Central Serotonergic Receptors Research Articles

Different Etiologies and Pathophysiologies of Premature Ejaculation Determine its Treatment

For many years, different views have existed regarding etiology and treatment of premature ejaculation (PE). On one hand it was argued that PE is caused by psychological factors, like unresolved unconscious conflicts, relationship problems, and/or self-learned behaviour. On the other hand, it has been argued that PE is caused by either somatic factors, like hypersensitivity of the glans penis, a higher cortical representation of the pudendal nerve, or neurobiological factors, like disturbances in the central serotonergic neurotransmission and serotonergic receptor functioning. Until recently, there has not been a theory integrating these different views. Recenty, Waldinger emphasized that the occurrence of PE does not automatically imply the existence of a male sexual disorder. PE is a frequent males sexual complaint, but its occurrence is not always the result of mental or physical pathology. Therefore, Waldinger proposed a new classification of PE for the pending DSM-V. According to this new classification there are four PE syndromes; lifelong PE, acquired PE, natural variable PE and premature-like ejaculatory dysfunction. These syndrome are distinguished by the duration of the IELT, frequency of complaints, its course in lifetime, etiology, pathophysiology and treatment. For example, men with lifelong PE usually ejaculate within 1 minute after penetration from about the first sexual encounters. As this disorder is also recognized in male rats, it is highly likely that this disorder is mainly neurobiologically determined. These men need drug treatment to delay ejaculation. In contrast, the new defined category of men with premature-like ejaculatory dysfunction complain of PE while having normal IELT (3-7 minutes) and even long IELTs (10-25 minutes). As the IELT is normal and there is nothing biologically disturbed in these men, it is very likely that this syndrome is mainly psychological and perhaps even culturally determined. These men should not be treated with medication, but with counselling, psycho-education or psychotherapy in order to learn how to cope with their complaints. Acquired PE may be psychologically or somatically determined. These men need either counselling or psychotherapy, or adequate treatment of the underlying somatic disorder (thyroid or urological diseases). Lastly, a second new defined category are men with natural variable PE. These men only occasionally have early ejaculations. There is no indication that occasional occurrence of PE is either related to psychological or somatic pathology. Therefore it is assumed that natural variable PE is only a manifestation of normal ejaculatory performance. In case of seeking treatment, these men need reassurance or counselling. The new classification of PE integrates both psychological as neurobiological etiologies and pathophysiologies of PE. These different etiologies determine the different treatments of PE, which is either medication, somatic treatment, psychotherapy, counselling, psychoeducation or reassurance.

A Case of Serotonin Syndrome and Mutism associated with Methadone

A patient was seen on the palliative care service at our institution who developed serotonin syndrome and mutism associated with methadone use. Serotonin syndrome is often described as a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities, but not all of these findings are consistently present in all patients with the disorder. The incidence of the serotonin syndrome is thought to mirror the increasing number of proserotonergic agents being used in clinical practice. In 2002, the Toxic Exposure Surveillance System, which receives case descriptions from office-based practices, inpatient settings, and emergency departments, reported 26,733 incidences of exposure to selective serotonin-reuptake inhibitors (SSRIs) that caused significant toxic effects in 7349 persons and resulted in 93 deaths. Serotonin syndrome is not an idiopathic drug reaction; it is a predictable consequence of excess serotonergic agonism of central nervous system (CNS) receptors and peripheral serotonergic receptors. The myriad of symptoms with which serotonin syndrome may present is compounded by the fact that more than 85% of physicians are unaware of serotonin syndrome as a clinical diagnosis. Other SSRIs such as fluoxetine and fluvoxamine have been shown to increase methadone plasma concentrations in dependent patients. Although the exact mechanism is unknown, there are several pathways via which a significant interaction could occur. This would include the effects methadone has on N-methyl-D-aspartate (NMDA) in addition to the impact of methadone on the cytochrome P450 enzyme system. The mainstay of treatment of serotonin syndrome is withdrawal of the offending agent and supportive care. These actions resulted in resolution of our patient's symptoms. Serotonin syndrome is becoming more common, and with the utilization of polypharmacy on many palliative care services should be considered as unifying differential diagnosis in the appropriate setting.

