Number Of 5-HT2 Receptors Research Articles

Effect of acute and repeated administration of paracetamol on opioidergic and serotonergic systems in rats

We investigated the antinociceptive effect of paracetamol or morphine after repeated administration and the changes in the characteristics of central mu-, kappa- and 5-HT2 receptors. Male rats were injected twice a day for seven days with paracetamol (400 mg/kg, i. p.) or morphine (5 mg/kg, s. c.). The antinociceptive effect was evaluated 30 min after single and multiple doses of paracetamol and morphine through the hot-plate test. Binding techniques were used to evaluate the receptor characteristics in the frontal cortex. Both paracetamol and morphine induced an antinociceptive effect on day 1 but only paracetamol maintained this effect for seven days while morphine did not. The number of mu-opioid receptors decreased on days 1, 3, and 7 by a similar percentage after paracetamol administration (by 29, 31 and 34 %, respectively), while morphine produced a progressive decrease in comparison with controls (by 37, 49 and 60 %, respectively) and kappa-opioid receptors were unaffected. Both drugs similarly decreased the 5-HT2 receptor number on all days of treatment (by about 30 %). The opioidergic and serotonergic systems are involved in different ways in the induction and maintenance of antinociception after paracetamol or morphine treatment.

Effect of rofecoxib on nociception and the serotonin system in the rat brain

The purpose of the present study was to determine whether the antinociceptive activity of rofecoxib is mediated, at least in part, through changes in the brain serotonergic system. Male Wistar rats weighing 180-200 g (groups of eight) were subjected to the hot-plate and formalin tests after rofecoxib treatment. Cortical areas were removed for serotonin (5-HT) level, 5-HT2 and mu-receptor evaluation. Rofecoxib was administered orally at doses of 5, 10, 20 and 50 mg/kg for the time course evaluation in the hot-plate test (30, 60 and 120 min), and at the dose of 10 mg/kg for the formalin test and biochemical determinations. The tests performed were the hot-plate and the formalin assays. HPLC was used to determine 5-HT levels and radioligand-binding assays were utilized to evaluate the characteristics of 5-HT2 and mu-receptors. The data were analysed by ANOVA or Student's t test. The lowest active dose of rofecoxib in the hot-plate test was 10 mg/kg. The percentage of the maximum possible effect (%MPE) values were: control = 1.7+/-3.4; treated 23.4+/-6.5 (p<0.05). The same dose had a significant effect on both phases of the formalin test. Pretreatment with p-chlorophenylalanine (PCPA) significantly decreased the activity of rofecoxib in the hot-plate test. Rofecoxib treatment increased serotonin levels and decreased the maximum number of 5-HT2 receptors. 5-HT levels (ng/g) were: control = 240.1 +/- 28.5, rofecoxib = 326.1 +/- 19.9 in the frontal cortex. The characteristics of mu-receptors did not change. These results suggest that rofecoxib may exert its therapeutic effect, at least in part, through the central serotonergic system. The opioidergic system, on the other hand, seems to be unaffected.

Increased Platelet 5-HT2 Receptor Binding After Electroconvulsive Therapy in Depression

We investigated the effect of electroconvulsive treatment (ECT) on platelet 14C-serotonin uptake, 3H-paroxetine binding and 5-HT2 receptors in 12 patients (10 women and 2 men) unresponsive to pharmacological treatment. The mean numbers of ECTs given was 6.1 +/- 1.5. Mean treatment days was 14.6 +/- 3.8. Mean percent reduction in MADRS scores was 80.7 +/- 19.7 (p < 0.002). The number of 5-HT2 receptors increased significantly and uniformly after ECT (p = 0.011). There was no correlation between the degree of increase in 5-HT2 receptor densities and the reduction in MADRS scores after ECT. There was no difference in mean Bmax for platelet 3H-paroxetine binding before and after ECT. Bmax increased in six patients and decreased in six patients. The study shows an increase in platelet 5-HT2-receptor densities in depression after repeated ECT. Recognizing the similarities between 5-HT2 receptors in platelets and cerebral cortex, it seems reasonable to assume that a similar upregulation of cortical 5-HT2 receptors occurs after ECT.

