Andrew D. Levy

Long-term fluoxetine, but not desipramine, inhibits the ACTH and oxytocin responses to the 5-HT1A agonist, 8-OH-DPAT, in male rats

The present studies determined whether serotonin 5-HT1A receptor-mediated function is modified by chronic exposure to antidepressants. Hormone responses to the 5-HT1A agonist, 8-OH-DPAT, were evaluated after long-term exposure to two antidepressants, the 5-HT uptake blocker, fluoxetine, and the norepinephrine uptake blocker, desipramine (DMI). In addition, the density and affinity of 5-HT1A receptors in the hypothalamus and cerebral cortex were measured. Male rats received fluoxetine (10 mg/kg i.p.), DMI (5 mg/kg i.p.) or saline injections once daily for 21 days. 8-OH-DPAT (0-500 micrograms/kg s.c.) was administered 18 h after the final antidepressant injection and 15 min before sacrifice. 8-OH-DPAT significantly increased plasma ACTH, corticosterone, oxytocin and prolactin, but not renin or vasopressin concentrations. Chronic injections of fluoxetine inhibited the ACTH, corticosterone and oxytocin responses to 8-OH-DPAT, suggesting reduced 5-HT1A receptor function. In contrast, chronic DMI did not alter the hormone responses to 8-OH-DPAT. The density and affinity of 5-HT1A receptors in the frontal cortex or hypothalamus were not altered by either fluoxetine or DMI. To verify that the observed effects require prolonged exposure to fluoxetine, rats received a single injection of fluoxetine (10 mg/kg, i.p.), 3 h before 8-OH-DPAT (0-500 micrograms/kg s.c.). Acute fluoxetine did not reduce any of the hormone responses to 8-OH-DPAT. In conclusion, the results suggest that chronic, but not acute, exposure to fluoxetine decreases 5-HT1A receptor function. This effect is not seen in rats chronically exposed to DMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonergic regulation of renin and prolactin secretion

Drugs that, directly or indirectly produce activation of serotonin (5-HT) receptors increase plasma concentrations of both prolactin and renin. The serotonergic regulation of prolactin and renin secretion share several common characteristics. Serotonergic neurons originating in the dorsal raphe and terminating in the hypothalamus stimulate the secretion of both prolactin and renin. Destruction of cells in the hypothalamic paraventricular nucleus (PVN) inhibits both the prolactin and renin responses to 5-HT agonists and 5-HT-releasing drugs. Activation of 5-HT2 receptors increases the secretion of both prolactin and renin, while activation of other 5-HT receptor subtypes has differential effects on these hormones. However, there are also differences between the serotonergic mechanisms that regulate the secretion of prolactin and renin. Activation of 5-HT1A receptors increases the secretion of prolactin but not of renin. In addition, activation of peripheral 5-HT2 receptors stimulates the secretion of renin, while activation of peripheral 5-HT3 receptors increases plasma levels of prolactin but not renin. In humans, the effect of 5-HT-releasing drugs and 5-HT agonists on plasma prolactin concentrations has been studied to a greater extent than effects on most other hormones. In contrast, the renin response to 5-HT agonists and 5-HT releasers has not been well characterized in humans. Because of the important role of the renin-angiotensin system in cardiovascular regulation, studies on the serotonergic regulation of renin release in humans could increase our understanding of cardiovascular disorders associated with altered serotonergic function. Examples include anxiety and consequences of cocaine abuse. In conclusion, comparing the serotonergic regulation of prolactin and renin secretion indicates similarities that might shed light on common brain mechanisms that regulate neuroendocrine function.

Endocrine and receptor pharmacology of serotonergic anxiolytics, antipsychotics and antidepressants

Several classes of drugs that modify serotonin (5-HT) neurotransmission are either currently used, or are being evaluated for their potential use in the treatment of anxiety, schizophrenia, and depression. 5-HT1A agonists are considered potential anxiolytics, while some atypical antipsychotics are potent 5-HT2 antagonists (and also have modest dopamine D2 affinity). Furthermore, there is a diverse group of serotonergic drugs that may be effective antidepressants. Secretion of ACTH, corticosterone/cortisol, prolactin, renin, oxytocin and vasopressin are stimulated by activation of different 5-HT receptor subtypes, while other neurotransmitter receptors also influence the secretion of these hormones. We compared the receptor binding profiles of 5-HT anxiolytics, antipsychotics and antidepressants with their endocrine effects. These comparisons could aid in understanding both the therapeutic and side effects of these drugs.