Role of cholecystokinin and central serotonergic receptors in functional dyspepsia

Symptoms of functional dyspepsia are characterized by upper abdominal discomfort or pain, early satiety, postprandial fullness,bloating, nausea and vomiting. It is a chronic disorder, with symptoms more than 3 mo per year,and no evidence of organic diseases. Dysfunctional motility, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. It is believed that these pathophysiological mechanisms interact to produce the observed symptoms. Dyspepsia has been categorized into three subgroups based on dominant symptoms. Dysmotility-like dyspepsia describes a subgroup of patients whose symptom complex is usually related to a gastric sensorimotor dysfunction. The brain-gut peptide cholecystokinin (CCK) and serotonin (5-HT) share certain physiological effects. Both have been shown to decrease gastric emptying and affect satiety. Furthermore the CCK induced anorexia depended on serotonergic functions probably acting via central pathways. We believe that abnormalities of central serotonergic receptors functioning together with a hyper responsiveness to CCK or their interactions may be responsible for the genesis of symptoms in functional dyspepsia (FD).

Central serotonergic and noradrenergic receptors in functional dyspepsia

Functional dyspepsia is a symptom complex characterised by upper abdominal discomfort or pain, early satiety, motor abnormalities, abdominal bloating and nausea in the absence of organic disease. The central nervous system plays an important role in the conducting and processing of visceral signals. Alterations in brain processing of pain, perception and affective responses may be key factors in the pathogenesis of functional dyspepsia. Central serotonergic and noradrenergic receptor systems are involved in the processing of motor, sensory and secretory activities of the gastrointestinal tract. Visceral hypersensitivity is currently regarded as the mechanism responsible for both motor alterations and abdominal pain in functional dyspepsia. Some studies suggest that there are alterations in central serotonergic and noradrenergic systems which may partially explain some of the symptoms of functional dyspepsia. Alterations in the autonomic nervous system may be implicated in the motor abnormalities and increases in visceral sensitivity in these patients. Noradrenaline is the main neurotransmitter in the sympathetic nervous system and again alterations in the functioning of this system may lead to changes in motor function. Functional dyspepsia causes considerable burden on the patient and society. The pathophysiology of functional dyspepsia is not fully understood but alterations in central processing by the serotonergic and noradrenergic systems may provide plausible explanations for at least some of the symptoms and offer possible treatment targets for the future.

Genetically Selected High Capacity Runners Have Altered Serotonergic and Dopaminergic Receptor mRNA in the Brain

Although adaptations in peripheral systems such as liver function and skeletal muscle composition can contribute to ones capacity to sustain aerobic activity, central neural circuits regulating fatigue may also play a critical role. We evaluated possible differences in central fatigue pathways, including the serotonergic (5-HT) and dopaminergic (DA) systems, between two contrasting rat-lines selectively bred for endurance treadmill running capacity. The lines were designated as Low Capacity Runners (LCR) and High Capacity Runners (HCR). Using in situ hybridization, we examined baseline differences in central serotonergic (5-HT transporter, 5-HT1A, 5-HT1B) and dopaminergic (DR-D1, DR-D2) receptor mRNA in LCR versus HCR. Rats were tested on a treadmill 3 weeks prior to sacrifice to verify trait differences. HCR ran 2 times faster,10 times farther, and 5 times longer than the LCR. Interestingly, HCR had higher levels of 5-HT1B mRNA in the dorsal and median raphe nuclei relative to LCR, but similar levels of 5-HT transporter and 5-HT1A mRNA in these areas. Furthermore, HCR expressed higher levels of DR-D2 mRNA than LCR in only the rostral-mid nucleus accumbens, but not other levels of the nucleus accumbens or caudate putamen. There was no difference in DR-D1 mRNA levels in the nucleus accumbens or caudate putamen between HCR and LCR. These data suggest that constraint of the central serotonergic and dopaminergic responses, via 5-HT1B and DR-D2 inhibitory autoreceptors, during exercise may be involved in the mechanisms by which HCR have delayed onset of fatigue.

Blood oxygen partial pressure affects plasma prolactin concentration in humans.