76-9 - Increased platelet 5-HT 2 receptor binding after electroconvulsive therapy in depression

We investigated the effect of electroconvulsive treatment (ECT) on platelet 14C-serotonin uptake, 3H-paroxetine binding and 5-HT2 receptors in 12 patients (10 women and 2 men) unresponsive to pharmacological treatment. The mean numbers of ECTs given was 6.1 +/- 1.5. Mean treatment days was 14.6 +/- 3.8. Mean percent reduction in MADRS scores was 80.7 +/- 19.7 (p < 0.002). The number of 5-HT2 receptors increased significantly and uniformly after ECT (p = 0.011). There was no correlation between the degree of increase in 5-HT2 receptor densities and the reduction in MADRS scores after ECT. There was no difference in mean Bmax for platelet 3H-paroxetine binding before and after ECT. Bmax increased in six patients and decreased in six patients. The study shows an increase in platelet 5-HT2-receptor densities in depression after repeated ECT. Recognizing the similarities between 5-HT2 receptors in platelets and cerebral cortex, it seems reasonable to assume that a similar upregulation of cortical 5-HT2 receptors occurs after ECT.

Serotonin and opiate involvement in the antinociceptive effect of acetylsalicylic acid.

Acetylsalicylic acid (ASA), 400 mg/kg i.p., displayed antinociceptive activity in both the hot-plate and the formalin test. ASA significantly increased brain serotonin (5-HT) content and reduced the number of 5-HT2 receptors in cortical brain membranes 30 min after drug administration. Pretreatment with naloxone abolished the antinociceptive activity of both ASA and morphine in the hot-plate and formalin tests and prevented the increase in cerebral 5-HT concentration and the reduction in 5-HT2 receptors in cortical membranes induced by ASA. The serum salicylate concentrations were not affected by pretreatment with naloxone. These data indicate a central antinociceptive activity of ASA and suggest that ASA may exert its antinociceptive action through serotonergic and opiatergic pathways.

Tranylcypromine Does Not Enhance the Effects of Amitriptyline on 5-HT2Receptors in Rat Cerebral Cortex

The combination of amitriptyline (a tricyclic antidepressant) and tranylcypromine (a monoamine oxidase inhibitor) has been reported to be effective for treatment of refractory depressed patients. In the study reported here, this drug combination was compared with amitriptyline administered alone on the number and affinity of 5-HT2 receptors in rat brain. Male Sprague-Dawley rats were given vehicle (distilled water), amitriptyline (3.5 mg/kg/day), or tranylcypromine and amitriptyline (0.5 and 3.5 mg/kg/day, respectively) in combination subcutaneously via osmotic minipumps for 4, 10, or 28 days. A membrane fraction prepared from whole cortex was employed for studying binding to 5-HT2 receptors ([3H]ketanserin as the radioligand). The combination of amitriptyline and tranylcypromine produced a small but significantly greater down-regulation (decrease in number) of 5-HT2 sites than did amitriptyline alone after 10 days of administration; at 4 and 28 days, both amitriptyline and the drug combination had produced down-regulation, but there was not a significant difference between the two treatments. These data suggest that the antidepressant efficacy observed with this combination is not likely due to an enhanced effect on 5-HT2 receptors.

Modulation of central noradrenergic function by RS‐15385‐197

1. RS-15385-197, a highly potent and selective alpha 2-adrenoceptor antagonist, was examined in a variety of in vitro and in vivo functional tests to assess the selectivity of its interaction with central noradrenergic neurones in the rat. 2. In hypothalamic slices, RS-15385-197 was potent in augmenting K(+)-evoked release of [3H]-noradrenaline, with an EC50 of 9 nM. Idazoxan and yohimbine showed 100 fold less activity. This was due to its antagonist action at presynaptic alpha 2-adrenoceptors, as RS-15385-197 (10 microM), did not directly release [3H]-noradrenaline from cortical slices unlike reserpine (10 microM), and did not inhibit noradrenaline re-uptake into cortical synaptosomes. 3. In vivo, RS-15385-197 (0.5 mg kg-1, p.o.) increased levels of 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the cerebral cortex without modifying levels of 5-hydroxyindoleacetic acid (5-HIAA). This dose, but not a lower dose (0.1 mg kg-1, p.o.) caused beta-adrenoceptor down-regulation in the cortex when administered once daily for 14 days whereas 5-HT2 receptor number was unaltered, indicating a selective effect on noradrenergic transmission. 4. Selective depletion of cortical 5-HT by administration of p-chlorophenylalanine (PCPA; 100 mg kg-1, i.p. for 14 days) or 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms i.c.v.) prevented the beta-adrenoceptor down-regulation caused by RS-15385-197, indicating that a tonic 5-hydroxytryptaminergic input was required for it to elicit beta-adrenoceptor down-regulation. It was not possible to prevent the loss of activity of RS-15385-197 in these 5-HT-depleted animals by co-administration with the 5-HT1A partial agonist, 8-hydroxy-n-dipropyl aminotetralin (8-OH-DPAT, 0.3 mg kg-1, i.p. twice daily for final 3 days).5. At a dose (1 mg kg-1, p.o.) which completely prevented the hypoactivity produced by clonidine(0.1 mgkg-1, p.o.), RS-15385-197 did not affect behavioural stereotypy induced by 8-OH-DPAT(0.3 mg kg-1, s.c.). Similarly, following chronic dosing with the racemate, RS-15385-196 (3 mg kg-1,p.o., once daily for 14 days), there was no effect on the behavioural and hypothermic response to 8-OH-DPAT (0.5 mg kg-1, s.c.). Therefore, RS-1 5385-197 was selective for central alpha2-adrenoceptors over 5-HT1A receptors in in vivo functional tests.6. Thus, RS-15385-197 was highly selective in interacting with central noradrenergic neurones in the rat in vitro and in vivo. It is therefore currently the agent of choice for investigations of the role of alpha 2-adrenoceptors in the CNS.

