The effects of metergoline and other serotonin receptor antagonists on serum corticosterone in rats.

Metergoline antagonized the elevation of serum corticosterone by quipazine in rats. The ED50 of metergoline was less than 0.1 mg/kg, ip, and the effects of a 3 mg/kg dose persisted for more than 24 h. Metergoline did not antagonize the elevation of serum corticosterone by theophylline or ketamine (i.e. did not prevent corticosterone release nonspecifically) and did not affect the concentration of quipazine in the brain. Since quipazine is a serotonin receptor agonist, the antagonistic effects of metergoline may have been due to competition with quipazine at serotonin receptor sites in the brain. Some other agents capable of blocking serotonin receptors also antagonzied the elevation of serum corticosterone by quipazine. These included LY53857, which gave complete blockade at 3 mg/kg, and cyproheptadine and spiperone, which gave significant but incomplete antagonism at 1 mg/kg. Methysergide at 3 mg/kg did not alter the effect of quipazine. Metergoline did not antagonize the elevation of serum corticosterone by other agents throught to act via serotoninergic mechanisms, namely fluoxetine, fenfluramine, L-5-hydroxytryptophan, N,N-demthyl-5-methoxytryptamine, and 1-(m-trifluoromethylphenyl)piperazine. Thus, the interactions between metergoline and quipazine may have occurred at receptors that are not serotonin receptors or that represent a subset of serotonin receptors not mediating the actions of serotoninergic agents other than quipazine.     

Serotonergic stimulation of pituitary-adrenal activity in the mouse.

Female CF1 mice were given L-5-hydroxytryptophan (5-HTP), quipazine, or 6-methoxy-1,2,3,4-beta-carboline (6-MeO-THBC) in conjunction with various serotonergic drugs to determine if the pituitary-adrenal stimulation produced by the former compounds is serotonergically mediated. Corticosterone (CS) responses to 5-HTP were uninfluenced by pretreatment with a tryptophan hydroxylase inhibitor, p-chlorophenylalanine (PCPA), but were significantly potentiated by a serotonin (5-HT) reuptake inhibitor (Lilly 110140), attenuated by two 5-HT receptor blockers, cyproheptadine and methergoline, and almost completely abolished by 2 extracerebral aromatic L-amino acid decarboxylase inhibitors, MK 486 and a low dose of Ro 4-4602. It was also established that L-tryptophan could stimulate pituitary-adrenal activity in animals pretreated with the monoamine oxidase (MAO) inhibitor pargyline. Serotonergic drugs were generally not as effective in modulating the responses to quipazine and 6-MeO-THBC. It is concluded that (1) 5-HTP stimulates pituitary-adrenal activity in mice by being converted to 5-HT and acting on 1 or more groups of serotonergic receptors; (2) these receptors are located either in an area of the brain outside of the blood-brain barrier such as the median eminence or in a peripheral tissue(s); (3) tryptophan-derived 5-HT can stimulate these receptors, but only if allowed to accumulate by inhibiting its catabolism; and (4) it is not yet clear whether pituitary-adrenal responses to quipazine and 6-MeO-THBC are mediated by a serotonergic mechanism.     

Serotonin receptor subtypes involved in the elevation of serum corticosterone concentration in rats by direct- and indirect-acting serotonin agonists

