Buspirone: effects on prolactin and growth hormone as a function of drug level in generalized anxiety

Certain evidence suggests that buspirone, a novel nonbenzodiazepine anxiolytic, may be a 5-HT1A serotonergic agonist and may antagonize postsynaptic dopaminergic receptors. The latter property raises questions regarding a dyskinesia- or extrapyramidal symptom-inducing potential. We monitored serum prolactin and growth hormone in 10 subjects with generalized anxiety disorder and 10 matched controls before and after 4 weeks of pharmacotherapy. A drug effect upon serotonin-modulated prolactin release or on the tubero-infundibular dopamine axis (prolactin; growth hormone) was negligible at clinically effective dosages of buspirone. Concomitant buspirone levels also failed to demonstrate any significant relationships.     

Effect of pindolol on endocrine and temperature responses to buspirone in healthy volunteers

Ten healthy subjects received buspirone (30 mg orally) with and without pre-treatment with the 5-HT1A receptor antagonist, pindolol (80 mg over 3 days). Following pindolol treatment the growth hormone and hypothermic responses to buspirone were significantly decreased. There was also a delay in the onset of the prolactin response to buspirone but the total amount of prolactin secretion, calculated as area under the curve, was not significantly reduced. The data suggest that the growth hormone and hypothermic responses to buspirone in humans are mediated by 5-HT1A receptors, but an explanation founded on pharmacokinetic factors cannot presently be excluded. Both this latter possibility and the lack of selectivity of pindolol for 5-HT receptors indicate the need for the further neuroendocrine studies of the mode of action of buspirone, preferably with more selective 5-HT1A receptor antagonists.     

Somatodendritic 5-HT(1A) autoreceptors mediate the anti-aggressive actions of 5-HT(1A) receptor agonists in rats: an ethopharmacological study with S-15535, alnespirone, and WAY-100635.

To elucidate the relative contribution of somatodendritic 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors in the specific anti-aggressive properties of 5-HT(1A) receptor agonists, the influence of the novel benzodioxopiperazine compound S-15535, which behaves in vivo as a competitive antagonist at postsynaptic 5-HT(1A) receptors and as an agonist at 5-HT(1A) autoreceptors, upon offensive and defensive aggression was investigated in wild-type rats using a resident-intruder paradigm. S-15535 exerted a potent dose-dependent decrease in offensive, but not defensive, aggressive behavior (inhibitory dose (ID)(50) = 1.11 mg/kg). This anti-aggressive profile was roughly similar to that of the potent pre- and postsynaptic 5-HT(1A) full agonist alnespirone (ID(50) = 1. 24). The drug's profound anti-aggressive actions were not accompanied by sedative side effects or signs of the "5-HT(1A) receptor-mediated behavioral syndrome," which are characteristically induced by prototypical 5-HT(1A) receptor agonists like 8-OH-DPAT and buspirone. The selective pre- and postsynaptic 5-HT(1A) antagonist WAY-100635, which was inactive given alone, abolished the anti-aggressive effects of S-15535 and alnespirone, thereby confirming the involvement of 5-HT(1A) receptors. Furthermore, combined administration of S-15535 and alnespirone elicited an additive anti-aggressive effect, providing further support for somatodendritic 5-HT(1A) receptor involvement. Finally, the postsynaptic 5-HT(1A) antagonistic properties of S-15535 were confirmed by showing blockade of the alnespirone-induced hypothermia, a postsynaptic 5-HT(1A) mediated response in the rat. These data provide extensive evidence that the anti-aggressive effects of 5-HT(1A) receptor agonists are expressed via their action on somatodendritic 5-HT(1A) autoreceptors, thereby most likely attenuating intruder-activated serotonergic neurotransmission.     