Responses of plasma prolactin (PRL) concentration to acute and repeated changes in blood oxygen partial pressure (PO2a) at rest were investigated in two studies (A; B), with special reference to possible effects mediated via serotonin (5-HT) synthesis. In A, nine male subjects inhaled for 105 min gas containing different oxygen fractions for 6 days. Gas concentrations consisted of 14% (A14), 21 % (A21), 40% (A40), 60% (A60) and 80% (A80) O2 mixed with N2 as well as 100% O2 (A100). Venous and capillary blood samples were drawn before and every 15 min during gas inhalation for analysis of plasma PRL and PO2a. In B, two groups of subjects (B I; B II) were exposed to 30 min day(-1) of gas inhalation over 14 consecutive days. Gas concentration consisted for B I of 14% O2/86% N2 and for B II of 100% O2. During pre- and post-examination a baseline blood sample was drawn, followed by a neuroendocrine test of serotonergic function using a partial 5-HT1A receptor agonist (60 mg of buspirone hydrochloride). In A, each increase of inhaled oxygen fraction also resulted in higher blood POb2a. In A14, A21 and A40, plasma PRL concentrations did not change from basal level. Increases in plasma PRL concentration were found in A60 after 30 min as well as in A80 and A100 after 15 min. A higher blood PO2a induced a higher plasma PRL secretion but also an earlier decline from peak plasma PRL value despite continued inhalation of the respective oxygen concentration. During post-examination in B, basal plasma PRL concentrations were increased in B I and decreased in B II. Plasma PRL response to stimulation challenge was not affected by treatments. Thus, chronic adaptations of basal plasma PRL concentrations to decreased/increased blood PO2a were not related to up/down-regulation, respectively, of central serotonergic receptor function.

Decreased Neuroendocrine Responses to Meta-Chlorophenylpiperazine (m-CPP) but Normal Responses to Ipsapirone in Marathon Runners

Several clinical studies suggest antidepressive and anxiolytic effects of regular aerobic exercise. To study the effects of exercise on central serotonergic receptor sensitivity, we performed neuroendocrine challenges using oral doses of meta-chlorophenylpiperazine (m-CPP, 0.4 mg/kg), ipsapirone (0.3 mg/kg) and placebo in 12 marathon runners and 12 healthy controls not practicing regular exercise. After administration of the nonselective serotonergic agonist m-CPP, which exerts a number of well-reproducible effects mainly by means of its action on 5-HT2C receptors, marathon runners showed a significantly reduced cortisol response in comparison to the control group. There was also a statistical trend toward a blunted prolactin response after m-CPP in the athlete group. In contrast, the increase of cortisol and the hypothermia observed after administration of the 5-HT1A agonist ipsapirone were of the same magnitude in both groups. The behavioral response to m-CPP or ipsapirone and the mean maximal increases of plasma adrenaline and noradrenaline did not differ between the marathon and the control group. In conclusion, exercise-induced downregulation of 5-HT2C receptors could play an important role in mediating the anxiolytic and antidepressive effects of exercise.

Nonulcer Dyspepsia: A Look Into the Future

Nonulcer Dyspepsia: A Look Into the Future

Psychosis in advanced Parkinson's disease

Psychosis, linked to chronic levodopa and other antiparkinsonian drug treatments, is a common and incapacitating complication of advanced Parkinson's disease (PD). The psychosis may be due, in part, to overstimulation of central serotonergic (5-HT) receptors. We treated 16 PD patients who had psychosis of 6 to 60 months' duration with the 5-HT3 receptor antagonist ondansetron (12 to 24 mg daily) in an open-label, short-term (4 to 8 weeks) trial. There was marked to moderate improvement (p < 0.01) in measures of visual hallucinations, paranoid delusions, confusion, and the associated global functional impairment in all but one of the patients, and there was moderate improvement in the Brief Psychiatric Rating Scale and the Nurse's Observation Scale for Inpatient Evaluation; the Mini-Mental State Examination scores remained unaltered. Ondansetron did not cause any worsening in basic PD symptoms or levodopa efficacy and was well tolerated with no major side effects. Our study suggests that pharmacologic blockade of central 5-HT receptors may become a strategy to attenuate PD psychosis without inducing motor deterioration or suppression of antiparkinsonian action of levodopa, and it lends support to the hypothesis that serotonergic mechanisms are pathogenetically important in the emergence of psychosis in PD.