The serum corticosterone concentration in rats was increased by injection of quipazine, a relatively nonselective serotonin (5-hydroxytryptamine; 5-HT) agonist, or 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), a serotonin agonist selective for the 5-HT1A subtype of receptor. The quipazine-induced increase in serum corticosterone was antagonized by 17 different serotonin antagonists; of these, MDL 11939, pirenperone, setoperone, mianserin, LY 281067, ketanserin, ritanserin and clozapine have relatively selective affinity for the 5-HT2 subtype of receptor. The 8-OH-DPAT-induced increase in serum corticosterone was not antagonized by metergoline, the most potent antagonist of the quipazine effect, but was antagonized by pindolol or penbutolol, 5-HT1A receptor antagonists. Pindolol did not block the effect of quipazine. The results support earlier evidence that serum corticosterone concentration in rats can be increased by activation of either 5-HT1A or 5-HT2 receptors. Indirect-acting serotonin agonists - fluoxetine, L-5-hydroxytryptophan and p-chloroamphetamine - also increased serum corticosterone concentrations. The increases elicited by those agents, which earlier had been reported not to be blocked by metergoline pretreatment, also were not blocked by pretreatment with pindolol or with the combination of metergoline and pindolol. Thus, an involvement of a specific serotonin receptor subtype in the actions of these indirect agonists has not been established.     

Metergoline, naloxone, and sodium valproate did not modify arginine vasopressin response to insulin-induced hypoglycemia in man

The present study was carried out in order to determine whether insulin-induced hypoglycemia exerts its stimulatory effect on plasma concentrations of arginine vasopressin (AVP) by interacting with a serotonergic, a GABA-ergic or an opioid pathway. For this purpose, the effect of the serotonergic antagonist metergoline (10 mg/day for 4 days po), the GABA-ergic agonist sodium valproate (600 mg in three divided doses po) and the opioid-receptor blocker naloxone (10 mg in a iv bolus) on the AVP response during an insulin (0.15 IU/kg bw) tolerance test (ITT) was evaluated in three groups of 6 normal men each. In all men, control ITTs were performed without drug treatments. Basal and ITT-stimulated AVP secretion was not modified by drug administration, suggesting that serotonergic, GABAergic and naloxone-sensitive opioid receptors are not involved in the regulation of AVP secretion in response to insulin-induced hypoglycemia.     

Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats during development of hypertension

Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats (SHR) during development of hypertension were investigated using in vivo and in vitro methods. Plasma ACTH responses to hemorrhage and ether stress were significantly smaller in 7-week-old SHR than in age-matched Wistar-Kyoto rats (WKY), while plasma corticosterone baseline levels and its response to stress were greater in SHR than in WKY. There was no significant difference in the plasma ACTH response to ether stress between bilaterally adrenalectomized SHR and WKY replaced with a 25% corticosterone pellet for 6 days. Adrenalectomy prevented the development of hypertension in SHR; however, corticosterone replacement restored hypertension. Plasma ACTH showed a smaller response to iv CRH injection in SHR than in WKY, while the ACTH response to arginine vasopressin was not different between SHR and WKY. CRH concentrations in the median eminence, posterior pituitary, and cerebral cortex were lower in SHR than in WKY, while the CRH concentration in the median eminence was not different in SHR and WKY when they were adrenalectomized with or without corticosterone replacement. Basal in vitro CRH release from hypothalamic tissue was reduced in SHR, while CRH release in response to 56 mM KCl was not different in SHR and WKY. These results suggest that adrenocortical function is enhanced in young SHR, that reduced ACTH response to stress and exogenous CRH in SHR may be ascribed to higher plasma corticosterone levels, and that corticosterone is essential for the development of hypertension in SHR.     

Serotonergic responses to corticosterone and testosterone in the limbic system

Glucocorticoids secreted peripherally during stressful events act on central monoaminergic systems. In particular, serotonergic mediation of social behavior, such as aggression and reproduction, may be affected by glucocorticoids. This study was undertaken to determine if systemically administered corticosterone would rapidly affect central monoaminergic activity. Male Anolis carolinensis (N = 8 each group) were injected intraperitoneally with 10 or 100 micrograms corticosterone, 10 micrograms testosterone, or saline. Twenty minutes after treatment, brains were rapidly dissected and frozen and then microdissected (punch diameter 300 microm) and analyzed by high-performance liquid chromatography. Serotonergic turnover (estimated by 5-hydroxyindoleacetic acid/serotonin) in the hippocampus and medial amygdala was significantly enhanced by systemic corticosterone. Both of these regions of the brain have been associated with social stress. Testosterone also enhanced turnover in the hippocampus. The effect of corticosterone and testosterone may be to modulate socially induced differences in serotonergic response. Rapid, but short-lived, glucocorticoid stimulation of serotonin release suggests a possible mechanism for mediation of changing social behavioral events.     