5-Hydroxytryptamine1A receptor-mediated effects of buspirone, gepirone and ipsapirone

The effects of the nonbenzodiazepine anxiolytic agents, buspirone, gepirone and ipsapirone on body temperature and corticosterone secretion were studied in the rat. The administration of buspirone, gepirone and ipsapirone resulted in dose-related decreases in body temperature and increases in the plasma concentration of corticosterone. Spiperone produced a dose-related inhibition of the hypothermic and corticosterone responses to gepirone. Spiperone also inhibited ipsapirone-induced changes in body temperature and hormone secretion. Although spiperone also blocked the buspirone-induced stimulation of corticosterone, it did not attenuate the hypothermic response to buspirone at the dose tested. (-)-Pindolol, a potent 5-HT1A antagonist, prevented gepirone- and ipsapirone-induced hypothermia and corticosterone secretion. (-)-Pindolol also blocked the hypothermic but not the corticosterone response to buspirone. Ketanserin, a 5-HT2 antagonist, did not inhibit the hypothermic or corticosterone responses produced by these novel anxiolytic agents. It is concluded that buspirone, gepirone and ipsapirone produce hypothermia and increase plasma concentrations of corticosterone by activating 5-HT1A receptor mechanisms.     

Food intake, neuroendocrine and temperature effects of 8-OHDPAT in the rat

Administration of 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT) to rats produced dose-dependent decreases in food intake and hypothermia, increases in plasma prolactin and corticosterone, and a decrease in plasma growth hormone. 8-OHDPAT administration also induced the serotonin behavioral syndrome at all doses. Pretreatment with metergoline did not affect the 8-OHDPAT-induced behavioral syndrome or decrease in food intake but attenuated the prolactin increase and, furthermore, potentiated 8-OHDPAT-induced hypothermia. Pretreatment with ritanserin or naloxone did not modify 8-OHDPAT-induced changes in food intake, temperature or prolactin. Similarly, pretreatment with phenoxybenzamine, propranolol, clonidine, haloperidol and methiothepin also did not attenuate 8-OHDPAT-induced decreases in food intake. Administration of pindolol alone produced hyperthermia, decreased food intake and enhanced prolactin secretion. Pindolol thus appears to act as a partial 5-HT agonist in addition to being an antagonist at central 5-HT receptors.     

Neuroendocrine responses to the serotonin2 agonist DOI are differentially modified by three 5-HT1A agonists.

Evidence suggests that activation of 5-HT1A receptors leads to inhibition of 5-HT2-mediated behavior. The purpose of this study was to investigate the interaction between 5-HT1A and 5-HT2 receptor-mediated hormone secretion. Rats were pretreated with the 5-HT1A agonists buspirone (0, 0.5, 2.0 mg/kg, i.p.), 8-OH-DPAT (0, 0.05, 0.2 mg/kg, s.c.) or ipsapirone (0, 1.0, 2.5 mg/kg, i.p.), 45 min before decapitation. The 5-HT2 agonist DOI was administered (0-10 mg/kg, i.p.) 15 min after injection of the 5-HT1A agonists. The three 5-HT1A agonists differentially altered the DOI-induced increase of concentrations of hormone in plasma. None of the three 5-HT1A agonists influenced the basal levels of renin, ACTH and prolactin but 8-OH-DPAT and buspirone increased the basal level of corticosterone in plasma. Also, 8-OH-DPAT increased the effects of DOI on the concentration of ACTH in plasma but ipsapirone and buspirone did not. None of the 5-HT1A agonists significantly affected DOI-induced increase of concentration of corticosterone in plasma. Buspirone and 8-OH-DPAT potentiated the effect of DOI on prolactin in plasma, but ipsapirone did not. Ipsapirone potentiated the effect of DOI on the concentration of renin in plasma but this effect was not observed in 8-OH-DPAT- and buspirone-pretreated rats. The results do not support the hypothesis for a functional interaction between 5-HT1A and 5-HT2 receptors, since the three 5-HT1A agonists did not have the same influence on the hormonal effects of DOI.     

EEG effects of buspirone and pindolol: a method of examining 5-HT<Subscript>1A</Subscript> receptor function in humans

