Effect of pindolol on thel-5-htp-induced increase in plasma prolactin and cortisol concentrations in man

Previous studies with direct-acting serotonin (5-HT) agonists and antagonists have demonstrated that stimulation of 5-HT_1A, 5-HT_1C and 5-HT₂ receptors may promote cortisol and prolactin (PRL) secretion in man. There is also evidence that 5-HT_1C/2 receptor stimulation contributes to the cortisol and PRL responses following administration of the 5-HT precursor,l-5-hydroxytryptophan (l-5-HTP), in man. To clarify the possible contribution of 5-HT_1A receptor stimulation to the ability ofl-5-HTP to stimulate cortisol and PRL secretion in man, the effect of pindolol, a beta adrenoceptor antagonist that is also a 5-HT_1A partial agonist, on thel-5-HTP-induced increases in cortisol and PRL secretion, was examined in 12 normal male volunteers. Pretreatment with pindolol, 30 mg orally, significantly inhibited the PRL but not the cortisol response tol-5-HTP, 200 mg PO. Pindolol alone decreased basal plasma PRL levels and increased basal plasma cortisol levels, possibly due to 5-HT_1A antagonist and agonists effects, respectively. These data, coupled with observations from other studies, suggest that thel-5-HTP-induced increase in PRL but not cortisol secretion requires 5-HT_1A receptor activation. PRL secretion due to 5-HT formed from exogenousl-5-HTP may require the availability of both intact 5-HT_1A and 5-HT₂/5-HT_1C receptors, since blockade of either receptor type inhibited the PRL response tol-5-HTP. The implication of this synergistic effect for interpretation of neuroendocrine studies involving the serotonergic system in man is discussed.     

Inhibitory effect of ritanserin on the 5-hydroxytryptophan-mediated cortisol,ACTH and prolactin secretion in humans

Oral administration of the serotonin (5-HT) precursorl-5-hydroxytryptophan (5-HTP), 200 mg, significantly increased plasma cortisol levels in man.l-5-HTP had no significant effect on the plasma prolactin levels. A borderline effect of 5-HTP on plasma ACTH levels was found. Pretreatment with the 5-HT₂/5-HT_1C antagonist ritanserin (5 mg, PO, b.i.d. for 2 days) significantly inhibited 5-HTP-induced cortisol secretion. Ritanserin had no effect on the basal plasma cortisol or prolactin levels. These data are suggestive that 5-HTP stimulates cortisol secretion in man via 5-HT₂/5-HT_1C receptor mechanisms.     

Clomipramine enhances prolactin and growth hormone responses to l-tryptophan

The effects of the 5-hydroxytryptamine (5-HT) uptake inhibitor clomipramine on the prolactin (PRL) and growth hormone (GH) responses to l-tryptophan (LTP) were assessed in six normal subjects. Oral administration of 20 mg clomipramine 2 h prior to LTP infusion (50 mg/kg) significantly enhanced both endocrine responses, suggesting that the increases in plasma PRL and GH produced by LTP are mediated by 5-HT pathways. These findings, taken together with previous observations that 5-HT₂ receptor antagonists do not attenuate the PRL response to LTP, suggest that the 5-HT-induced release of PRL in man may be mediated by 5-HT₁ receptors.     

L-Tryptophan and prolactin release: Evidence for interaction between 5-HT1 and 5-HT2 receptors

The effects of the selective 5-HT₂ receptor antagonist, ritanserin, on the growth hormone (GH) and prolactin (PRL) responses to intravenous L-tryptophan (LTP) were assessed in 8 normal volunteers. Administration of ritanserin (40 mg orally) prior to infusion of LTP (5 g) significantly enhanced the PRL responses but not those of GH. The results are consistent with previous proposals that the endocrine responses to LTP are mediated by 5-HT₁ rather than 5-HT₂ receptors and also suggest that 5-HT₂ receptor antagonists may increase certain 5-HT₁ mediated responses in the human brain.     

Ritanserin,a 5-HT2 receptor antagonist,does not modify ECT-induced prolactin release

The effect of pretreatment with ritanserin, a potent and selective serotonin-S₂ (5-HT₂) receptor antagonist, on the prolactin (PRL) response to electroconvulsive therapy (ECT) was studied in seven female patients suffering from major depressive disorder. They were given either ECT alone, or ECT after 10 or 20 mg ritanserin PO, and PRL was estimated in blood samples taken at times –5, 0, +5, +15, +30 and +60 min. The PRL responses after drug administration were not different from the responses after ECT alone. We conclude that, if serotonergic mechanisms are involved in the ECT-induced PRL increase, this neuroendocrine response seems to be rather a 5-HT₁ than 5-HT₂ receptor mediated event.     