Selective down-regulation of the agonist-dependent high affinity state of rat cortical 5-HT2 receptors following chronic treatment with amperozide.

Amperozide, a putative antipsychotic drug, is a selective serotonin 5-HT2 receptor antagonist with moderate affinity for the rat brain dopamine D2 receptor. The aim of the present study was to investigate the regulation of 3H-ketanserin binding of the rat cerebral cortex 5-HT2 receptor following chronic amperozide treatment. Amperozide (5 mg/kg/day p.o. for three weeks) significantly reduced the number of 5-HT2 receptors in rat cerebral cortex (172.9 +/- 8.3 vs 128.4 +/- 4.8 fmol/mg protein; p < 0.001, n = 5-6). There was no change of Kd of 3H-ketanserin. The agonist serotonin (5-HT) recognized two sites of 3H-ketanserin binding in membranes from both saline- and amperozide-treated rats as analysed by non-linear regression using LIGAND. The concentration of high affinity sites was reduced by 51% (53.1 +/- 2.9 vs 25.7 +/- 3.7 fmol/mg protein; p < 0.01, n = 3) while the amount of the low affinity sites remained unchanged. Serotonin displacement of 3H-ketanserin binding was sensitive to regulation by GTP. The present data indicated that GTP regulation was partially lost following chronic amperozide treatment. Displacement of the antagonists methysergide and amperozide were not affected by GTP. In conclusion, the down-regulation of the 5-HT2 receptors appears mainly due to a decrease of the serotonin-recognized high affinity state, and the loss of GTP sensitivity may indicate a decreased ability to form the high affinity state of the receptor. Such a molecular regulation might underlie an altered 5-HT responsiveness and thus be of therapeutic value.

Effect of ethanol administration and withdrawal on serotonin receptor subtypes and receptor-mediated phosphoinositide hydrolysis in rat brain.

The effect of short-term (15 days) and long-term (60 days) ethanol treatment and withdrawal on agonist-stimulated phosphoinositide (Pl) hydrolysis, serotonin receptor subtypes (5HT1A and 5HT2), and alpha 1-adrenergic receptors were studied in rat cerebral cortex. Short-term ethanol treatment had no significant effect on serotonin (5HT), norepinephrine (NE), and calcium ionophore (A23187)-stimulated [3H]-inositol-1-phosphate ([3H]-IP1) formation and 5-HT2 receptors as measured by 125I-lysergic acid diethylamide (125I-LSD) binding, in rat cerebral cortex. However, 15 days of ethanol treatment, followed by 24 hr of withdrawal resulted in a decrease in Bmax of 125I-LSD binding without significant change in KD, as well as a decrease in 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. 5HT1A and alpha 1-adrenergic receptors were determined by using [3H]-8-hydroxy-2-(di-N-propylamino)tetralin and [3H]-prazosin as radioligand, respectively. We also observed that long-term ethanol treatment had no significant effect on Bmax and KD of 5HT2, 5HT1A, and alpha 1-adrenergic receptors, as well as NE and A23187-stimulated [3H]-IP1 formation, but significantly decreased the 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. It is possible that a decrease in 5HT-induced PI turnover after long-term ethanol exposure may be due to a decrease in coupling of 5HT2 receptors to G protein or PLC enzyme, whereas the decrease in 5HT-induced PI turnover after withdrawal may be due to a decrease in functional 5HT2 receptor number.