Rationale. An involvement of 5-HT_1A receptors is postulated in the pathophysiology of affective disorders and mechanism of action of antidepressants. Methods for studying their functional integrity in humans are, however, limited. Preliminary data suggests that activation of somatodendritic 5-HT_1A receptors cause a negative shift in the EEG frequency spectrum. Animal research suggests that pindolol is an agonist at these receptors but an antagonist at postsynaptic 5-HT_1A receptors. Objective. We postulated that while pindolol would antagonise known postsynaptic mediated neuroendocrine responses to the 5-HT_1A agonist buspirone, both drugs would have a similar effect on the EEG frequency spectrum. Methods. Fourteen healthy men were administered placebo or pindolol (20 mg orally) 90 min before placebo or buspirone (30 mg orally) in a double blind cross-over study. Plasma prolactin and growth hormone were assayed and EEGs recorded before and after drug administration. Results. A significant negative shift in the EEG frequency spectrum was found for both buspirone and pindolol, with the combination producing a similar effect to each drug alone. In contrast, the neuroendocrine response to buspirone was significantly attenuated by pindolol. Conclusions. The data obtained are consistent with the EEG effects of buspirone and pindolol being mediated by somatodendritic 5-HT_1A receptors, in contrast to the neuroendocrine response, which is known to be mediated by postsynaptic receptors. The development of this novel method of assessing somatodendritic 5-HT_1A receptors in humans is a potentially important advance which may allow the testing of hypotheses of its involvement in depression and response to antidepressants. Electronic Publication     

The interaction of serotonin depletion with anxiolytics and antidepressants on reticular-elicited hippocampal RSA

Hippocampal rhythmical slow activity (RSA) can be elicited by stimulation of the midbrain reticular formation. Buspirone, chlordiazepoxide and imipramine are all anxiolytic and have all been shown to decrease the frequency of RSA. All these compounds have been suggested to affect, directly or indirectly, 5-HT metabolism and function. The present experiments tested the possibility that buspirone, chlordiazepoxide and imipramine reduce RSA frequency via 5-HT1A autoreceptors. Rats received buspirone (10 mg/kg), chlordiazepoxide (5 mg/kg) and imipramine (30 mg/kg) after 5-HT depletion with p-chlorophenylalanine (PCPA, 100 mg/kg/day for 3 days or 350 mg/kg/day for 2 days) or after pretreatment with 5-HTP (40 mg/kg, to replete 5-HT) as well as pCPA. The frequency-reducing effects produced by buspirone and chlordiazepoxide were unchanged by either dose of pCPA, whereas the frequency-reducing effect of imipramine was completely eliminated by the high dose of pCPA. Pindolol, but not beta-blockers (a combination of metoprolol and ICI118 551), was able to block the effect of imipramine on RSA frequency. Pindolol has been reported to block the effects of buspirone but not chlordiazepoxide. These data suggest that: (1) buspirone obtains its frequency-reducing effects via pre- or post-synaptic 5-HT1A receptors rather than 5-HT1A autoreceptors; (2) chlordiazepoxide obtains its frequency-reducing effect via benzodiazepine receptors and GABA with no direct or indirect involvement of 5-HT systems; and (3) imipramine obtains its frequency-reducing effect by increasing the availability of 5-HT at 5-HT1A receptors which are not autoreceptors.     

Involvement of somatodendritic 5-HT(1A) receptors in Delta(9)-tetrahydrocannabinol-induced hypothermia in the rat

Previously, it has been reported that modulating serotonergic neurones by use of selective serotonin reuptake inhibitors (SSRI) can alter the hypothermic response produced by Delta(9)-tetrahydrocannabinol (Delta(9)-THC). The aim of the present study was to investigate the effect that activation or antagonism of 5-hydroxytryptamine (5-HT(1A)) receptors has on Delta(9)-THC-induced hypothermia. Delta(9)-THC (0.5, 2 and 5 mg/kg iv) decreased body temperature in a dose-related manner. Whilst having no significant effect on body temperature when administered 40 min prior to vehicle injection, the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY 100635; 1 mg/kg sc) significantly potentiated the hypothermia produced by 2 and 5 mg/kg Delta(9)-THC. In order to investigate whether this effect was due to antagonism at somatodendritic autoreceptors in midbrain raphe nuclei, WAY 100635 or the 5-HT(1A) agonist 8-hydroxy-(di-n-propylamino) tetralin (8-OH-DPAT) was microinjected into either the median raphe nuclei (MRN) or dorsal raphe nuclei (DRN) 40 min prior to Delta(9)-THC injection. Following microinjection into the DRN, neither WAY 100635 (0.5 nmol/0.5 microl/10 s) nor 8-OH-DPAT (15.2 nmol/0.5 microl/10 s) had any significant effect on Delta(9)-THC-induced hypothermia. However, WAY 100635 when microinjected into the MRN significantly potentiated Delta(9)-THC-induced hypothermia, and 8-OH-DPAT microinjected into the MRN significantly inhibited Delta(9)-THC-induced hypothermia. It is suggested from these studies that the potentiation of Delta(9)-THC-induced hypothermia by WAY 100635 when administered peripherally is mainly due to antagonism at somatodendritic 5-HT(1A) autoreceptors in the MRN.     