The effect of lithium on 5-HT-mediated neuroendocrine responses and platelet 5-HT receptors

The effect of lithium on serotonin (5-HT)-mediated responses in the brain was assessed by measuring changes in the prolactin (PRL) and growth hormone (GH) responses to l-tryptophan (LTP) in eight normal subjects. On the 4th day of lithium treatment the PRL responses were significantly enhanced, and this enhancement was still apparent after 20 days' treatment. In contrast, GH responses to LTP were not altered. Lithium had no effect on platelet 5-HT content, platelet imipramine binding and platelet 5-HT receptor binding. The ability of lithium to enhance some aspects of brain 5-HT function may be important in its mode of action in manic-depressive illness and may be particularly relevant to its potentiation of the antidepressant effect of tricyclic antidepressants.     

Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat

Recently developed agents specifically acting on different 5-hydroxytryptamine (5-HT) receptor populations were used to analyze the functional role of 5-HT₂ receptor subtypes in the sleep-wakefulness cycle of the rat. The 5-HT₂ receptor antagonist ritanserin injected intraperitoneally (IP) (0.04–2.5 mg/kg) induced an increase in deep slow wave sleep (SWS2) duration at the expense of wakefulness (W), light slow wave sleep (SWS1) and paradoxical sleep (PS). The stimulation of 5-HT₂ receptors by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced a dose-related increase in W and a dose-dependent decrease in both SWS2 and PS. Pretreatment with ritanserin (0.16–2.5 mg/kg) or with cinanserin (2.5–5 mg/kg), another 5-HT₂ receptor antagonist, dose-dependently reversed the W enhancement and the SWS2 deficit produced by DOM, but not the PS deficit. Sleep-wakefulness alterations (increase in W and SWS1 combined with a suppression of SWS2 and PS) observed after IP injection of two putative 5-HT₁ receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (2.5 mg/kg) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) (0.63 mg/kg), were not modified by ritanserin pretreatment (0.16–2.5 mg/kg). These results further support the hypothesis that the serotonergic system plays an active role in the regulation of the sleep-wakefulness cycle in the rat and that 5-HT₂ receptors are involved in this action. In addition it is suggested that 5-HT₁ receptor subtypes are unlikely to interact with 5-HT₂ receptors in the sleep-wakefulness modulation mediated through 5-HT₂ receptors.     

Allosteric properties of the 5-HT2 receptor system of the rat tail artery

Summary We present an analysis of the interactions of 5-hydroxytryptamine (5-HT) and antagonists (methysergide, ketanserin, ritanserin) with the 5-HT₂ receptor system of strips of rat tail artery. The mode of action of ritanserin was also studied on strips of calf coronary arteries. 1. Ketanserin competitively antagonized 5-HT-induced effects in rat tail artery with an affinity (pK_B = 9.4 nmol/l) consistent with the assumption of an interaction of 5-HT and ketanserin at 5-HT₂-receptors. 2. Methysergide reduced to 50–60% the maximum response to 5-HT in rat tail artery. Concentration-effect curves for 5-HT became biphasic in the presence of methysergide with quickly and slowly developing contractions at low and high concentrations of 5-HT, respectively. 100 nmol/l ketanserin completely restored effects of 5-HT depressed by low concentrations of methysergide (< 10 nmol/l). Higher concentrations of methysergide in the presence of 100 nmol/l ketanserin again depressed the effects of 5-HT. 3. Ritanserin resembles methysergide by causing insurmountable antagonism of 5-HT-induced contractions which can be prevented by ketanserin in both rat tail artery and calf coronary artery. These results are inconsistent with competition between ritanserin and 5-HT for the 5-HT₂ receptor. 4. The findings are consistent with the assumption of an interaction of ketanserin and methysergide or ritanserin with an allosteric site near the 5-HT₂-receptor. Both methysergide and ritanserin appear to antagonize the effects of 5-HT through an allosteric site which is distinct from the 5-HT₂ receptor. Send offprint requests to A. J. Kaumann at the above address     

Dose-related effects of selective 5-HT2 receptor antagonists on slow wave sleep in humans

The effects of the selective 5-HT₂ receptor antagonists, ritanserin (1, 5 and 10 mg) and ICI 169,369 (50 and 100 mg), were studied on the sleep EEG of healthy volunteers using home-based Medilog 9000 cassette monitoring. Ritanserin (5 and 10 mg) produced a significant increase in slow wave sleep (SWS) while ICI 169,369 also increased SWS but only at a dose of 100 mg. These findings are consistent with the proposal that selective 5-HT₂ receptor blockade increases SWS in humans; however, the data cannot exclude involvement of the closely related 5-HT_1c receptor in this effect.     