Effect of ACTH, adrenalectomy and the combination treatment on the density of 5-HT2 receptor binding sites in neocortex of rat forebrain and 5-HT2 receptor-mediated wet-dog shake behaviors.

The effect of ACTH and/or adrenalectomy on serotonin (5-HT)2 receptor binding sites was evaluated in the neocortex of rat forebrain. One day after the adrenalectomy or sham operation, ACTH (50 micrograms/day) was injected subcutaneously into adult male SD rats for 10 consecutive days. Saturation analysis showed that subchronic ACTH treatment significantly increased the Bmax values for 3H-ketanserin binding without any change in the Kd values. Moreover, this ACTH-induced increase in the Bmax values was prevented by adrenalectomy. The concentrations of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) measured by HPLC-ECD were not altered by these manipulations. Ten-day administration of corticosterone (20 and 50 mg/kg) also increased 5-HT2 receptor density in the neocortex of rat forebrain. 5-HT2 (and 5-HT1C) receptor agonist, (+/-)DOI-induced wet-dog shakes in ACTH and/or adrenalectomy-treated rats were also examined. Ten-day administration of ACTH enhanced (+/-)DOI-induced wet-dog shakes and this increase was prevented by adrenalectomy. These results indicate that subchronic adrenocorticotropin-adrenal axis activation of rats increases both the number of 5-HT2 receptors in neocortex of forebrain and the wet-dog shake responses induced by (+/-)DOI.

Suicide risk and serotonin.

The accumulating research evidence for the psychobiological reconceptualization of suicidal behaviour is briefly reviewed, particularly regarding the serotonin hypothesis of suicide risk. The first suggestion of a link between suicide and serotonin came with the biochemical results from postmortem brain studies of suicide victims. Currently available research data suggest decreased brain stem levels of serotonin and 5-HIAA, altered distribution of presynaptic binding of the ligand 3H-imipramine to serotonin neurons and a region-specific increase in the number of postsynaptic 5HT2 receptors in the prefrontal cortex in suicide victims. Early CSF studies have indicated decreased CSF 5-HIAA in patients recently attempting suicide and follow-up studies of large samples of mood-disorder patients confirm the original hypothesis that low CSF 5-HIAA predicts suicide risk after attempted suicide. However, the clinical utility of these compelling biological correlates of suicide in the management of suicide risk in psychiatric patients will depend on the results of psychopharmacological treatment research targeting suicidal behaviour.

Changes in Dopamine 2 and Serotonin Receptors in Rat Brain after Long-Term Verapamil Treatment: Comparison of Verapamil and Lithium

Rat brain 5-HT2 and dopamine2 receptors were assessed following a chronic (3 weeks) administration of verapamil, lithium, and a combination of these two drugs. A significant increase in the number of 5-HT2 receptors was observed in the frontal cortex after the verapamil treatment, but the lithium and combined treatment had no effect on the densities of either binding sites. These data suggest that one or more of the mechanisms of the antimanic effect of verapamil may be involved in the change in 5-HT2 binding sites in a manner that is different from that of lithium.