Serotonergic mechanisms in anxiolytic effect of tandospirone in the Vogel conflict test.

To clarify which 5-HT1A receptors, autoreceptors located in the raphe nuclei or post-synaptic receptors in the forebrain areas receiving a 5-HT input, mediate the anticonflict action of tandospirone (a 5-HT1A receptor-related anxiolytics), the behavioral effects of tandospirone were studied in 5,7-dihydroxytryptamine (5,7-DHT) treated rats. By measuring both monoamines and their metabolite levels and densities of [3H]8-OH-DPAT binding in 5,7-DHT-treated rat brain, we confirmed that pretreatment with 5,7-DHT destroyed 5-HT neurons selectively without affecting postsynaptic 5-HT1A receptors located on the postsynaptic neurons. This selective destruction produced no significant changes in the drinking behavior of rats in either punished or unpunished sessions of the Vogel conflict test. Furthermore, this destruction altered neither the effect of tandospirone on punished responding in this procedure nor the potency of tandospirone to induce a flat body posture in rats, which is known as the "serotonin behavioral syndrome". These results suggested that the anticonflict action of tandospirone may be produced, at least in part, by binding to postsynaptic 5-HT1A receptors and activating them as agonists, and not to 5-HT1A autoreceptors located on the cell bodies of 5-HT neurons.     

Effects of buspirone on dopamine dependent behaviours in rats

Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.     

Pharmacology of flibanserin

Flibanserin has preferential affinity for serotonin 5-HT(1A), dopamine D(4k), and serotonin 5-HT(2A) receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT(1A) agonist, a very weak partial agonist on dopamine D(4) receptors, and a 5-HT(2A) antagonist. In vivo flibanserin binds equally to 5-HT(1A) and 5-HT(2A) receptors. However, under higher levels of brain 5-HT (i.e., under stress), flibanserin may occupy 5-HT(2A) receptors in higher proportion than 5-HT(1A) receptors. The effects of flibanserin on adenylyl cyclase are different from those of buspirone and 8-OH-DPAT, two other purported 5-HT(1A) receptor agonists. Flibanserin reduces neuronal firing rate in cells of the dorsal raphe, hippocampus, and cortex with the CA1 region being the most sensitive in the brain. Flibanserin-induced reduction in firing rate in the cortex seems to be mediated through stimulation of postsynaptic 5-HT(1A) receptors, whereas the reduction of the number of active cells seems to be mediated through dopamine D(4) receptor stimulation. Flibanserin quickly desensitizes somatic 5-HT autoreceptors in the dorsal raphe and enhances tonic activation of postsynaptic 5-HT(1A) receptors in the CA3 region. Flibanserin preferentially reduces synthesis and extracellular levels of 5-HT in the cortex, where it enhances extracellular levels of NE and DA. Flibanserin displays antidepressant-like activity in most animal models sensitive to antidepressants. Such activity, however, seems qualitatively different from that exerted by other antidepressants. Flibanserin seems to act via direct or indirect stimulation of 5-HT(1A), DA, and opioid receptors in those animal models. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses.     

Effect of sustained administration of the 5-HT1A receptor agonist flesinoxan on rat 5-HT neurotransmission.