The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects ofm-chlorophenylpiperazine

m-Chlorophenylpiperazine (mCPP), a major metabolite of the atypical antidepressant trazadone, has been observed to produce marked physiological and behavioral effects in both humans and animals. These effects have been attributed to the interaction of mCPP with serotonergic receptors. The present study was designed to characterize those interactions of mCPP with central serotonergic receptors which mediate mCPP-induced stimulus control. A series of serotonergic antagonists (mesulergine, pizotyline, ketanserin, spiperone, risperidone, ritanserin, metergoline, pirenpirone, and LY53857) was tested for the ability to block the mCPP stimulus. The affinity of these antagonists for 5-HT2A and 5-HT2C receptors was then correlated with maximal percent inhibition of the mCPP stimulus. Kd at the 5-HT2C receptor was inversely proportional (r = -0.75, P < 0.05), and Kd at the 5-HT2A receptor directly proportional (r = +0.67, P < 0.05) to the maximal percent inhibition of the mCPP stimulus. The 5-HT2C selectivity ratio [Kd(5-HT2A)/Kd(5-HT2C)] of the antagonists was directly proportional (r = +0.86, P < 0.01) to maximal percent inhibition of the mCPP stimulus. A multiple regressions analysis indicated that 81% of the variance in the ability of a given antagonist to block the mCPP stimulus could be predicted on the basis of its affinity for 5-HT2A and 5-HT2C receptors. It is concluded that the stimulus effects of mCPP are mediated predominantly by a combination of agonist activity at 5-HT2C receptors and antagonist activity at 5-HT2A receptors.

Food intake and rumen motility in dwarf goats. Effects of some serotonin receptor agonists and antagonists.

The serotonergic regulation of feeding behaviour has not so far been studied in ruminants. Therefore, the effects of some serotonin (5-HT) receptor agonists and antagonists on food intake and forestomach motility were studied in dwarf goats. Goats ate less food when treated intravenously (IV) with the 5-HT precursor 5-HTP (25 micrograms, 50 micrograms or 100 micrograms kg-1 min-1 over 15 min) than when they were treated with 5-HT (which does not pass the blood-brain barrier) or with saline. Accordingly, IV dexfenfluramine infusions (50 micrograms or 100 micrograms kg-1 min-1 over 15 min), which induces release of brain 5-HT, also led to dose-related reductions in food intake. In contrast, no anorectic effects were observed after IV infusions with the selective 5-HT reuptake inhibitor fluoxetine (100 micrograms kg-1 min-1 over 15 min), the selective 5-HT1A agonist 8-OH-DPAT (0.5 micrograms kg-1 min-1 over 15 min), or eltoprazine (4 or 8 micrograms kg-1 min-1 over 15 min), a mixed 5-HT1A/5HT1B receptor agonist. None of the 5-HT antagonists tested gave any increase in food consumption in this model. Interestingly, the non-selective 5-HT receptor antagonist methysergide (360 micrograms/kg IV) reduced food intake. This effect was most noticeable at 3 h after injection. The 5-HT3 receptor antagonist ondansetron (IV 10 micrograms kg-1 min-1 over 15 min) and the peripheral 5-HT2 receptor antagonist xylamidine (IV 100 micrograms kg-1 min-1 over 10 min) failed to modify food intake. These results provide evidence for central serotonergic involvement in the control of feeding. However, this control system differs markedly in goats and rodents. Dexfenfluramine, 5-HTP and eltoprazine administered at similar dose rates to those used in the food intake experiments induced some clinical signs including inhibition of forestomach contractions. These results, together with our earlier in vivo and in vitro observations, suggest that the inhibitory effects of serotonin receptor agonists on forestomach contractions are due to interactions with both peripheral and central serotonergic receptors. The change in smooth muscle tension, which leads to a change in the signals transmitted via vagal afferents to the central nervous system, appears not to modify feeding behaviour in dwarf goats.

Role of central serotonergic (5-HT2) receptor in blood pressure regulation in rats.

To investigate the role of the serotonergic nervous system in blood pressure regulation, 5 micrograms of 5-hydroxytryptamine (5-HT) was given i.c.v. before and after 1 microgram of i.c.v. xylamidine or 200 micrograms of i.c.v. ketanserin or 200 micrograms of i.v. ketanserin in conscious Wistar Kyoto rats. Also i.v. (0.5, 1, 2 micrograms) or i.c.v. (1 microgram) phenylephrine (PHE) were given before and after 1 microgram of i.c.v. xylamidine. I.c.v. 5-HT elicited a consistent pressor response of approximately 27mmHg and slight decrease in heart rate. MAP and heart rate did not change after xylamidine or ketanserin. Whereas pressor response to i.c.v. 5-HT after i.c.v. ketanserin or i.c.v. xylamidine was suppressed, it did not change after i.v. ketanserin. Neither i.c.v. nor i.v. PHE-induced pressor response was influenced by i.c.v. xylamidine pretreatment. These data suggest that the central 5-HT2 receptor may subserve pressor function in rats.