5‐HT2 Receptors, Roles and Regulation

Stimulation of 5-HT2 receptors in mammals by agonists causes detrimental neurological, psychological, and circulatory effects. 5-HT2 antagonists block the elicited effects, but by themselves, they do not cause any apparent behavioral, neurological or subjective effects. However, 5-HT2 antagonists increase slow wave sleep and have a therapeutic action on impaired circulation, dysthymia, and negative symptoms in schizophrenia. Chronic treatment of rodents with various 5-HT2 antagonists was reported to cause an anomalous desensitization and 5-HT2 receptor down regulation. In this study we further investigated the 5-HT2 receptor regulation in vivo and in vitro by agonist and antagonist treatment. Treatment of rats with the 5-HT2 agonist, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) (2.5 mg/kg s.c., every 8 h), rapidly caused desensitization of the head twitch response (-20% and -80% after 2 and 4 injections) and a decrease in the number of frontal cortical 5-HT2 receptors labeled with [3H]ketanserin (-24% and -41%, 24 h after 2 and 4 injections). The receptor resynthesis/degradation revealed half-times of 5 days initially to 3 days in the later drug-free period. Administration of the antagonist ketanserin (2.5 mg/kg, s.c., every 8 h) 15 min before the agonist, antagonized the acute behavioral effect but did not prevent the 5-HT2 receptor down regulation after 4 treatments. In contrast, ketanserin by itself, given 4 times, caused a reduction in the Bmax-value of [3H]ketanserin binding by 19% and given 10 times it caused a reduction in the Bmax-values by 28% and 31% of [3H]ketanserin and [3H]DOB binding in the frontal cortex. Hence 5-HT2 receptors labeled by an antagonist and an agonist ligand were similarly decreased. In vascular smooth muscle cells in culture kept for at least 24 h in a serotonin-free medium before treatment, the 5-HT2 receptor mediated 5-HT-induced inositol phosphate formation, was rapidly desensitized by agonist treatment: -20% after 15 min and -80% after 1 h incubation of the cells with 10(-5) M 5-HT or DOM. After 2 h and 24 h treatment resensitization occurred with half-times of 5 h and 12 h, respectively. Pretreatment of the cells for 15 min or 24 h with 10(-7) M of the antagonists setoperone or ketanserin, followed by extensive washing, caused a reduction in the 5-HT-induced inositol phosphate formation by about 50% with setoperone and by 30% with ketanserin. Effects of 15 min and 24 h drug pretreatment were similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased number of 5HT2 receptors in the “learned helplessness” rat

Increased number of 5HT2 receptors in the “learned helplessness” rat

Evidence for the 5-HT Hypothesis of Suicide A Review of Post-mortem Studies

Although suicide was traditionally considered an extreme response to stress, with the most frequent stress being depressive illness, severity of depression does not distinguish those who commit suicide from non-suicide attempters. A biological role involving the serotonergic system, possibly associated with a genetic risk factor, has been postulated. Low levels of 5-HT and 5-HIAA have been found in post-mortem examinations of brain-stem tissues of suicide victims (levels in cortical tissue were generally normal). An increased number of 5-HT2 receptors was found in the pre-frontal cortex of suicide victims, such upregulation having been demonstrated in induced 5-HT deficiency states; 5-HT1A receptors were also increased. Receptor populations may be altered by chronic psychotropic medication; e.g. 5-HT2 downregulation occurs following administration of antidepressants. There is some indication that the adrenergic system may be involved as well, but this will require further study. Antidepressant drugs may be effective in preventing suicide in patients with non-depressive syndromes who exhibit suicidal behaviour.

P-171 - Changes in the number of 5-HT1A and 5-HT2 receptors under the conflict situation in rats

P-171 - Changes in the number of 5-HT1A and 5-HT2 receptors under the conflict situation in rats

Circadian studies of 5HT2 receptors: effects of clorgyline administration.

This paper demonstrates the application of an assay design that is particularly valuable for estimating receptor number (Bmax values) and affinity (Kd values) in many small samples of tissue. It is illustrated by its application to a study of possible circadian rhythms in the numbers of 5HT2 receptors in the rat cerebral cortex. The assay design involves the use of only two radioligand concentrations, the lower one being close to Kd (estimated from pilot studies) and the upper one close to 4 times this concentration. The results show that chronic clorgyline (1 mg/kg/day/28 days) administration to rats results in an 18% decrease in the number of cortical 5HT2 receptors (as measured by specific [3H]ketanserin binding). There is no significant circadian rhythm in receptor number in either the control or the MAOI-treated group. There is however, evidence of co-variation between the pairs of control animals housed in the same cage, and interestingly, that this effect is abolished by treatment with the MAOI.

Changes in cortical 5-HT2 receptors following 5-HTP and paroxetine administration in rats.