Evidence that blockade of post-synaptic 5-HT1 receptors elicits feeding in satiated rats

The effects of nine central 5-HT antagonists on food intake in free feeding male rats were examined. The 5-HT₂ antagonists ritanserin and ketanserin and the selective 5-HT₃ antagonists ICS 205-930 and MDL 72222 had no effect on food intake. In contrast, the non-selective 5-HT antagonists metergoline, methiothepin, mesulergine, mianserin and methysergide (all of which have high affinity for various 5-HT₁ receptor subtypes), dose-dependently increased food intake during a 4-h daytime test. Furthermore, metergoline dose dependently increased food intake over a 24-h period. Suprisingly, mesulergine decreased food intake over a 24-h period at the same doses that increased daytime food intake. This may indicate that the increase in daytime feeding produced by mesulergine is a non-specific response. Although the antagonists used have varying degrees of selectivity for 5-HT receptor subtypes, the pattern of results suggests that postsynaptic 5-HT₁ receptors (possibly of the 5-HT_1C type) play an important role in the control of feeding in rats.     

Competitive antagonism by recognised 5-HT2 receptor antagonists at 5-HT1C receptors in pig choroid plexus

Summary The effects of several antagonists, known to interact with 5-HT₂ receptors (ritanserin, LY 53857, ICI 169,369, methysergide, mesulergine and ketanserin), were tested against 5-HT-stimulated production of inositol phosphate in pig choroid plexus, a 5-HT_1C receptor model. These antagonists produced dextral shifts of the concentration response curve to 5-HT in a parallel manner, without depressing significantly the maximal response. The following pA₂ values (in parentheses) were obtained: mesulergine (8.88), methysergide (8.85), LY 53857 (8.69), ritanserin (8.69), ICI 169,369 (7.86), and ketanserin (6.57). These pA₂ values were in good agreement with the pK_D values determined in radioligand binding studies performed in pig choroid plexus with [³H]mesulergine. The present data demonstrate that several drugs described as 5-HT₂ receptor selective antagonists (e.g. ritanserin, LY 53857 and ICI 169,369) are also potent, competitive and surmountable antagonists at 5-HT_1C receptors. Thus, the results provide further evidence for the pharmacological similarity of 5-HT_1C and 5-HT₂ receptors. However, in contrast to the situation described with methysergide, ritanserin and LY 53857 in several 5-HT₂ receptor models, none of these antagonists acted in a non-competitive or unsurmountable fashion at 5-HT_1C receptors. These results suggest, but do not firmly rule out, that at least in the presence of the drugs tested in the present study, 5-HT_1C receptors in the choroid plexus do not undergo an allosteric modulation; these findings are apparently in contrast to a model proposed previously for 5-HT₂ receptors (Kaumann and Frenken 1985, Naunyn-Schmiedeberg's Arch Pharmacol 328: 295–300) Send offprint requests to P. Schoeffter at the above address     

The behavioural responses to 8-OH-DPAT,ipsapirone and the novel 5-HT1A receptor agonist Bay Vq 7813 in the pig

Summary In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT_1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol-3(2H)one-1,1-dioxide), which act as partial agonists at 5-HT_1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg/kg i. m., ipsapirone, 2–5 mg/kg i.m., and Bay Vq 7813, 0.5–2 mg/kg i.m. or i.v., were head shakes. The potency of the three drugs to induce this behaviour correlated with their activity at 5-HT_1A receptors as determined by inhibition of forskolin-stimulated adenylate cyclase, substantiating that the head shake response has potential as a quantitative probe of in vivo receptor function. The 5-HT₂/5-HT_1C receptor antagonist ritanserin did not counteract the head shakes induced by ipsapirone, suggesting that neither 5-HT₂ nor 5-HT_1C receptors are involved in mediation of this response to this 5-HT_1A receptor agonist in pigs. Once daily administration of Bay Vq 7813 or ipsapirone for 3–5 days led to a reduction in the head shake response. 1-Pyrimidinylpiperazine (1-PP), a pharmacologically active metabolite shared by ipsapirone, Bay Vq 7813, and related pyrimidinylpiperazine derivatives, did not induce behavioural alterations in pigs. The data provide further evidence that marked species differences exist in functional responses to 5-HT receptor ligands. Send offprint requests to W. Löscher at the above address     

