Search

The potential antipsychotic agents BMY 14802, remoxipride, tiospirone and gevotriline (WY 47,384) have a relatively high affinity for sigma binding sites in brain tissue. In the present study, the effects of these sigma ligands on concentrations of prolactin and corticosterone in serum in the rat were investigated. In addition, the effects of these agents on the synthesis and/or release of dopamine from tuberoinfundibular and nigrostriatal neurons were determined. Concentrations of prolactin and corticosterone in serum were increased dose-dependently by BMY 14802, tiospirone, remoxipride and gevotriline. The activity of tyrosine hydroxylase within the terminals of tuberoinfundibular dopamine neurons in vivo also was increased by BMY 14802, tiospirone and gevotriline, but not by remoxipride. The extracellular concentrations of dopamine and dihydroxyphenylacetic acid in the striatum, as determined by in vivo microdialysis, were increased by BMY 14802 (5-20 mg/kg, s.c.) and remoxipride (3 mg/kg, s.c.). These data suggest the involvement of sigma receptors in the regulation of secretion of prolactin and corticosterone, as well as the activity of tuberoinfundibular and nigrostriatal dopamine neurons. Moreover, the pattern of neurochemical and neuroendocrinological responses to these sigma ligands resembled those which have been determined previously for atypical antipsychotics and support the contention that these sigma ligands may be antipsychotic agents with an atypical profile of action.

Oral administration of the serotonin (5-HT) precursor L-5-hydroxytryptophan (5-HTP), 200 mg, significantly increased plasma cortisol levels in man. L-5-HTP had no significant effect on the plasma prolactin levels. A borderline effect of 5-HTP on plasma ACTH levels was found. Pretreatment with the 5-HT2/5-HT1c antagonist ritanserin (5 mg, PO, b.i.d. for 2 days) significantly inhibited 5-HTP-induced cortisol secretion. Ritanserin had no effect on the basal plasma cortisol or prolactin levels. These data are suggestive that 5-HTP stimulates cortisol secretion in man via 5-HT2/5-HT1c receptor mechanisms.

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.

Plasma prolactin (PRL) and growth hormone (GH) levels are determined, in part, by the effects of dopamine (DA) at pituitary and hypothalamic DA receptors, respectively. To determine if chronic cocaine abuse alters dopaminergic activity, basal PRL and GH concentrations were measured in 16 male patients meeting DSM-III-R criteria for cocaine dependence (8 cocaine users and 8 cocaine + alcohol users) and 8 normal controls. In addition, the functional responsivity of DA receptors was assessed in the same group of patients by measuring the change in plasma PRL and GH concentrations following the administration of the direct-acting DA agonist, apomorphine (0.01 mg/kg, s.c.) or saline. No difference in basal plasma PRL and GH levels or plasma PRL and GH responses to apomorphine administration was found between the entire group of cocaine patients and normal controls. However, three of the cocaine patients had basal plasma PRL levels that were more than 2.5 SD greater than that of the normal controls, suggesting that some interference of dopaminergic inhibition of PRL secretion might be present in at least some cocaine users. Although baseline plasma PRL levels were elevated in a subgroup of cocaine users, these data do not support the hypothesis that chronic cocaine abuse produces consistent abnormalities in dopaminergic function at the pituitary or hypothalamus.

The effects of atypical neuroleptics within the neuroendocrine axis of rodents can be distinguished from those of typical neuroleptics by the production of: 1) a shortlived increase in serum PRL concentrations, 2) an acute increase in the activity of TIDA neurons, and 3) a marked increase in serum corticosterone concentrations. It is of interest to speculate that the pharmacological properties of atypical neuroleptics which mediate the unique neuroendocrine responses are of relevance to an understanding of the mechanisms which underlie the clinical profile of these antipsychotic agents.

Previous studies have demonstrated that the 5-hydroxytryptamine1A (5-HT1A) agonist buspirone stimulated rat prolactin (PRL) secretion. Administration of the 5-HT1A agonists gepirone (GEP) or ipsapirone (IPS) s.c. in doses from 1 to 10 mg/kg had no effect on PRL secretion in male rats. However, pretreatment with GEP (10 mg/kg) or IPS (10 mg/kg) significantly attenuated the increase in serum PRL concentration elicited by the 5-HT agonists 5-methoxy-N,N-dimethyltryptamine or 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212). To determine whether the inhibitory effect of GEP or IPS was related to a serotonergic mechanism or a more general inhibitory effect on PRL secretion, the ability of GEP and IPS to inhibit the haloperidol- or alpha-methyl-p-tyrosine-induced increase in PRL secretion was studied. GEP (1, 3 and 10 mg/kg) and IPS (10 mg/kg) inhibited the increase in PRL secretion produced by either haloperidol (0.25 mg/kg) or alpha-methyl-p-tyrosine (75 mg/kg). Furthermore, GEP produced a concentration-dependent inhibition of PRL secretion from anterior pituitary tissue incubated in vitro. The inhibitory effect of GEP was comparable to that of dopamine in this system. Moreover, haloperidol blocked completely the GEP-mediated suppression of PRL secretion in this preparation. These data suggest agonist properties of both GEP and IPS at D2 dopamine receptors. In light of other evidence that GEP has D2 antagonist effects in vivo, we hypothesize that GEP and perhaps IPS are partial dopamine agonists which may contribute to their antianxiety and/or antidepressant properties.

The racemic mixture of 3,4-methylenedioxymethamphetamine (MDMA), which has been reported to produce selective destruction of serotonergic neurons in the central nervous system, was studied to determine its neuroendocrine and temperature effects and mechanism of action. MDMA elevated serum concentrations of corticosterone in doses ranging from 3 to 20 mg/kg administered i.p. Serum corticosterone concentrations were elevated 30 min after the administration of MDMA (10 mg/kg i.p.) and remained elevated 4 hr later. Serum prolactin (PRL) concentrations were elevated by administration of MDMA in doses ranging from 1 to 20 mg/kg i.p., and were maximal 60 min after the injection of 10 mg/kg i.p., declining rapidly over the next 4 hr. MDMA also significantly elevated the body temperature of rats maintained at ambient (23 degrees C) temperature. MDMA-induced corticosterone secretion and hyperthermia were blocked by the 5-hydroxytryptamine (5-HT) antagonists, ketanserin and mianserin, which have a high affinity for 5-HT2 binding sites. Conversely, neither (-)-pindolol, a beta antagonist that also blocks 5-HT1A-mediated responses, nor the nonspecific 5-HT antagonists, cyproheptadine and metergoline, had an effect on MDMA-induced corticosterone secretion. None of the 5-HT antagonists blocked MDMA-induced PRL secretion. Pretreatment with fluoxetine (10 mg/kg i.p.) 16 hr before MDMA administration significantly blunted the effect of MDMA on corticosterone but not PRL secretion. Pretreatment with p-chlorophenylalanine (150 mg/kg i.p.) for 3 days depleted cortical and hypothalamic 5-HT and 5-hydroxyindoleacetic acid by approximately 80% and significantly attenuated MDMA-induced corticosterone and PRL secretion.(ABSTRACT TRUNCATED AT 250 WORDS)