Androgenic influence on serotonergic activation of the HPA stress axis

The higher incidence of stress-mediated affective disorders in women may be a function of gonadal hormone influence on complex interactions between serotonin and neural circuits that mediate the hypothalamic-pituitary-adrenal (HPA) stress axis. The paraventricular nucleus of the hypothalamus (PVN) receives serotonergic innervation, and selective serotonin reuptake inhibitors such as citalopram activate the HPA axis independent of stress. We have previously demonstrated that the magnitude of this serotonergic activation was greater in females and was attenuated by testosterone administration; however, the potential central sites of action where androgens reduce these serotonergic effects have not been determined. Therefore, we examined a time course of corticosterone production and used central c-Fos protein levels to assay neuronal activation in stress-related brain regions in female, male, and gonadectomized male mice after an acute citalopram injection (15 mg/kg). In the hippocampus, c-Fos-immunoreactivity was greater in males than in females or gonadectomized males. This same pattern emerged in the lateral septum after vehicle and gonadectomy reversed the effect of citalopram. These regions are important for inhibitory influences on the PVN, and accordingly, hippocampal c-Fos levels were negatively correlated with corticosterone production. No sex differences in c-Fos were detected in the PVN, cingulate cortex, or paraventricular thalamus in response to vehicle or citalopram. These data support brain region-specific regulation of the HPA axis where sex differences may be mediated partly through androgen enhancement of signaling in inhibitory regions.     

Administration of antisomatostatin serum to rats reverses the inhibition of pulsatile growth hormone secretion produced by injection of metergoline but not yohimbine

We attempted to determine whether release of endogenous somatostatin (SS) in rats might mediate the apparent inhibition of growth hormone (GH) secretion produced by metergoline of yohimbine injection. Plasma GH levels in adult male rats bearing chronic right-atrial cannulae were measured at 15-min intervals during a 4-hour period around the onset of the daily dark period. Plasma GH levels in control rats (vehicle-injected) rose rapidly from low levels (< 10 ng/ml) just before darkness to very high levels (> 300 ng/ml) around the onset of the dark period, then declined to low values within 2 h. Injection of the serotonin receptor antagonist metergoline (5 mg/kg) or the adrenergic blocker yohimbine (10 mg/kg) 2.25 h before darkness significantly suppressed the subsequent rise in plasma GH levels. The effect of metergoline, but not yohimbine, on plasma GH was markedly reversed when animals were injected intravenously with anti-SS serum (0.5 ml) 1 h after drug administration. These data suggest that circulating SS may mediate the GH inhibition produced by injection of a serotonin receptor blocker; however, other factors are apparently involved in the suppression of GH secretion by yohimbine.     

Activation of 5-HT 1 serotonin receptors in the medial basal hypothalamus stimulates prolactin secretion in the unanaesthetized rat

Prolactin concentrations were measured in plasma in unanaesthetized male rats chronically prepared with venous and intracerebral cannulae, before and after treatment with bilateral intracerebral injections of serotonin and fenfluramine. Serotonin 1, 5, and 10 nmol injected in the medial basal hypothalamus caused dose-related rises in prolactin concentrations. The secretion of prolactin was blocked by metergoline (2.5 mg/kg i.p.) and only partially by ketanserin (2.0 mg/kg i.v.). The 5-HT 1A agonist 8-OH-DPAT potently stimulated prolactin at doses of 1 and 5 nmol. Fenfluramine 10 and 100 nmol also caused increases in plasma prolactin when injected in the basal hypothalamus. Prolactin secretion was also evoked by serotonin injections in the preoptic/anterior hypothalamic area, but the response was not blocked by serotonin receptor antagonists. It is concluded that activation of 5-HT 1A receptors on or near prolactin-regulating neurons in the arcuate nucleus causes secretion of prolactin. The effectiveness of fenfluramine in increasing plasma prolactin suggests that endogenous serotonin released from terminals in the basal hypothalamus may mediate prolactin secretion physiologically.     