5-HT2a/2c receptor blockade by amesergide fully attenuates prolactin response tod-fenfluramine challenge in physically healthy human subjects

Prolactin responses tod-fenfluramine (d-FEN) challenge (0.5 mg/kg PO) were examined after pre-treatment with and without the 5-HT_2a/2c receptor antagonist amesergide in eight physically healthy male volunteers. Compared to pretreatment with placebo, pre-treatment with amesergide completely blocked the prolactin (PRL) response tod-FEN challenge in all subjects. These data are consistent with data demonstrating a complete blockade of the PRL response tod-FEN with the 5-HT_2a/2c receptor antagonist ritanserin, and suggest that the PRL response tod-FEN challenge in humans may largely be due to activation of the 5-HT_2a/2c receptor.     

Possible mechanism of action for the attenuation of ethanol intake induced by ritanserin in rats

The 5-HT₂ receptor antagonist, ritanserin, reduces alcohol intake in rats and the nucleus accumbens (NAC) has been proposed as a site of action for the drug. Recent microdialysis studies have shown that acute subcutaneous (SC) administration of ritanserin increases extracellular 5-HT levels in the NAC. The present study evaluated, in genetically heterogeneous rats with developed preference for 3% ethanol, whether the attenuation of ethanol intake induced by ritanserin might be related to its effect on the synaptic availability of 5-HT in the NAC. Damaging 5-HTergic neurons by intracerebroventricular infusion of 5,7-dihydroxytryptamine (5,7-DHT) abolished the effect of ritanserin on ethanol consumption. Injections of the 5-HT₃ receptor antagonist MDL 72222 into the NAC significantly reduced the inhibitory effect of SC injection of ritanserin, 1 mg/kg, and completely abolished the effect of ritanserin, 0.1 mg/kg. Subcutaneous injections of MDL 72222, 0.3 mg/kg 3times/day, suppressed the effect of SC ritanserin, 0.1 mg/kg. The present findings, together with those of previous experiments showing that the tryptophan hydroxylase inhibitor p-chlorophenylalanine abolishes the effect of ritanserin, support the hypothesis that its effect on ethanol intake may be due to increased synaptic availability of 5-HT into the NAC. Received: 22 March 1996/Final version: 10 July 1996     

The enhancement by lithium of the 5-HT1A mediated serotonin syndrome produced by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism

Administration of lithium chloride (10 mmol/kg on day 1 and 3 mmol/kg twice daily on subsequent days, SC) for 3–14 days enhances the components of the serotonin syndrome produced by 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) in the rat. The hypothermic response produced simultaneously was unaltered. Following lithium administration for 3 days the motor response to 5-methoxy,N,N-dimethyltryptamine was also facilitated. These data suggest that lithium administration enhances post-synaptic 5-HT receptor-mediated behavioural responses.(–)-Propranolol (20 mg/kg, IP) but not (+)-propranolol (20 mg/kg IP) fully antagonised the facilitated response to 8-OH-DPAT seen following lithium administration; ritanserin (200 g/kg, IP) was without effect. These findings favour a mechanism for the action of lithium involving the 5-HT_1A receptor.Depletion of 5-hydroxytryptamine (5-HT) with parachlorophenylalanine (PCPA, 300 mg/kg, IP on day 1 and 2 of lithium administration) did not prevent the facilitation by lithium of the response to 8-OH-DPAT. These data strengthen the suggestion that lithium has its effect on 5-HT_1A-mediated motor function by a post-synaptic action.By contrast, motor responses to the putative 5-HT_1B receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole (RU 24969) were unaltered by repeated lithium administration.     