A short-term treatment with flesinoxan (2.5 and 5 mg/kg/day x 2 days, s.c., delivered using osmotic minipumps) decreased significantly the spontaneous firing activity of dorsal raphe serotonin (5-HT) neurons of male Sprague-Dawley rats. This firing was still decreased following 1 week of treatment with flesinoxan (5 mg/kg/day) but was back to normal after a treatment of 2 weeks. This recovery of firing was associated with a 3-fold shift to the right of the dose-response curve of the effect of the 5-HT autoreceptor agonist lysergic acid diethylamide on the firing activity of 5-HT neurons, indicating a desensitization of somatodendritic 5-HT1A autoreceptors. At the postsynaptic level, long-term treatment with flesinoxan (5 mg/kg/day x 14 days) did not modify the responsiveness of dorsal hippocampus CA3 pyramidal neurons to microiontophoretic applications of 5-HT and flesinoxan nor to endogenous 5-HT released by the electrical stimulation of the ascending 5-HT pathway, indicating an unchanged sensitivity of postsynaptic 5-HT1A receptors. Finally, in rats treated with flesinoxan for 2 weeks, the administration of the selective 5-HT1A receptor antagonist (N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohe xanecarboxamide trihydroxychloride (WAY 100635, 100 and 500 microg/kg, i.v.) did not increase the firing activity of dorsal hippocampus CA3 pyramidal neurons, thus failing to reveal an enhanced tonic activation of postsynaptic 5-HT1A receptors as for other antidepressant drugs, including the 5-HT1A receptor agonist gepirone. The marked potency and the long dissociation constant of flesinoxan for the 5-HT1A receptors may account for the latter discrepancy. In conclusion, as for selective 5-HT re-uptake inhibitors, monoamine oxidase inhibitors and 5-HT1A receptor agonists, flesinoxan produced most of the adaptive changes exerted by these antidepressant drugs on the 5-HT system.     

Effect of reserpine on behavioural responses to agonists at 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor subtypes.

Rats were given a single dose of reserpine (5 mg/kg s.c.) and behavioural responses to agonists at 5-HT receptor subtypes compared with those of control animals 21 days later. The following effects of activating postsynaptic 5-HT1A receptors by the agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were significantly increased: tail-flick, reciprocal forepaw treading, flat body posture. The hyperphagic effect of activating presynaptic 5-HT1A receptors by 8-OH-DPAT tended to increase and hypothermia on activating postsynaptic 5-HT1A sites tended to decrease. The hyperlocomotor effect of activating 5-HT1A sites also tended to decrease possibly as a result of a dependence of this response on the known depletion of catecholamines by reserpine. Head shakes on activating 5-HT2A receptors by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and two effects of activating 5-HT2C receptors by 1-(3-chlorophenyl) piperazine (mCPP) were significantly increased (hypophagia, anxiety) and a third effect, hypolocomotion tended to increase but hypophagia on activating postsynaptic 5-HT1B receptors by CP-94, 253 was significantly attenuated. The results are discussed with particular reference to altered 5-HT function in depression.     

Novel anxiolytics discriminate between postsynaptic serotonin receptors mediating different physiological responses on single neurons of the rat hippocampus

Summary The effects of buspirone on hippocampal pyramidal cells of the CA1 region were examined by means of intracellular recordings in in vitro hippocampal brain slices. Bath administration of buspirone elicited a long lasting hyperpolarization which was mediated by an increase in potassium conductance and resembled the hyperpolarizing component of the response to 5-HT (5-hydroxytryptamine). Buspirone, however, failed to mimic the depolarizing action of 5-HT or to reduce the calcium-activated afterhyperpolarization. Quantitative comparisons of the hyperpolarizing responses of 5-HT and buspirone revealed that the maximal hyperpolarization induced by buspirone was significantly smaller than that induced by 5-HT. Since the buspirone induced hyperpolarization was also accompanied by a surmountable antagonism of 5-HT responses, these results indicate that buspirone behaves as a partial agonist at a subpopulation of 5-HT receptors in the CA1 region of the hippocampus. Administration of the buspirone congeners gepirone and isapirone also elicited a hyperpolarization and reduced 5-HT responses, although they lack anti-dopaminergic activity, indicating that the effects observed with buspirone are unlikely to be mediated through dopamine receptors. These results indicated that novel anxiolytics can discriminate between functional 5-HT receptors. In conjunction with previous biochemical and electrophysiological studies, the present results suggest that their administration might alter the balance of serotonergic actions on postsynaptic neurons. Send offprint requests to R. Andrade at the above address     

Pharmacological analysis of the hypothermic effects of NAN-190 and its analogs,postsynaptic 5-HT1A receptor antagonists,in mice