Attenuation of hormone responses to the 5-HT1A agonist ipsapirone by long-term treatment with fluoxetine, but not desipramine, in male rats

The present study had two objectives: (1) to provide information on neuroendocrine challenge tests that can lead to diagnostic tests in humans; and (2) to confirm our previous observation that chronic fluoxetine selectively inhibits serotonin (5-HT1A) receptor function. We determined the effect of chronic fluoxetine and desipramine (DMI) on the hormone response to ipsapirone, a 5-HT1A agonist and a potential anxiolytic drug. Ipsapirone increased oxytocin, adrenocorticotropic hormone (ACTH), corticosterone, and prolactin, but not renin or vasopressin concentrations in plasma. Chronic fluoxetine, but not DMI, significantly inhibited the effect of ipsapirone on plasma oxytocin, ACTH and corticosterone concentrations. Chronic fluoxetine also reduced the Bmax for 3H-8-hydroxy-2-(dipropylamino) tetralin (3H-8-OH-DPAT) labelled 5-HT1A receptors in the midbrain. Neither antidepressant altered the density or affinity of 5-HT uptake sites. In conclusion, the present results confirm our previous results using 8-OH-DPAT as a challenge, and suggest that chronic 5-HT uptake inhibition results in adaptive changes leading to decreased function of the 5-HT1A receptor system. Finally, because ipsapirone may be administered to humans, it might be usable to evaluate 5-HT1A receptor function in depressed patients.

Hypothalamic paraventricular, but not supraoptic neurons, mediate the serotonergic stimulation of oxytocin secretion

The purpose of the present studies was to determine whether cells in the hypothalamic paraventricular (PVN) or supraoptic (SON) nuclei mediate the serotonergic stimulation of oxytocin secretion. The serotonergic stimulus consisted of injection of the 5-HT-releasing drug p-chloroamphetamine (8 mg/kg, IP). The validity of this approach was verified by comparing this drug with another 5-HT releaser, d-fenfluramine (5 mg/kg, IP). Both 5-HT releasers increased plasma oxytocin concentration. Furthermore, the 5-HT uptake blocker fluoxetine (10 mg/kg, IP) blocked the effects of both p-chloroamphetamine and d-fenfluramine on plasma oxytocin concentrations, suggesting that both 5-HT releasers must be taken up through the 5-HT transporter into 5-HT nerve terminals to increase oxytocin secretion. In the lesion experiments, cells in the hypothalamic PVN or SON were destroyed by injection of the cell-selective neurotoxin ibotenic acid. The PVN lesions reduced basal levels and inhibited the effect of p-chloroamphetamine (8 mg/kg, IP) on plasma oxytocin concentration. In contrast, SON lesions did not alter basal oxytocin levels and did not reduce the oxytocin response to p-chloroamphetamine, suggesting that the SON is not involved in the serotonergic stimulation of oxytocin secretion. Site specificity of the PVN lesions was confirmed when injections of ibotenic acid into the hypothalamic dorsomedial nucleus (DMN), immediately caudal to the PVN, potentiated the oxytocin response to p-chloroamphetamine, suggesting that the DMN exerts an inhibitory influence on the secretion of oxytocin. Taken together, the data suggest that the serotonergic stimulation of oxytocin secretion involves PVN, but not SON, oxytocin neurons.

Repeated cocaine modifies the neuroendocrine responses to the 5-HT1C/5-HT2 receptor agonist DOI

Endocrine responses to the serotonin (5-HT) 5-HT1C/5-HT2 agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were utilised to evaluate cocaine-induced alterations in postsynaptic 5-HT receptor function. Rats received cocaine HCl (0, 5 or 15 mg/kg i.p.) twice daily for 7 days. Effects of DOI (0, 0.5, 2 or 10 mg/kg i.p.) on plasma adrenocorticotropic hormone (ACTH), corticosterone, prolactin, oxytocin and renin concentrations were assessed 42 h after the final cocaine injection. DOI dose dependently increased the plasma concentrations of each hormone. Cocaine potentiated the DOI-induced elevations of plasma ACTH, corticosterone and prolactin concentrations. In contrast, the oxytocin response was reduced, and the renin response was unaltered by cocaine exposure. The data suggest that 5-HT2 receptor-mediated responses for ACTH, corticosterone and prolactin secretion become supersensitive following repeated cocaine. In contrast, the 5-HT2 receptor-mediated response for oxytocin secretion is subsensitive. The cocaine-induced changes in postsynaptic 5-HT receptor function are likely a consequence of deficits in the function of 5-HT nerve terminals, that we have documented previously.

Neuroendocrine responses to cocaine do not exhibit sensitization following repeated cocaine exposure

Cocaine-induced enhancement of motor activity and extracellular dopamine concentrations exhibits sensitization upon repeated exposure. In this study, the neuroendocrine responses to cocaine were examined following cocaine pretreatment regimens which have been shown to produce behavioral sensitization. Adult male rats were injected with cocaine (15 mg/kg, IP) once daily for 14 days, followed by a dose-response challenge with cocaine (1-15 mg/kg, IP) either 18 hours or 7 days after the final pretreatment injection. Blood was collected 15 minutes following injections for radioimmunoassay of ACTH, corticosterone, prolactin, and renin. Cocaine increased plasma ACTH and corticosterone, while it decreased prolactin and renin concentrations. Pretreatment with cocaine for 2 weeks did not alter any of these endocrine responses after either the 18 hour or 7 day interval between pretreatment and challenge injections. In contrast, sensitization to the locomotor stimulant effects of cocaine was observed on the final day of pretreatment injections, and 7 days later. These data suggest that these endocrine effects of cocaine do not exhibit sensitization following repeated cocaine exposure.