Biochemical and behavioural effects of isamoltane,a β-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain

Summary The biochemical and behavioural effects of isamoltane, a \-adrenoceptor and 5-HT_1B receptor antagonist that has higher affinity for 5-HT_1B receptors than for 5-HTIA receptors, on 5-HT neurotransmission in the rat brain were examined. In binding experiments isamoltane was found to be about five times more potent as a ligand for the 5-HT_1B receptor than for the 5-HT_1A receptor (K_i values 21 and 112 nmol/l, respectively). Isamoltane increased the K⁺-evoked overflow of ³H from ³H-5-HT loaded slices of rat occipital cortex at 0.1 mol/l, consistent with inhibition of the terminal 5HT autoreceptor. In vivo, isamoltane significantly increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus and hippocampus indicating an increased 5-HT turnover with a maximal effect at 3 mg/kg s.c. A higher dose produced a less pronounced effect. This effect did not seem to be due to the -adrenoceptor blocking action of isamoltane since the -adrenoceptor antagonists, (–)-alprenolol, betaxolol or ICI 118,551 had no significant effects on 5-HT turnover at 5 mg/kg s.c. Isamoltane at 3 mg/kg s.c. induced the wet-dog shake response which was blocked by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. In contrast, the same response induced by the 5-HT₂ receptor agonist quipazine was not blocked by pretreatment with p-chlorophenylalanine. The wet-dog shakes evoked by isamoltane and quipazine were blocked by ritanserin, which indicates that 5-HT₂ receptors are involved in their expression. These observations indicate that isamoltane, by inhibiting the terminal 5-HT autoreceptors, increased the synaptic concentration of 5-HT to a level that induced a behavioural response. Send of offprint requests to S. B. Ross at the above addressThe present results have been presented in part at the Second IUPHAR Satellite Meeting on Serotonin, Basel, Switzerland, July 11–13, 1990     

Microinjection of propranolol into the dorsal periaqueductal gray causes an anxiolytic effect in the elevated plus-maze antagonized by ritanserin

The 5-HT_1A/1B receptor antagonist propranolol was injected into the dorsal periaqueductal gray (DPAG) of rats exposed to the elevated plus-maze in order to investigate the participation in anxiety of 5-HT mechanisms operating in this brain region. Microinjection ofd,l- orl-propranolol into the DPAG increased the percentage of total arm entries without affecting the total number of entries into either open or enclosed arms of the maze, an effect characteristic of anxiolytic drugs injected systemically. The doses of 5 nmoll-propranolol and 10 nmold,l-propranolol caused anxiolytic effects of comparable magnitude, while the doses of 2.5 nmol of the former and 5 nmol of the latter were ineffective. Therefore, thel-isomer is likely to be the main one responsible for the pharmacological activity observed. In addition, the anxiolytic effect of 10 nmold,l-propranolol was antagonized by 10 nmol of the 5-HT_2/1C receptor antagonist ritanserin, previously injected into the DPAG. The present as well as previously reported results suggest that the anxiolytic effect of propranolol injected into the DPAG is due to increased release of 5-HT acting on post-synaptic 5-HT₂ receptors, resultant from blockade of 5-HT_1B autoreceptors that inhibit amine release from serotonergic nerve endings.     

Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT2A receptor binding in the rat

Rationale Tryptophan depletion is used to reduce central serotonergic function and to investigate its role in psychiatric illness. Despite widespread clinical use, its effects on serotonin (5-HT) receptors have not been well characterized. Objective The aim of this study was to examine the effect of acute (ATD) and chronic tryptophan depletion (CTD) on free-plasma tryptophan (TRP), central TRP and 5-HT and brain 5-HT_1A and 5-HT_2A receptor binding in the rat. Methods TRP and 5-HT were measured by high-performance liquid chromatography and receptor levels determined by homogenate radioligand binding and in-vitro receptor autoradiography. Results Free-plasma TRP, central TRP and central 5-HT levels were significantly and similarly reduced by ATD and 1- and 3-week CTD compared to controls. ATD significantly reduced 5-HT_1A binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT_1A binding (frontal cortex, remaining cortex and hippocampus) or 5-HT_2A binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT_2A binding or postsynaptic 5-HT_1A binding. Furthermore, 3-week CTD did not significantly alter 5-HT_1A binding but significantly increased cortical 5-HT_2A binding without affecting striatal or hippocampal levels. In the CTD 1 and 3-week groups, rat body weight was significantly decreased as compared to controls. However, weight loss was not a confounding factor for decreased cortical 5-HT_2A-receptor binding. Conclusion ATD-induced reduction in somatodendritic 5-HT_1A autoreceptor binding may represent an intrinsic ‘homeostatic response’ reducing serotonergic feedback in dorsal raphe projection areas. In contrast, the increase in 5-HT_2A receptor after CTD may be a compensatory response to a long-term reduction in 5-HT.     