Test-dependent changes in nociception after administration of the putative serotonin antagonist metitepin in mice

Intraperitoneal administration of the putative serotonin receptor antagonist metitepin (0.06–1.0 mg/kg) in mice induced dose-dependent antinociception in the increasing temperature hot-plate test and the formalin test, but elicited hyperalgesia in the tail-flick test. Reduced motor activity was observed after injection of the largest dose of metitepin, but did not influence the behavioural responses in the tests. Selective lesions of ascending serotonergic pathways induced by administration of the neurotoxin p-chloroamphetamine 5 and 6 days before testing (40 mg/kg each day) did not directly affect the responsiveness in any of the tests but enhanced the metitepin-induced antinociception in the hot-plate and formalin tests. The hyperalgesia in the tail-flick test was not affected by the lesions. The results suggest that metitepin may alter nociception in mice by exhibiting both agonist and antagonist properties on central serotonergic receptors.

Effect of meta-chlorophenylpiperazine (mCPP), a central serotonin agonist and vascular serotonin receptor antagonist, on blood pressure in SHR.

mCPP (meta-chlorophenylpiperazine) has agonist activity at some central serotonin receptors and antagonist activity at peripheral vascular 5HT2 receptors, both effects that have been postulated to lower blood pressure. mCPP (10 and 30 mg/kg, i.p. 1 hr after administration) increased serotonin and decreased 5-hydroxy-indolacetic acid (5-HIAA) brain concentrations and elevated serum corticosterone and prolactin, indications of central serotonergic agonist activities. The same doses of mCPP also antagonized vascular 5HT2 receptors as measured by blockade of pressor responses to serotonin in pithed rats. Although mCPP could be demonstrated to activate central serotonergic receptors and block peripheral vascular 5HT2 receptors, mCPP (10 and 30 mg/kg, i.p.) produced little effect on blood pressure in either the anesthetized or conscious spontaneously hypertensive rat (SHR) up to 1 hr after intraperitoneal administration. The findings are consistent with initial studies in normotensive humans that have not demonstrated a reduction in blood pressure clinically after mCPP in doses that produce elevations in serum cortisol and prolactin levels.

Effects of the putative 5-HT 1A receptor agonist 8-OH-2-(di-n-propylamino)tetralin on nociceptive sensitivity in mice

The ability of 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT) to alter nociceptive sensitivity in mice was studied using the tail-flick, hot-plate and formalin tests. Subcutaneous (SC) adminstration of 8-OH-DPAT (0.63–1.0 mg/kg) dose-dependently increased the temperature at which hindpaw lick occurre in a hot-plate test using slowly rising temperature and increased the latencies to hindpaw lick, but reduced the latencies to jump in a conventional hot-plate test. Intracerebroventricular (ICV) injections (0.25–1.0 μg) produced similar results in the conventional hot plate test. Following intrathecal (ITH) injections (0.25–1.0 μg), however, the latencies to hindpaw lick were elevated without any change in jump latencies. In the formalin test a low systemic dose of 8-OH-DPAT (0.63 mg/kg) elicited hyperalgesia, while hypoalgesia was found after a high dose (1.0 mg/kg). ICV injection of 1.0 μg produced hypoalgesia in the formalin test while the same dose injected ITH was without effect. 8-OH-DPAT did not alter tail-flick latencies, either by SC, ICV or ITH administration. Previous studies have shown that 8-OH-DPAT stimulates central serotonergic receptors, and shows selectivity for the 5-HT 1A recognition site. The present findings indicate an involvement of 5-HT 1A receptors in the processing of nociceptive information both at spinal anpraspinal sites. However, stimulation of 5-HT 1A receptors does not seem to affect spinal, nociceptive reflexes.