Repeated cocaine exposure inhibits the adrenocorticotropic hormone response to the serotonin releaser d-fenfluramine and the 5-HT1A agonist, 8-OH-DPAT

The influence of cocaine exposure on serotonergic neurons and postsynaptic 5-HT1A receptor-mediated responses was evaluated by measuring neuroendocrine responses to a serotonin (5-HT) releaser or a 5-HT1A agonist. Male rats received cocaine (15 mg/kg, i.p.) or saline twice daily for 7 days. Forty-two hr after the final cocaine injection, the 5-HT releaser d-fenfluramine (0, 0.2, 0.6, 2, or 5 mg/kg, i.p.) or the 5-HT1A agonist, 8-OH-DPAT (0, 10, 50, 200 or 500 micrograms/kg, s.c.) were administered. Blood samples were then collected for analysis of plasma ACTH, prolactin, and renin concentrations. The ACTH responses to d-fenfluramine and 8-OH-DPAT were inhibited in cocaine pretreated rats. However, the prolactin responses to d-fenfluramine and 8-OH-DPAT were not significantly modified by cocaine exposure. Additionally, the renin response to d-fenfluramine was unaltered by repeated cocaine administration, while 8-OH-DPAT did not alter renin secretion in either pretreatment group. In contrast to published reports which show that cocaine exposure produces supersensitive 5-HT2A and/or 5-HT2C receptor-mediated responses, the present data suggest that repeated cocaine exposure produces subsensitivity to at least some postsynaptic 5-HT1A receptors. Cocaine-induced deficits in the ACTH response to 5-HT releasers may reflect 5-HT1A receptor subsensitivity, but presynaptic deficits cannot be excluded. Examination of the ACTH response to 5-HT1A agonists may represent a valuable approach to determine deficits in 5-HT function in human cocaine abusers.

Prior chronic exposure to cocaine inhibits the serotonergic stimulation of ACTH and secretion of corticosterone

The effect of long-term pretreatment with cocaine on serotonergic regulation of ACTH (adrenocorticotropic hormone; corticotropin) and secretion of corticosterone in rats was investigated. The following observations were made: (1) Pretreatment with cocaine had no significant effect on basal levels of ACTH and corticosterone in plasma. However, cocaine caused a reduction in the ability of the 5-HT (5-hydroxytryptamine, serotonin) releaser p-chloroamphetamine (PCA) to increase corticosterone in plasma, 42 hr after the last injection of cocaine. (2) Exposure to cocaine for 7 days was sufficient to produce a maximal inhibition of the PCA-induced increase in ACTH in plasma. (3) The inhibitory effect of cocaine on PCA-induced release of ACTH was more marked than on corticosterone. (4) Conversely, the dose-dependent stimulatory effect of two 5-HT1 agonists, RU 24969 (5-methoxy-3-(1,2,3,4-tetrahydro-4-pyridinyl)-1H-indole) and m-CPP (m-chlorophenylpiperazine), on ACTH and corticosterone was not reduced by 7 days of exposure to cocaine. Taken together, these findings indicate that pretreatment with cocaine reduced the function of serotonergic nerve-terminals but not postsynaptic receptors, that stimulate ACTH and secretion of corticosterone.

Repeated injections of cocaine inhibit the serotonergic regulation of prolactin and renin secretion in rats

Alterations in serotonergic function following repeated cocaine injections were examined using neuroendocrine responses to a serotonin (5-HT) releaser and 5-HT agonists. Forty-two hours following administration of cocaine (1-15 mg/kg i.p.) twice daily for 7 or 30 days, male Sprague-Dawley rats were injected with the 5-HT releaser p-chloroamphetamine (PCA; 8 mg/kg i.p.) and blood samples were collected 1 h later for radioimmunoassays of plasma prolactin, plasma renin activity (PRA) and plasma renin concentration (PRC). PCA significantly increased secretion of prolactin and renin. These responses were attenuated in rats pretreated with cocaine for 30 days. In rats receiving cocaine for 7 days, the attenuation of PCA-induced secretion of prolactin and renin was less consistently observed. To determine whether these alterations were due to pre- or postsynaptic effects, rats were injected with cocaine (15 mg/kg i.p.) twice daily for 7 days, and the neuroendocrine responses to the direct 5-HT agonists RU 24969 and m-CPP were examined, 42 h after the last cocaine injection. Pretreatment with cocaine potentiated RU 24969-induced stimulation of plasma prolactin concentration. However, cocaine did not alter the ability of m-CPP to increase plasma prolactin concentrations. The stimulation of renin secretion in response to both 5-HT agonists was not altered by cocaine pretreatment. The data suggest that repeated cocaine impairs the function of serotonergic nerve terminals that regulate these endocrine responses. Furthermore, the 5-HT receptors that mediate prolactin secretion may exhibit supersensitivity.