Simultaneous administration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis

Dynamic changes of the thrombus after its formation due to platelet activation may affect the speed of thrombolysis. In the present study, we wanted to evaluate the role played by thromboxane A2 (TXA2) and serotonin (5HT) in mediating platelet activation during lysis of intracoronary thrombi with human recombinant tissue-type plasminogen activator (t-PA). Coronary thrombi were induced in 26 anesthetized, open-chest dogs by inserting a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Presence of the thrombus was documented for 30 minutes. The dogs were then assigned to one of four groups as follows: group 1 dogs (n = 8), serving as controls, received a bolus of heparin (200 units/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg/min) for up to 90 minutes or until reperfusion was achieved; group 2 dogs (n = 10) received, immediately before heparin and t-PA, an intravenous bolus of SQ29548 (SQ) (0.4 mg/kg, a selective TXA2-receptor antagonist) and LY53857 (LY) (0.2 mg/kg, a selective serotonin S2-receptor antagonist); group 3 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of SQ alone (0.4 mg/kg); and group 4 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of LY alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central serotonergic agents raise the repetitive extrasystole threshold of the vulnerable period of the canine ventricular myocardium.

Systemic administration of three central serotonergic agents, melatonin, 5-methoxytryptophol, and 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212), produced significant increases in the threshold of the vulnerable period for repetitive electrical activity in the canine cardiac ventricle. MK-212 was effective despite bilateral vagotomy. The specific serotonin antagonist, metergoline, blocked the effect of MK-212 on the threshold. An increase in central serotonergic activity may inhibit the flow of arrhythmogenic sympathetic nerve traffic from the brain to the heart.     

A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats.

We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin 1 alpha. These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.     

Effect of diet and fenfluramine on thermogenesis in the rat: possible involvement of serotonergic mechanisms

A single injection of 5-hydroxytryptamine (5HT, 1 mg/kg, s.c.) in rats stimulated resting oxygen consumption (Vo2) by 21 percent; this was reduced (to 8 percent) by pretreatment with hexamethonium (5 mg/kg, s.c.). DL-fenfluramine injection (20 mg/kg, s.c.) stimulated metabolic rate (Vo2) by about 40 percent, but caused only 11 and 15 per cent increases in animals pretreated with hexamethonium or metergoline (5 mg/kg, s.c.), respectively. Interscapular brown adipose tissue (BAT) activity, assessed from mitochondrial GDP-binding, was increased by 96 per cent in intact tissue 1 h after fenfluramine injection; this response was completely prevented by surgical sympathectomy of interscapular BAT. Metergoline significantly inhibited (by 46 percent) the acute thermic response (postprandial rise in Vo2) to a 40-kJ meal in normal rats, and depressed resting Vo2 in protein-deficient rats by 18 percent, but did not affect resting Vo2 in control animals. BAT activity (mitochondrial GDP-binding) was elevated by 56 per cent in rats fed the low-protein diet, but this difference was almost completely abolished by prior treatment with metergoline. These data demonstrate a potent thermogenic effect of fenfluramine which apparently involves serotonergic pathways and activation of sympathetic outflow to BAT, and indicate that acute thermic responses to food and chronic thermogenic responses to low-protein diets may also involve serotonergic mechanisms.     

Elevation of serum corticosterone in rats by dopamine agonists related in structure to pergolide

Two chemical analogs of pergolide were examined to test further the idea that pergolide elevates serum corticosterone concentration in rats by activation of brain dopaminergic receptors. LY116467, which contains an N-methyl substituent in place of the N-n-propyl substituent in pergolide, was less potent than pergolide in lowering brain levels of 3,4-dihydroxyphenylacetic acid (Dopac), the metabolite of dopamine. LY116467 increased serum corticosterone concentration in rats at a dose of 3 mg/kg (a higher dose than is required for pergolide), and the effect was prevented by spiperone pretreatment. LY141865, which has been reported to differ from pergolide in not activating dopamine-sensitive adenylate cyclase and which was found in this study to have much less affinity for serotonin receptors than does pergolide, increased serum corticosterone in much the same manner as pergolide, only slightly higher doses being required. The effect of LY141865 was prevented by pretreatment with haloperidol but not domperidone. Both haloperidol and domperidone increased serum prolactin concentration when given alone or in combination with LY141865, indicating they were both capable of blocking peripheral (pituitary) dopamine receptors. In contrast, haloperidol but not domperidone caused a marked elevation in brain levels of Dopac and of homovanillic acid and prevented the lowering of these brain dopamine metabolites by LY141865. The ability of LY141865 to increase serum corticosterone concentration was attenuated in rats that had received four daily injections of pergolide mesylate, indicating corss-tolerance had occurred. These results strengthen the hypothesis that activation of brain dopaminergic receptors leads to increased serum corticosterone concentration in rats.     

Formation of 5-hydroxykynurenine and 5-hydroxykynurenamine from 5-hydroxytryptophan in rabbit small intestine

In order to clarify the role of indoleamine 2,3-dioxygenase [indole:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.17] in the metabolism of serotonin, DL-5-hydroxy[methylene-(14)C]tryptophan, a precursor of serotonin, was incubated with slices of rabbit ileum. Resulting metabolites were separated by DEAE-cellulose column and polyamide column chromatography and identified by various chromatographic techniques and enzymatic analysis. Metabolites obtained in significant amounts were serotonin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-hydroxykynurenine, 5-hydroxykynurenamine, and 4,6-dihydroxyquinoline, representing 13.2, 15.8, 7.0, 21.9, 1.3, and 2.6% of the total metabolites, respectively. The first three compounds were previously reported to be major metabolites produced from 5-hydroxytryptophan by the action of aromatic L-amino acid decarboxylase and monoamine oxidase, whereas the last three are formed by the cleavage of the indole ring by the action of indoleamine 2,3-dioxygenase. In the presence of pargyline, a monoamine oxidase inhibitor, the major metabolites obtained were serotonin, 5-hydroxykynurenine, and 5-hydroxykynurenamine, representing 29.6, 26.6, and 5.4% of the total metabolites, respectively. In the presence of RO4-4602, an aromatic amino acid decarboxylase inhibitor, 5-hydroxykynurenine was the sole major product. These results strongly suggest that the newly discovered metabolic pathway involving the cleavage of the indole ring of 5-hydroxytryptophan operates in vivo to a significant extent and that indoleamine 2,3-dioxygenase plays an important role in the regulation of serotonin levels in the small intestine of the rabbit.     

Effect of an antiserotoninergic drug, metergoline, on the ACTH and cortisol response to insulin hypoglycemia and lysine-vasopressin in man.

The effect of metergoline, a specific antiserotoninergic drug, on ACTH secretion was investigated in 29 normal volunteers and in 4 patients with increased ACTH production (3 with Addison's disease, 1 with Cushing's disease). In 15 normal subjects, a 4-day treatment with 10 mg daily of metergoline significantly blunted the ACTH response to insulin hypoglycemia. Mean peak ACTH values before and after treatment were, respectively, 333 +/- 39.2 (SE) and 235 +/- 38.8 pg/ml (P less than 0.05). The corresponding values of plasma cortisol were 29.6 +/- 2.96 and 20.5 +/- 2.67 mug/100 ml (P less than 0.05). In contrast, metergoline failed to affect the ACTH response to lysine-vasopressin (LVP) administered iv (8 subjects studied) and im (6 subjects studied). In 3 patients suffering from Addison's disease, an appreciable although not statistically significant lowering of the plasma ACTH levels was noted during metergoline administration. The mean pre- and post-treatment values of plasma ACTH in these patients were, respectively, 1116 +/- 192.2 and 666 +/- 100.8 pg/ml, 4240 +/- 50.0 and 3398 +/- 368.0 pg/ml, and 431 +/- 44.0 and 352 +/- 23.9 pg/ml. In one patient with Cushing's disease caused by a pituitary adenoma, metergoline did not appreciably modify plasma ACTH levels. Taken together, these results lend support to the concept of a physiological stimulating effect of serotonin on ACTH secretion. Moreover, they are compatible with the view that serotonin exerts its action chiefly at the hypothalamic level while LVP promotes ACTH release by a primary action on the pituitary.     

Effects of endomorphin-1 on open-field behavior and on the hypothalamic-pituitary-adrenal system

The effects of endomorphin-1 (EM1) on behavioral responses and on the hypothalamic-pituitary-adrenal system were investigated in mice. Locomotor activity was measured in an “open-field” apparatus, with parallel recording of the numbers of rearings and groomings. Different doses of the peptide (250 ng to 5 μg) were administered to the animals intracerebroventricularly 30 min before the tests. EM1 caused significant increases in the locomotor activity and the number of rearings. The effect of EM1 on the basal corticosterone secretion was also investigated. At a dose of 5 μg, the peptide significantly increased plasma corticosterone level. The corticotropin-releasing hormone (CRH) antagonist α-helical CRH_9–41, applied 30 min prior to EM1 administration, completely abolished the increases in both locomotion and the number of rearings and attenuated the corticosterone release evoked by EM1. These results suggest that the EM1-induced increases in locomotion and rearing activity as well as the pituitary-adrenal activation are mediated by CRH.     

Hypothalamic monoamine oxidase, a component in the serotonergic control of pituitary prolactin content in Carassius auratus L.

The role of the enzyme monoamine oxidase (MAO) was examined with regard to the control of pituitary prolactin content in the goldfish. Inhibition of MAO by means of intraperitoneal injection of pargyline resulted in significantly elevated brain serotonin content. Concomitantly, pituitary prolactin stores were also significantly elevated. Time-course and dose-response experiments revealed that pargyline at doses ≥25 mg/kg completely inhibited MAO and significantly increased brain serotonin and pituitary prolactin content within 12 hr. It is concluded that the enzyme MAO may be a significant component of the monoaminergic system of the goldfish, serving to modulate the serotonergic inputs to centers involved in the control of pituitary prolactin secretion.     

Serotonergic stimulation of prolactin and corticosterone secretion is mediated by different pathways from the mediobasal hypothalamus

In previous studies we obtained evidence that serotonin release by p-chloroamphetamine (PCA) causes an increase in corticosterone secretion but that this effect is not mediated via the raphe nuclei in the midbrain. In contrast, PCA-induced prolactin secretion was abolished by dorsal raphe lesions. In the present study, posterolateral cuts which interrupted caudal inputs to the hypothalamus attenuated the effect of PCA on plasma prolactin but did not block the PCA-induced increase in plasma corticosterone levels. Large lesions of the mediobasal hypothalamus produced a significant reduction of plasma corticosterone concentration but did not completely prevent the effect of PCA on corticosterone secretion. Hypophysectomy performed 24 h before sacrifice caused a marked decrease in plasma corticosterone levels but did not completely abolish the effect of PCA. These results suggest that PCA also stimulates corticosterone secretion via a direct action on the adrenal gland. The lesions in the mediobasal hypothalamus caused an increase in plasma prolactin concentration, and in these rats, PCA suppressed rather than stimulated prolactin secretion. This suggests that the known weak dopamine agonist activity of PCA is exposed when the effects of serotonin release in the brain are eliminated.