In this study, we examined the role of 5-hydroxytryptamine (5-HT)1A and alpha1-adrenergic receptors in the hypothermia induced by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190) and its analogs, 1-(2-methoxyphenyl)-4-[(4-succinimido)butyl]piperazine (MM77) and trans-1(2-methoxyphenyl)-4-[4-(2-phthalimido)cyclohexyl]piperazine (MP245), which--like NAN-190--showed a high affinity for 5-HT1A and alpha1-adrenoceptors. Administration of NAN-190 (a partial agonist of presynaptic and an antagonist of postsynaptic 5-HT1A receptors and alpha1-adrenoceptors), MM77 and MP245 (antagonists of postsynaptic 5-HT1A receptors), as well as 8-OH-DPAT (a 5-HT1A agonist) and prazosin (an alpha1-adrenoceptor antagonist) induced a dose-dependent hypothermia in mice. The silent antagonist of 5-HT1A receptors, WAY 100635, which abolished the hypothermic effect of 8-OH-DPAT, inhibited the hypothermia induced by NAN-190 administered at a dose of 1 mg/kg (but not 2 mg/kg) and by MP245 (0.5 and 1 mg/kg), but failed to change the MM77 (1 and 4 mg/kg)-induced decrease in body temperature in mice. The alpha1-adrenoceptor agonist St 587, which reduced the hypothermic effect of prazosin, inhibited the decrease in body temperature evoked by NAN-190 at the higher dose and by MP245 at both the doses used, but did not affect the MM77-induced hypothermia in mice. The obtained results suggest that the hypothermia in mice induced by NAN-190 and its constrained analog MP245 is connected with stimulation of 5-HT1A receptors and with blockade of alpha1-adrenoceptors, participation of these receptors not being equivalent, though. The origin of the hypothermia evoked by MM77 is still unknown.     

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--I. Effects of acute and long-term administration of tandospirone on serotonin neurotransmission.

The acute and long-term effects of the antidepressant/anxiolytic selective 5-HT1A receptor ligand, tandospirone (SM-3997) on 5-HT neurotransmission were assessed using single-cell extracellular recording in chloral hydrate-anaesthetized rats. The acute intravenous administration of tandospirone decreased the firing rate of 5-HT neurones of the dorsal raphe (ED50 = 9.1 +/- 1.1 micrograms/kg). A treatment with tandospirone for 2 days (10 mg/kg/day, s.c.), markedly reduced the firing activity of 5-HT neurones of the dorsal raphe; this was followed by a partial recovery after 7 days and by complete recovery after 14 days of administration of tandospirone. After treatment with tandospirone for 14 days (10 mg/kg/day, s.c.), the responsiveness of 5-HT neurones to the intravenous administration of LSD was reduced, suggesting that somatodendritic 5-HT autoreceptors had desensitized. The depressant effects of microiontophoretically-applied tandospirone and 5-HT, on the firing activity of CA3 pyramidal neurones in the hippocampus were blocked by the intravenous injection of the 5-HT1A receptor antagonist, BMY-7378. The depressant effect of microiontophoretically-applied 5-HT onto these same neurones was markedly reduced during concurrent background application of tandospirone, suggesting that the latter acted as a partial agonist at postsynaptic 5-HT1A receptors. The sustained administration of tandospirone for 14 days (10 mg/kg/day, s.c.) altered neither the effectiveness of microiontophoretically-applied 5-HT and tandospirone nor that of endogenous 5-HT, released by the electrical simulation of the afferent 5-HT pathway, in suppressing the firing activity of pyramidal neurones in the hippocampus, suggesting that postsynaptic 5-HT1A receptors had not desensitized. Furthermore, long-term treatment with tandospirone did not alter the sensitivity of the terminal 5-HT autoreceptor. It is thus concluded that desensitization of somatodendritic 5-HT autoreceptors permits 5-HT neurones to regain their physiological rate of firing during long-term treatment with tandospirone and, consequently, to release a normal amount of 5-HT into the synaptic cleft. This, combined with the sustained activation of normosensitive postsynaptic 5-HT1A receptors by tandospirone, during such a treatment, should result in an enhanced tonic activation of postsynaptic 5-HT1A receptors.     