Rats were pretreated with either carbidopa (25 mg/kg 30 min previously) or phenelzine (50 mg/kg 18 h and 12 mg/kg 90 min previously) before being given 5-HTP (150 or 350 mg/kg) or paroxetine (12 mg/kg). In carbidopa-treated animals, 5-HTP (150 mg/kg) evoked many wet-dog shakes (WDS) without changing receptor numbers, but an increase in the dose of 5-HTP to 350 mg/kg paradoxically increased the number of cortical 5-HT2 receptors. The increase was reversed by pretreating the rats with haloperidol (5 mg/kg), but this did not occur withα-methyl-para-tyrosine (250 mg/kg 16 h and 4 h before carbidopa). Apomorphine (2 mg/kg) in phenelzine-treated rats and apomorphine (10 mg/kg) in untreated rats increased 5-HT2 receptor numbers. The reason for the failure of 5-HTP to rapidly down-regulate 5-HT2 receptors is not known, but is thought to depend in some complex way on the proportion of 5-HTP that is decarboxylated to 5-HT outside serotonergic neurons, thus affecting the dopaminergic mechanism. In phenelzine-treated rats, paroxetine produced a 5-HT-dependent syndrome, which included WDS, and a significant reduction in cortical 5-HT2 receptors within 3 h. WDS were unaffected by administration of propranolol (20 mg/kg) or pindolol (5 mg/kg), confirming that WDS were independent of 5-HT1A receptors. The reduction of 5-HT2 receptors was not associated with migration of the receptors into the “light-density fraction” of the cortex, isolated by density-gradient centrifugation.

Effect of chronic treatment with 5-HT1 agonist (8-OH-DPAT and RU 24969) and antagonist (isapirone) drugs on the behavioural responses of mice to 5-HT1 and 5-HT2 agonists.

The effects of chronic (14 day) administration to mice of the 5-HT1 agonists 8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) IH indole (RU 24969) on the hypothermic response to 8-OH-DPAT and the locomotor response to RU 24969 have been examined. Chronic administration of 8-OH-DPAT (5 mg kg-1, s.c.) resulted in an attenuated hypothermic response to this drug given subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) but did not alter the locomotor response to RU 24969. Chronic injection of RU 24969 (3 mg kg-1, i.p.) produced an attenuated locomotor response to this drug given i.p. or i.c.v. but not the hypothermic response to 8-OH-DPAT (0.5 mg kg-1, s.c.). Chronic administration of the putative presynaptic 5-HT1 antagonist isapirone (10 mg kg-1, i.p.) decreased the hypothermic response following 8-OH-DPAT injection but did not alter RU 24969-induced locomotion. Chronic treatment with 8-OH-DPAT (5 mg kg-1, s.c.) produced a modest enhancement of the 5-HT2 receptor-mediated head-twitch behaviour initiated by 5-hydroxytryptophan injection while chronic isapirone decreased this behavioural response. 5-HT2 receptor number in frontal cortex was unaltered by isapirone treatment but markedly decreased (34%) by chronic 8-OH-DPAT. These data suggest that chronic administration of the 5-HT1 agonists induces tolerance in their respective responses but not cross-tolerance, while chronic isapirone may down-regulate the 5-HT1A site in a matter analogous to that seen by 5-HT2 receptors following 5-HT2 receptor antagonists. 7 The data further demonstrate that chronic treatment with 8-OH-DPAT and isapirone alter postsynaptic 5-HT2 receptor function although 5-HT2 receptor number in the frontal cortex did not correlate with the behavioural change.

Effects of antidepressant drug combinations on cortical 5-HT 2 receptors and wet-dog shakes in rats

Rats pretreated with the monoamine oxidase inhibitor, phenelzine 18 h (46.8 mg/kg) and 90 min (11.7 mg/kg) previously or only 90 min (46.8 mg/kg) previously developed a 5-HT dependent syndrome (including wet-dog shakes, WDS) when given the 5-HT uptake inhibitor, paroxetine (11.6 mg/kg). After 2 h, but only in rats pretreated with 2 injections of phenelzine, there was a gradual reduction in the number of cortical 5-HT2 receptors, determined in vitro with [3H]ketanserin, and this was temporally related to a reduction in the frequency of WDS. Both effects (down-regulation and WDS) were prevented by the 5-HT2 receptor antagonist, pirenperone. A second injection of paroxetine at 3 h evoked additional WDS in rats pretreated with 1 injection of phenelzine but not in rats pretreated with 2 injections, suggesting that spinal 5-HT2 receptors might also have been down-regulated at the same time. Similar results were obtained when rats were pretreated instead with the selective MAO A inhibitor, clorgyline or when given either citalopram or fenfluramine instead of paroxetine. 5-HTP also evoked WDS in phenelzine-treated rats and markedly increased brain 5-HT concentration but only slowly down-regulated 5-HT2 receptors; in carbidopa-treated animals, 5-HTP was without effect on receptor numbers despite production of frequent WDS. It thus appears that drugs which increase synaptic 5-HT (as indicated by production of WDS) by interference with the release or reuptake of 5-HT more readily down-regulate 5-HT2 receptors than 5-HTP which does not directly affect these mechanisms.