The effects of ketanserin on the hemodynamic response after intracerebroventricular administration of 5-hydroxytryptamine

Recently, the serotonergic nervous system has been receiving attention, as it participates in the hemodynamic regulation as well as in the pathogenesis of hypertension. The purpose of this experiment is to investigate the role of the central and peripheral serotonergic receptor in the hemodynamic responses induced by intracerebroventricular (i.c.v) administration of 5-hydroxytryptamine (5-HT). Eight week-old male spontaneously hypertensive rats (SHR) and age matched Wistar Kyoto rats (WKY) were used, and the experiment was performed under conscious and minimum restrained states. Five micrograms of 5-HT was given i.c.v. followed by i.c.v. administration of 200 micrograms ketanserin. Mean arterial pressure (MAP) and heart rate (HR) were observed continuously for 30 minutes. Then 5 micrograms of 5-HT was given i.c.v. again in the same rat (SHR -IC group, n = 7; WKY-IC group, n = 7). The rest of the rats received 200 micrograms of ketanserin intravenously (i.v.) after i.c.v. administration of 5 micrograms 5-HT, and the same amount of 5-HT was given i.c.v. after the ketanserin i.v. (SHR-IV group, n = 7; WKY-IV group, n = 6). Five-HT elicited a significant pressor response in all groups of rats and a slight non-significant increase in HR. In SHR-IC group and WKY-IC group, neither ketanserin i.c.v. nor the second 5-HT i.c.v. administration caused significant changes in MAP and HR. In SHR -IV group, i.v. ketanserin caused a significant decrease in MAP (-8.8 +/- 1.4 mmHg), but no significant change in MAP in WKY-IV group (-1.1 +/- 1.2 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Factors regulating central serotonergic receptor sensitivity

Factors regulating central serotonergic receptor sensitivity

Factors regulating central serotonergic receptor sensitivity

Factors regulating central serotonergic receptor sensitivity

A comparative electrophysiological and biochemical assessment of serotonin (5-HT) and a novel 5-HT agonist (MK-212) on central serotonergic receptors

The inhibitory effects of microiontophoretically-applied serotonin (5-HT) and 6-chloro-2[1-piperazinyl]pyrazine (MK-212) were examined on spontaneously firing somatosensory cerebral cortical neurons and dorsal raphe neurons in rats anesthetized with chloral hydrate. On cortical neurons, MK-212 caused only weak and variable inhibition of extracellularly recorded neuronal activity, compared to the effects of 5-HT. However, on raphe cells, MK-212 exerted potent inhibitory effects, equivalent to those observed with 5-HT. In contrast to the inhibitory actions of d-lysergic acid diethylamide (LSD) and 5-HT at presumed 5-HT autoreceptors, MK-212 did not affect the in vitro release of [ 3H]5-HT from slices of rat hypothalamus stimulated by methiothepin. These findings, coupled with previously reported behavioral, biochemical and electrophysiological effects of MK-212 may indicate that this novel serotonergic agonist uniquely discriminates between subsets of serotonergic receptors in the CNS.

Relation of Central α-Adrenoceptor and Other Receptors to the Control of Renin Secretion

The location and nature of the receptors in the brain on which clonidine acts to decrease renin secretion have been investigated in dogs. Clonidine was injected into the vertebral and carotid arteries, and its effects were compared with those of norepinephrine and epinephrine when injected into the third ventricle. It was also injected intravenously (IV) after transection of the brain stem and following treatment with intraventricular 6-hydroxydopamine. The results suggest that the renin-regulating receptors are located in the brain stem in a region different from the receptors mediating the depressor response, that they are α2-adrenoceptors, and that they are postsynaptic in location. Central α1-adrenoceptors appear to mediate increased renin secretion. Central serotonergic receptors also mediate increased renin secretion, but it is not known how the α1- and α2-adrenoceptors interact with the serotonergic systems. The location and nature of the receptors in the brain on which clonidine acts to decrease renin secretion have been investigated in dogs. Clonidine was injected into the vertebral and carotid arteries, and its effects were compared with those of norepinephrine and epinephrine when injected into the third ventricle. It was also injected intravenously (IV) after transection of the brain stem and following treatment with intraventricular 6-hydroxydopamine. The results suggest that the renin-regulating receptors are located in the brain stem in a region different from the receptors mediating the depressor response, that they are α2-adrenoceptors, and that they are postsynaptic in location. Central α1-adrenoceptors appear to mediate increased renin secretion. Central serotonergic receptors also mediate increased renin secretion, but it is not known how the α1- and α2-adrenoceptors interact with the serotonergic systems.