Dual effect of local application of nitric oxide donors in a model of incision pain in rats

The effects of chronic administration of the mixed serotonin [5-hydroxytryptamine (5-HT)]/norepinephrine re-uptake inhibitor venlafaxine (5 mg/kg daily by osmotic minipump for 28 days) on the sensitivity of somatodendritic 5-HT(1A) autoreceptors on serotonergic neurons innervating the hypothalamus, and on 5-HT(1B) autoreceptors in both hypothalamus and hippocampus, were determined using in vivo microdialysis in freely moving rats. Venlafaxine induced a reduction in sensitivity of 5-HT(1B) autoreceptors in hypothalamus, but did not affect the sensitivity of 5-HT(1A) autoreceptors, or of 5-HT(1B) autoreceptors in hippocampus. The corticosterone and oxytocin responses to the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.05 or 0.2 mg/kg), a measure of postsynaptic 5-HT(1A) receptor activity in the hypothalamus, were reduced in animals administered 5 or 10 mg/kg venlafaxine daily by intraperitoneal injection for 21 days. This desensitization of post-synaptic 5- HT(1A) receptors in the hypothalamus may be a consequence of increased 5-HT levels induced by desensitization of the presynaptic 5-HT(1B) receptors. These results taken together with those of previous studies suggest that the hypothalamus might be an important site of drug action, and that venlafaxine has an overall mechanism similar to that of selective serotonin re-uptake inhibitors.     

Hormonal response to buspirone is not impaired in major depression

It has been suggested that interactions between hypothalamic pituitary adrenal (HPA) axis and serotonin-1A (5-HT(1A)) receptor system are involved in the pathophysiology of major depression. Pharmacologic challenge test with 5-HT(1A) receptor agonists is a useful approach to study the sensitivity of 5-HT(1A) receptors in depressed patients and the interaction of these systems. A cross-sectional case-control study was designed to assess the effect of the 5-HT(1A) receptor agonist, buspirone, on 5-HT(1A) receptor function in 30 patients with major depression (DSM-IV) and in 30 age- and sex-matched healthy controls. Depressed patients showed a basal score in the Hamilton Rating Scale for Depression (HRSD) higher than 17. After the administration of a single oral dose of buspirone (30 mg), corticotrophin (ACTH), cortisol, and prolactin (PRL) peak response minus baseline (Delta) and area under the curve (AUC) were evaluated. No significant difference in the hormonal response between depressed patients and controls was observed. No correlation with the severity of depression (HRSD score) was found. These results indicate no consistent changes in the hormonal response to the 5-HT(1A) agonist buspirone in depressed patients. Therefore, this study does not support the hypothesis of an altered postsynaptic 5-HT(1A) receptor function in major depression.     

Evidence for postsynaptic mediation of the hypothermic effect of 5-HT1A receptor activation.

1. The 5-HT1A ligand BMY 7378 (8-[2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]8-azaspirol [4,5]-decane-7,9-dione dihydrochloride, 0.032-2 mg kg-1, s.c.) caused hyperphagia, a response to the activation of presynaptic 5-HT1A receptors. 2. BMY 7378 (8 mg kg-1, s.c.) and the 5-HT1A agonist (8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), 0.10 and 0.25 mg kg-1 s.c.) also caused hypothermia. This was inhibited by (-)-pindolol (1-mg kg-1, i.p.) and not prevented by pretreatments with p-chlorophenylalanine which grossly depleted 5-hydroxytryptamine (5-HT) from terminal regions. The hypothermic effects are explicable by activation of postsynaptic 5-HT1A receptors. Infusion of BMY 7378 (8-64 micrograms) into the dorsal raphe was without convincing hypothermic effect. 3. BMY 7378 (8 mg kg-1, s.c.) inhibited another effect of activation of postsynaptic 5-HT1A receptors, i.e., the induction of components of the 5-HT syndrome by 8-OH-DPAT (0.5, 1.0 mg kg-1, s.c.) which suggests that BMY 7378 has antagonistic as well as agonistic effects at these sites. 4. Partial agonist properties of BMY 7378 at postsynaptic sites were also indicated by doses for hypothermia being much greater than those for hyperphagia i.e., ED50 (hypothermia) greater than 2 mg kg-1, ED50 (hyperphagia) = 0.010 mg kg-1. This contrasts with the similar ED50 values for both the hypothermic (ED50 = 0.08-0.10 mg kg-1) and hyperphagic (ED50 = 0.06-0.10 mg kg-1) effects of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS)