-212 and MDL-72222 antagonized the effects produced by 2-methyl-5-HT in response to CRD. The antinociceptive effects produced by 8-OH-DPAT were not antagonized by i.t. pretreatment with methysergide. These results demonstrate that 5-HT1, 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception in response to noxious CRD in conscious rats.     

Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects.

Ten healthy male subjects were administered i.v. meta-chlorophenylpiperazine (MCPP) (0.1 mg/kg) after oral ritanserin (5-10 mg), a putative 5HT1c/5HT2 (serotonin) antagonist, or placebo. Behavioral responses, cardiovascular effects, and neuroendocrine responses (cortisol, growth hormone, and prolactin) were measured serially for 4 hours after MCPP infusion. Premedication with ritanserin attenuated the MCPP-induced increases in self-rated anxiety and prolactin, and completely antagonized MCPP cortisol elevations. In contrast, ritanserin did not significantly alter growth hormone response to MCPP. These findings suggest a role for 5-HT1c/5-HT2 receptors in the endocrine and behavioral responses to the mixed serotonin agonist MCPP in humans.     

Neuroendocrine and behavioral responses to mCPP in Obsessive-Compulsive Disorder

Patients with Obsessive-Compulsive Disorder (OCD) have been shown to demonstrate blunted cortisol and prolactin responses along with an exacerbation of obsessive-compulsive symptoms in response to oral administration of the pharmacological probe, meta-chlorophenylpiperazine (mCPP). In an attempt to replicate these findings, mCPP was administered orally in the dose of 0.5 mg/kg body weight in a randomized double-blind design to 34 OCD patients who were either drug-naive or drug-free for a minimum period of four weeks. The cortisol and prolactin responses were contrasted with those of 18 drug-free healthy subjects. The OCD patients showed significantly blunted cortisol and prolactin responses to mCPP challenge as compared to normal subjects. However, mCPP did not produce any significant exacerbation of obsessive-compulsive symptoms in the patient group. The results are suggestive of a serotonin (5-HT) receptor hyporesponsivity in the HPA axis. Even though previous studies indicate a hyperresponsivity of the 5-HT receptor system in the orbitofrontal-striatal-pallido-thalamo-cortical pathway as shown by significant symptom worsening following serotonergic challenge, the present study failed to replicate those results. 5-HT receptor hyporesponsivity in the HPA axis may be considered as a biological "trait marker" of OCD, and may not be directly involved in the mediation of symptomatology of the disorder.     

Effects of short-term administration of valproate on serotonin-1A and dopamine receptor function in healthy human subjects

OBJECTIVE: To examine the effects of short-term valproate treatment on human brain serotonin and dopamine function by means of challenge tests with ipsapirone, a partial agonist at 5-HT1A receptors, and apomorphine, a dopamine receptor agonist. DESIGN: Experimental challenge-rechallenge, within-subjects repeated measures, before and at the end of 14 days of treatment with valproate at a dosage of 625 mg/d (reached gradually over the first 5 days). PARTICIPANTS: Eight healthy male volunteers (mean age 38 years) selected for good physical and mental health who were nonsmokers. OUTCOME MEASURES: Pharmacological probes were used to evaluate the effects of valproate. In the ipsapirone challenge, changes in adrenocorticotropic hormone (ACTH), cortisol and body temperature were measured, and in the apomorphine challenge, growth hormone (GH) and prolactin were the dependent variables. RESULTS: Valproate treatment did not significantly alter the ACTH, cortisol or body temperature responses to ipsapirone (20 mg by mouth), which reached equivalent plasma levels at each challenge. Similarly, valproate treatment did not alter the GH or prolactin responses to apomorphine (5 micrograms/kg subcutaneously). CONCLUSIONS: These results suggest that short-term treatment with valproate at a dose of 625 mg/d does not alter hypothalamic or pituitary 5-HT1A or dopamine receptor responses to challenges with ipsapirone and apomorphine, respectively.     

Rodent data and general hypothesis: antipsychotic action exerted through 5-HT2A receptor antagonism is dependent on increased serotonergic tone

Summary. The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390). Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments. PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however in a meta-analysis of six experiments, the locomotion displayed by MK-801-treated animals was diminished 17% by PCPA pretreatment. The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP). On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment. The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA. These results suggest that (1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems. (2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors. (3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism. Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone. Accepted February 9, 1998; received December 16, 1997     

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. I. Enhanced response in depression and mania

The serum cortisol concentration following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, a precursor of serotonin (5-HT), was significantly greater in unmedicated depressed and manic patients than in normal controls. Increases in serum cortisol levels greater than 5 micrograms/dL were significantly more frequent in both unmedicated depressed and manic patients than in the normal controls. There was significant test-retest reliability. Baseline serum cortisol concentration correlated negatively with the cortisol response to 5-HTP in normal controls. These results suggest increased 5-HT receptor sensitivity may be present, possibly in the hypothalamus or pituitary, in some patients with affective disorders. These results are consistent with the hypothesis that decreased serotonergic activity, which would be expected to produce increased 5-HT receptor sensitivity, may be present in both depression and mania.     

Inhibition of rat nucleus tractus solitarius neurones by activation of 5-HT2C receptors

In vivo, nucleus tractus solitarius (NTS) neurones receiving monosynaptic vagal input and inactive intermediate neurones were inhibited by both DOI and a selective 5-HT2C receptor agonist, MK-212. Cells receiving a more polysynaptic input were excited by DOI and although MK-212 also excited a few of these cells, the majority of cells in these groups were unaffected by MK-212. The inhibitory, but not the excitatory actions of both MK-212 and DOI were prevented by a selective 5-HT2C receptor antagonist, RS-102221. In contrast, most dorsal vagal preganglionic neurones were unaffected by application of either DOI or MK-212, the few remaining cells being excited by both agonists. These data demonstrate that DOI-evoked inhibition of NTS cells activated by vagal afferent input and DOI-evoked excitation of vagal preganglionic neurones is mediated by 5-HT2C receptors.     

The N-methyl-D-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and p-chloroamphetamine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocks the ability of D-methamphetamine (MA) to deplete striatal dopamine (DA). We now report that MK-801 attenuates decreases in serotonin (5-HT) concentration induced by MA and two other amphetamine analogues, 3,4-methylenedioxymethamphetamine (MDMA) and p-chloroamphetamine (PCA). Rats were injected with saline (1.0 ml/kg) or MK-801 (0.5, 1.0 or 2.5 mg/kg) followed by either saline (1.0 mg/kg), MA (4, 2 or 1 injection(s); 10.0, 20.0 or 40.0 mg/kg), MDMA (20.0 or 40.0 mg/kg) or PCA (5.0 or 10.0 mg/kg). In some experiments, two injections of MK-801 or saline were used. Seventy-two hours after the last injection rats were sacrificed and concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and DA were determined in hippocampus and striatum. MA caused a depletion of 5-HT to 33% of control in hippocampus and to 50% of control in striatum after the 4 x 10.0 mg/kg dose regimen. When MK-801 (2.5 mg/kg) was co-administered with MA, concentrations of 5-HT did not differ from control levels in either brain region. MDMA depleted 5-HT to approximately 58% of control in hippocampus and 66% of control in striatum at the 40 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)