Age-associated changes in the serotonergic system in rat superior colliculus and pretectum.

The purpose of this study was to investigate whether aging alters serotonergic innervation of the superior colliculus and pretectum in rats. The superior colliculus has one of the highest concentrations of serotonin in the rat central nervous system. Young and old male F344 rats (<6 months, and >18 months, albino and pigmented) were used in all experiments. Coronal sections through the superior colliculus and pretectum were incubated with antibodies to serotonin, the serotonin 2A receptor, and the serotonin transporter. Immunocytochemical staining was analyzed semi-quantitatively. The results indicate that with age there is an increase in serotonin immunoreactivity throughout the entire superior colliculus and pretectum, a decrease in levels of serotonin 2A receptor staining in select layers of superior colliculus, and no change in serotonin transporter immunoreactivity. Albino rats differ from pigmented rats in that they have enhanced serotonergic immunoreactivity in the superficial layers of superior colliculus, a region that receives direct retinal input. These data suggest that the age-related changes in the serotonergic system in the superior colliculus and pretectum may account for some of the alterations in light-mediated behaviors with aging.

Localization of 5-HT(7) receptors in rat brain by immunocytochemistry, in situ hybridization, and agonist stimulated cFos expression.

5-HT(7) receptors are recently identified members of the serotonin receptor family that have moderate to high affinity for several important psychotropic drugs. However, the lack of selective ligands has impeded the study of the brain distribution of these receptors. In this report, we describe the localization of 5-HT(7) receptor in rat forebrain by immunocytochemistry, in situ hybridization of 5-HT(7) mRNA, and functional stimulation of cFOS expression by 5-HT(7) receptor activation. The anatomical localization of 5-HT(7) mRNA in situ hybridization signal. Prominent immunostaining was apparent in numerous sites within the cerebral cortex, hippocampal formation, tenia tecta, thalamus and hypothalamus. 5-HT(7) receptors were detected in suprachiasmatic nucleus by both immunocytochemistry and in situ hybridization. At a microscopic level, both cell bodies and proximal fibers were strongly stained in these regions, suggesting a somatodendritic subcellular distribution. 5-HT(7) receptor-like immunoreactivity was further compared with 5-HT(7) mediated biological function by administering 8-OH-DPAT intracerebroventricular injection (icv)with WAY 100135 (to block 5-HT(1A) receptors) followed by double immunostaining localization of cFos activation and 5-HT(7) receptors. In all regions examined, cFos stimulation and 5-HT(7)-like immunoreactivity colocalized to the same neurons. Furthermore, cFos activation by 8-OH-DPAT was blocked by pimozide--a 5-HT(7) antagonist. Therefore, by using multiple strategies, we were able to localize 5-HT(7) receptors in rat brain unequivocally. The distribution of these receptors is consistent with their involvement in the control of circadian activity and the action of anti-depressants and atypical neuroleptics.

Increased spinal monoamine concentrations after chronic thoracic dorsal rhizotomy in goats.

In goats, bilateral thoracic dorsal rhizotomy (TDR) causes severe ventilatory failure during exercise, followed by progressive functional recovery. We investigated spinal neurochemical changes associated with TDR and/or functional recovery by measuring spinal concentrations of the monoamines serotonin (5-HT), norepinephrine, and dopamine via HPLC. Changes in 5-HT and calcitonin gene-related peptide were visualized with immunohistochemistry. Goat spinal cords were compared 4-15 mo after TDR from T(2) to T(12) (n = 7) with sham-operated (n = 4) or unoperated controls (n = 4). TDR increased the concentration of cervical 5-HT (C(5)-C(6); 122% change), caudal thoracic norepinephrine (T(7)-T(11); 53% change), and rostral thoracic dopamine (T(3)-T(6); 234% change). TDR increased 5-HT-immunoreactive terminal density (dorsal and ventral horns) and nearly eliminated calcitonin gene-related peptide immunoreactivity in the superficial laminae of the dorsal horn in rostral thoracic segments; both effects became less pronounced in caudal thoracic segments. Thus TDR elevates monoamine concentrations in discrete spinal regions, including possible compensatory changes in descending serotonergic inputs to spinal segments not directly affected by TDR (i.e., cervical) but associated with functionally related motor nuclei (i.e., phrenic nucleus).

Localization of serotonin(5A) receptors in discrete regions of the circadian timing system in the Syrian hamster.

Endogenous serotonin and serotonergic drugs influence many aspects of circadian rhythms, including phase shifts, onset of locomotor activity, and period length and integrity of rhythms during exposure to constant light. The receptor subtype(s) mediating all of these circadian effects of serotonin has (have) not been identified. Immunoreactivity for the serotonin(5A) (5-HT(5A)) receptor has recently been identified in the rat suprachiasmatic nucleus (SCN). In this study, we investigated the distribution of the 5-HT(5A) receptors in four neural components of the circadian timing system (the SCN, the intergeniculate leaflet, and the median and dorsal raphe nuclei), in the Syrian hamster. Single and dual immunohistochemistry were conducted using an affinity-purified rabbit antibody generated against a peptide sequence unique to the 5-HT(5A) receptor, guinea pig anti-5-HT antisera and guinea pig anti-GABA antisera. For single labeling, immunoreactivity was visualized using DAB-nickel as the chromagen. All four regions showed strong, yet distinct, immunoreactivity for the 5-HT(5A) receptor. No specific labeling was present in the absorption or omission controls. For double labeling, immunoreactivity was visualized using immunofluorescence with Cy5- and FITC-labeled second antibodies followed by confocal microscopy. In the raphe nuclei, 5-HT-immunoreactivity and 5-HT(5A)-immunoreactivity were co-localized in cell bodies and axons. GABA-immunoreactive fibers surrounded some of the 5-HT(5A) receptor-immunoreactive cell bodies in the raphe nuclei. In conclusion, the 5-HT(5A) receptors are localized within several important neuroanatomical substrates of the circadian timekeeping system, and within the raphe nuclei, appear to be present on serotonin neurons. These findings suggest that some of the circadian effects of 5-HT may be mediated by the 5-HT(5A) receptor, which may function as a presynaptic autoreceptor.

The incidence of recurrence after endoscopic carpal tunnel release.

Endoscopic carpal tunnel release has been used to decompress the median nerve in carpal tunnel syndrome for over the past decade, with an advantage (over the traditional "open" release) being decreased pain in the postoperative period. The goals of this study were to attempt to define the recurrence rate after endoscopic carpal tunnel release and to determine if it differs from that of open technique. The charts of 191 consecutive carpal tunnel syndrome patients treated operatively at the University of Missouri were reviewed. For this study, recurrent carpal tunnel syndrome was defined as documented cases in which the symptoms had resolved following surgical release but subsequently recurred, requiring surgical rerelease of the carpal tunnel. All endoscopic releases were performed using the Chow two-portal technique. Statistical analysis was performed using Fisher's exact test. A total of 103 patient hands had open carpal tunnel releases; 88 were endoscopically released. Total follow-up time (from the initial release) averaged 29 months for the open group and 22 months for the endoscopic group. There were no recurrences in the open group and six recurrences in the endoscopic group (7 percent, p = 0.008). All six recurrences were in worker's compensation patients. The median time between endoscopic release and rerelease was 8.5 months. There seems to be a statistically higher incidence of recurrence of carpal tunnel syndrome after endoscopic release compared with the traditional "open" release in our cases. Although the pathogenesis of this increased rate of recurrence is not clear, this should be considered when planning surgical release of the volar carpal ligament for carpal tunnel syndrome.

5-HT5a receptors in the carotid body chemoreception pathway of rat.

By using a specific antibody, 5-HT5a receptor-like immunoreactivity was revealed in the chemoreceptive, oxygen sensitive, carotid body (CB) type I cells, and neurons of the petrosal ganglion (PG) and the superior cervical ganglion (SCG) in rat. mRNA encoding for the 5-HTa receptor was also detected in these tissues by RT-PCR, and confirmed with DNA sequencing. The present study provides direct evidence that 5-HT5a receptors are expressed in the CB, PG and SCG, which all likely play fundamental roles in arterial chemoreception.

Age-related changes in serotonin in the hypoglossal nucleus of rat: implications for sleep-disordered breathing.

We are attempting to determine the neuronal factors that influence upper airway patency during sleep in the elderly. Serotonin has a facilitatory effect on hypoglossal motoneurons that innervate the tongue, and manipulations of the serotonergic system alter airway patency. We hypothesized that age-associated changes in serotonergic input to the hypoglossal nucleus might be a factor in the increased susceptibility to sleep-disordered breathing in the elderly. We used light microscopic immunocytochemistry to study the distribution of serotonin in the hypoglossal nucleus in young and old rats. Rats > 18 months had fewer serotonin immunoreactive axons and boutons in the hypoglossal nucleus than rats < 6 months. These data suggest that normal aging may result in a change in the availability of serotonin that results in decreased facilitation of hypoglossal motoneurons.

A comparison of the oxytocin and vasopressin responses to the 5-HT1A agonist and potential anxiolytic drug alnespirone (S-20499).

The effect of the serotonin1A (5-HT1A) agonist alnespirone (S-20499) on the secretion of both oxytocin and vasopressin was examined in the same conscious, unrestrained male rats. The dose-response and time-course effects on the secretion of oxytocin and vasopressin revealed that alnespirone stimulated oxytocin in a dose-dependent manner, but did not increase vasopressin secretion. Time of maximal effect following injection of alnespirone (5 mg/kg, i.p.) was as early as 15 min postinjection, with significant stimulation persisting for 30 min. Pretreatment with a low dose of the 5-HT1A/beta-adrenoceptor antagonist (-)-pindolol (0.3 mg/kg, s.c.), 30 min prior to injection of alnespirone (0, 2, 5, and 10 mg/kg, i.p.) shifted the dose-response curve to the right and inhibited the effect of alnespirone on plasma oxytocin concentration. Furthermore, pretreatment with a low or a high dose of the 5-HT1A/2A/dopamine D2 antagonist spiperone (0.01 or 3 mg/kg, s.c.) dose dependently shifted the alnespirone dose-response curve effect of alnespirone to the right. None of these drugs, alone or in combination, altered plasma vasopressin levels. These studies suggest that 5-HT1A receptor mechanisms mediate the effect of alnespirone on the secretion of oxytocin. Furthermore, these studies suggest that 5-HT1A receptor mechanisms do not participate in the serotonergic regulation of vasopressin secretion.

Alterations in 8-hydroxy-2-(dipropylamino)tetralin-induced neuroendocrine responses after 5,7-dihydroxytryptamine-induced denervation of serotonergic neurons.

In the present study, we examined denervation-induced changes in the sensitivity of hypothalamic postsynaptic serotonin1A (5-HT1A) receptor function with respect to changes in the dose-dependent elevation in plasma hormones [adrenocorticotropic hormone (ACTH), corticosterone, prolactin, oxytocin, prolactin, renin and vasopressin] by the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT). Rats received intracerebroventricular (i.c.v.) injections of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or vehicle (0.1% ascorbate in saline) 3 weeks before challenge with increasing doses of 8-OH-DPAT (0, 10, 50 or 200 micrograms/kg s.c.). The effectiveness of 5,7-DHT-induced destruction of serotonergic neurons was confirmed by a 93% reduction in [3H]paroxetine-labeled 5-HT uptake sites in the hypothalamus. No changes in basal levels of ACTH, corticosterone, oxytocin, prolactin, renin and vasopressin were observed in rats that received i.c.v. 5,7-DHT injections. The dose-response curves for 8-OH-DPAT-induced elevations of plasma corticosterone and prolactin levels were shifted to the left in rats treated with 5,7-DHT, whereas no significant difference in the ACTH dose-response curve was observed between rats treated with vehicle and rats treated with 5,7-DHT. In contrast, the maximal oxytocin response to 8-OH-DPAT was attenuated in rats treated with 5,7-DHT. A 5,7-DHT-induced decline in the synthesis of oxytocin could explain this phenomenon. Although 8-OH-DPAT did not increase plasma levels of renin or vasopressin in rats treated with vehicle, 8-OH-DPAT produced an elevation (75%) in plasma renin concentration but not in vasopressin levels in rats that received i.c.v. injections of 5,7-DHT. No change was observed in [3H]8-OH-DPAT labeled 5-HT1A receptors in the hypothalamus. In summary, denervation of hypothalamic serotonergic nerve terminals produces supersensitivity of some neuroendocrine responses to 8-OH-DPAT independent of changes in the density of hypothalamic 5-HT1A receptors.

Plasma renin activity and angiotensin I and aldosterone concentrations in cats with hypertension associated with chronic renal disease.

OBJECTIVE: To determine plasma renin activity (PRA), angiotensin I (Ang I), and aldosterone (ALDO) values in clinically normal cats and hypertensive cats with renal disease, and the relation of renin-angiotensin-aldosterone activation in response to treatment with beta-blockers or angiotensin-converting enzyme inhibitors. ANIMALS: 5 normotensive healthy control cats and 12 Untreated hypertensive cats with chronic renal disease. PROCEDURE: Untreated hypertensive cats received either propanolol (n = 6) or enalapril (n = 6) as initial antihypertensive treatment. PRA and baseline plasma Ang I and ALDO concentrations were measured prior to treatment. The difference in Ang I values at 2 hours (Ang I generated) and at time 0 (baseline Ang I) was divided by 2 to give the PRA value. Values for PRA, Ang I, and ALDO were obtained from 5 clinically normal, normotensive cats, and compared with those of hypertensive cats. RESULTS: Mean +/- SD PRA and baseline Ang I concentration were not significantly different between normotensive and hypertensive cats. Mean ALDO concentration was significantly (P = 0.0235) higher in hypertensive cats with renal disease (186.18 +/- 145.15 pg/ml), compared with that in normotensive controls (51.1 +/- 16.76 pg/ml). Eight hypertensive cats with ALDO concentration > 2 SD above the mean concentration in control cats had low (n = 3), normal (n = 4), or high (n = 1) PRA, suggesting variable activation of the renin-angiotensin-aldosterone axis in the hypertensive state. Overall, enalapril was effective long-term monotherapy in only 1 of 6 cats, and propranolol was ineffective as long-term monotherapy. CLINICAL RELEVANCE: Evaluation of the renin-angiotensin-aldosterone system in cats with hypertension associated with renal disease may lead to greater understanding of the pathophysiologic mechanisms of this disorder. In addition, identification of biochemical markers in hypertensive cats may permit selection of appropriate antihypertensive drugs. Propranolol and enalapril were ineffective antihypertensive agents in most cats of this study.

Intensive venous sampling of adrenocorticotropic hormone in rats with sham or paraventricular nucleus lesions.

Adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary is predominantly regulated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) synthesized in neurons of the paraventricular nucleus (PVN) of the hypothalamus. Secretion of ACTH occurs in pulsatile bursts. To explore the relationship between hypothalamic control and the pulsatile pattern of ACTH secretion, we measured ACTH in 2 min blood samples over 4 h in rats with intact and lesioned PVN during hypovolemic-stress or control conditions and also measured median eminence (ME) levels of CRH, AVP, and oxytocin (OT). Mean plasma ACTH was highest in the sham lesioned-hypovolemic group, lowest in the sham lesioned-control group and intermediate in the two PVN-lesioned groups. CRH in the ME was negligible in the lesioned animals and correlated with OT and AVP. Pulsatile secretion was observed despite PVN ablation. Visual inspection of composite time series suggested different temporal patterns of ACTH secretion. Principal components analysis of the individual ACTH time series revealed three significant eigenvectors which correlated differentially with the three treatment groups. Neither lesioned group had the steep rise over 10 min seen in plasma ACTH in the non-lesioned groups. Delayed ACTH rise after 30-60 min occurred in all but the sham control group. Our data suggest that CRH is responsible for immediate secretion of ACTH in response to hypovolemic stress and that regulators from non-PVN sites may be responsible for more delayed secretion of ACTH in this setting. The persistence of ME AVP and OT levels in the face of > 90% reduction in ME CRH levels leaves open the question of a role for one or both of these peptides in the delayed ACTH response following stress onset and in the generation of pulsatile ACTH secretory bursts.

Modulation of ventilatory control during exercise.

The control of ventilatory responses to mild or moderate dynamic exercise has been the subject of considerable debate for over a century. The prevailing view has been that the ventilatory response to exercise is stereotypical and rather unmalleable. However, paradigms involving novel associations of stimulus inputs have been shown to modulate breathing in short and longer time scales. The scope of this review includes examples of modified ventilatory responses to exercise which have been investigated in terms of neural mechanisms. An attempt to synthesise the available data into a model of neuromodulation is presented.

Neuroendocrine pharmacology of three serotonin releasers: 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAi) and p-methylthioamphetamine (MTA).

Serotonin (5-hydroxytryptamine, 5-HT)-releasing drugs are important experimental tools to examine the role of serotonergic nerve terminals in the secretion of hormones. The drugs 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAI) and p-methylthioamphetamine (MTA) have been suggested to be 5-HT releasers. The present study characterized MBDB, MMAI and MTA by using their effects on the secretion of the hormones adrenal corticotrophin (ACTH), corticosterone, prolactin, oxytocin and renin. The time course of the effect of MBDB, MMAI and MTA (5 mg/kg, i.p.) showed that the peak effect on plasma ACTH occurred 10 min after the injection, whereas the prolactin response did not reach a maximum until 30 min after injection. MBDB increased plasma renin concentration within 10 min, whereas the effect of MTA was significant only at 30 min after injection. All three 5-HT releasers decreased HR (within 5 min) and blood pressure (at 15 min after injection). MBDB, MMAI and MTA increased plasma ACTH, corticosterone, prolactin and renin levels in a dose-dependent manner, whereas no changes were observed in plasma vasopressin concentrations. MTA and MMAI, but not MBDB, significantly increased plasma oxytocin concentrations in a dose-dependent manner. Pretreatment of rats with fluoxetine blocked the ACTH response to MBDB and MMAI, but not to MTA. The prolactin response to all three 5-HT releasers was blocked by fluoxetine. The oxytocin response to MTA and MMAI was inhibited by fluoxetine. The renin responses to all three 5-HT releasers were not significantly inhibited by fluoxetine. The results suggest that MBDB, MMAI and MTA can increase the secretion of several hormones, at least in part, through stimulation of serotonergic neurotransmission. However, these three 5-HT releasers seem to have effects on other (and as yet uncharacterized) mechanisms that can stimulate the secretion of some hormones.

Neuroendocrine and cardiovascular effects of serotonin: selective role of brain angiotensin on vasopressin.

Central serotonin (5-HT) and angiotensin (ANG II) stimulate arginine vasopressin (AVP), oxytocin (OT), and adrenocorticotropin (ACTH) secretion and increase blood pressure. Studies were conducted in conscious rats to determine whether neuroendocrine activation by 5-HT requires a brain angiotensinergic intermediate pathway. In the first study, ANG II formation was inhibited by the angiotensin-converting enzyme inhibitor enalapril before injection of the 5-HT releaser/uptake inhibitor d-fenfluramine. Fenfluramine (2 mg/kg ip) stimulated AVP, OT, corticosterone, and prolactin (PRL) secretion (P<0.01). Enalapril (60 mg/l in drinking water for 4 days and 10 mg/kg ip 2 h before the rats were killed) inhibited only the AVP response (P<0.01) to d-fenfluramine. In the second study, the effect of intracerebroventricular injection of the 5-HT2A/2C antagonist LY-53857 (10 microgram), or the ANG II AT1 antagonist DuP-753 (10 microgram), on intracerebroventricular 5-HT (10 microgram)-stimulated AVP, OT, ACTH, PRL, renin secretion, mean arterial pressure (MAP) and heart rate (HR) was tested. LY-53857 inhibited the AVP, OT, and ACTH responses to 5-HT (P<0.01), whereas DuP-753 inhibited only the AVP response (P<0.01). Intraventricular injection of 5-HT increased MAP and decreased HR. The MAP response was not affected by LY-53857 or DuP-753, and at no time did MAP decline below starting levels. The decreased HR was inhibited by LY-53857 but not by DuP-753. These results demonstrate that 5-HT-induced AVP secretion is mediated selectively via brain angiotensinergic mechanisms by way of the AT1 receptor.

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.

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.

Brain catecholamines mediate the delayed reduction in renin release after injection of fenfluramine.

The present studies examined whether brain or peripheral catecholaminergic mechanisms mediate the fenfluramine-induced reduction in plasma renin activity and concentration. Fenfluramine reduced plasma renin activity and concentration to 35% of basal levels in vehicle pretreated rats. This reduction was prevented in rats whose central catecholaminergic neurons were destroyed by i.c.v. injection of 6-hydroxydopamine (6-OHDA) two weeks prior to the experiment. In contrast, the suppressive effects of fenfluramine on plasma renin activity and concentration was not altered in rats that were surgically adrenal medullectomized and chemically sympathectomized by 6-OHDA. To determine whether alpha 2 adrenoceptors mediate the suppressive effects of fenfluramine, rats were pretreated with increasing doses of the alpha 2 adrenoceptor antagonist yohimbine 1 h before the administration of fenfluramine. Although yohimbine alone increased plasma renin activity and concentration, it did not prevent the suppressive effects of fenfluramine. In conclusion, the data suggest that central, but not peripheral catecholamines mediate the suppressive effect of fenfluramine on renin secretion. This effect is not mediated by alpha 2 adrenoceptors.

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)

Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI).

Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT uptake blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT1C/2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT1C agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injection and 30 min before decapitation. Chronic treatment with both fluoxetine and DMI produced a potentiation in most hormone responses to the 5-HT agonists (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) and MK-212, although there were several differences in individual hormone responses to the two 5-HT agonists. Fluoxetine and DMI potentiated the MK-212- and DOI-induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone (corticotropin) and prolactin levels. In contrast, the effect of the high dose of MK-212 on plasma prolactin concentration was reduced by both antidepressants. Only MK-212 increased vasopressin levels and this effect was potentiated by fluoxetine, but not by DMI. Fluoxetine also significantly increased the resting level of plasma vasopressin. DMI potentiated the effect of MK-212 on plasma renin concentration. Pretreatment with fluoxetine significantly increased (38%) the Bmax for the 5-HT1C/2 agonist sites ([125I]DOI) in the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)