Participation of cyclooxygenase pathway in the vasoconstriction induced by 5-HT in the in situ autoperfused kidney of long-term diabetic rats

We attempted to characterize the 5-hydroxytryptamine (5-HT) receptor type/subtype and mediator mechanisms involved in the contractile effects of 5-HT in the in situ autoperfused kidney of long-term diabetic rats. Diabetes was induced in male Wistar rats by a single subcutaneous injection of alloxan. Intra-arterial (i.a.) bolus injection of 5-HT (0.00000125 to 0.1 μg/kg) increased renal perfusion pressure in a dose dependent way but did not affect the systemic blood pressure in long-term diabetic rats. The selective 5-HT₂ receptor agonist, α-methyl-5-HT, caused a local vasoconstrictor effect in the in situ autoperfused rat kidney similar to 5-HT. However, BW723C86, a selective 5-HT_2B receptor agonist, m-CPP (1-(3-chlorophenyl)piperazine), a selective 5-HT_2B/2C receptor agonist, the 5-HT₁ receptor agonist, 5-carboxamidotryptamine (5-CT), and the selective 5-HT₃ receptor agonist, 1-phenylbiguanide did not modify the renal perfusion pressure. In long-term diabetic rats, vasoconstriction elicited by 5-HT and α-methyl-5-HT was significantly decreased by ritanserin (a 5-HT₂ receptor antagonist), spiperone (a 5-HT_2A receptor antagonist), and the cyclooxygenase (COX) inhibitors, indomethacin (non-selective COX inhibitor), FR 122047 or nimesulide (selective COX-1 and COX-2 inhibitors, respectively), but was not modified by pretreatment with SB 206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2.b:4,5-b′]dipyrrole(1H)-carboxamide hydrochloride), a non-selective 5-HT_2C receptor antagonist, prazosin, propranolol, enalapril or losartan. The results of protein expression support these results: COX-1 and COX-2 are expressed in renal tissue. Inducible COX (COX-2) is overexpressed in long-term diabetes. Our data suggest that, in the in-situ autoperfused kidney of long-term diabetic rats, 5-HT vasoconstrictor action is mediated, through cyclooxygenase pathway, by local activation of 5-HT_2A receptors.     

Further pharmacological characterization of 5-HT2C receptor agonist-induced inhibition of 5-HT neuronal activity in the dorsal raphe nucleus in vivo

Background and purpose:

Recent experiments using non-selective 5-hydroxytryptamine (5-HT)_2C receptor agonists including WAY 161503 suggested that midbrain 5-HT neurones are under the inhibitory control of 5-HT_2C receptors, acting via neighbouring gamma-aminobutyric acid (GABA) neurones. The present study extended this pharmacological characterization by comparing the actions of WAY 161503 with the 5-HT_2C receptor agonists, Ro 60-0275 and 1-(3-chlorophenyl) piperazine (mCPP), as well as the non-selective 5-HT agonist lysergic acid diethylamide (LSD) and the 5-HT releasing agent 3,4-methylenedioxymethamphetamine (MDMA).

Experimental approach:

5-HT neuronal activity was measured in the dorsal raphe nucleus (DRN) using extracellular recordings in anaesthetized rats. The activity of DRN GABA neurones was assessed using double-label immunohistochemical measurements of Fos and glutamate decarboxylase (GAD).

Key results:

Ro 60-0175, like WAY 161503, inhibited 5-HT neurone firing, and the 5-HT_2C antagonist SB 242084 reversed this effect. mCPP also inhibited 5-HT neurone firing (∼60% neurones) in a SB 242084-reversible manner. LSD inhibited 5-HT neurone firing; however, this effect was not altered by either SB 242084 or the 5-HT_2A/C receptor antagonist ritanserin but was reversed by the 5-HT_1A receptor antagonist WAY 100635. Similarly, MDMA inhibited 5-HT neurone firing in a manner reversible by WAY 100635, but not SB 242084 or ritanserin. Finally, both Ro 60-0275 and mCPP, like WAY 161503, increased Fos expression in GAD-positive DRN neurones.

Conclusions and implications:

These data strengthen the hypothesis that midbrain 5-HT neurones are under the inhibitory control of 5-HT_2C receptors, and suggest that the 5-HT_2C agonists Ro 60-0175, mCPP and WAY 161503, but not LSD or MDMA, are useful probes of the mechanism(s) involved.