Antagonism of drug-induced yawning and penile erections in rats

A number of centrally active drugs were tested for antagonism of physostigmine- or apomorphine-induced yawning and for apomorphine-induced penile erections. The alpha 2-adrenoceptor antagonists piperoxan and idazoxan inhibited the yawning response without affecting the penile erections. The 5HT agonist quipazine and the histamine antagonist dexchlorpheniramine inhibited the yawning response more effectively than the penile erections. Dexchlorpheniramine even enhanced the apomorphine-induced penile erections and induced penile erections in physostigmine-treated rats. The 5HT antagonists metergoline and methysergide blocked the apomorphine-induced penile erections without affecting the yawning response. The alpha 2-adrenoceptor agonist clonidine, the dopamine antagonist sulpiride, the antihistaminic mepyramine and the benzodiazepine chlordiazepoxide inhibited both yawning and penile erections at the same dose level. The alpha 1-adrenoceptor antagonists prazosin and phenoxybenzamine were inactive. It is concluded that yawning and penile erections can be differentially affected by drug treatments. Also, while concomitant yawning and penile erections can be selectively induced by a class of dopamine receptor agonists, the same selectivity does not apply to antagonism of these induced behaviours.     

Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT<Subscript>2C</Subscript> receptors in Wistar rats

Agomelatine, an antidepressant with melatonin agonist and 5-HT_2C antagonist properties, as well as two of its main metabolites, S 21517 (N-[2-(7-hydroxy-1-naphtyl)ethyl]acetamide) and S21540 (N-[2-(3-hydroxy-7-methoxynaphtalen-1-yl)ethyl]acetamide), have been assessed in vitro on pig choroid plexus preparations to determine their affinities for 5-HT_2C receptors and their effects on inositol phosphate production. These compounds were also tested for their ability to inhibit the penile erections induced by the 5-HT_2C receptor agonists, m-(chlorophenyl)piperazine (mCPP, 0.75 mg/kg, SC) and Ro 60-0175 (2.5 mg/kg, SC) in Wistar rats. These in vivo effects were compared to those of melatonin and the 5-HT antagonists pizotifen and SB 206,553. Agomelatine and S 21517 had moderate affinity for 5-HT_2C receptors and behaved in vitro as weak antagonists at this receptor subtype. S 21540 had a 10-fold lower affinity. Pizotifen and SB 206,553 antagonized mCPP- and Ro 60-0175-induced penile erections, suggesting that penile erections induced by mCPP or Ro 60-0175 resulted from the stimulation of 5-HT_2C receptors. Whereas increasing doses (from 1.25 to 40 mg/kg, IP) of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175, agomelatine (from 1.25 to 40 mg/kg, IP) dose-dependently decreased mCPP- as well Ro 60-0175-induced penile erections. Furthermore, increasing doses (from 1.25 to 40 mg/kg, IP) of S 21517 and S 21540, the two main metabolites of agomelatine, did not affect the penile erections induced by mCPP and Ro 60-0175. Considering the similar activity of melatonin and agomelatine at melatonin receptors, these data suggested that the reported effects were not due to the stimulation of melatonin receptors and that, contrary to melatonin, agomelatine exerted 5-HT_2C receptor antagonist properties in addition to its agonist activity at melatonin receptors. Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erections by agomelatine.Dr. Protais died in 2002     

Selective activation of 5HT1A receptors induces lower lip retraction in the rat

The induction of lower lip retraction (LLR) by serotonergic (5HT) compounds and antagonism of LLR by compounds acting via a variety of receptor systems was investigated. LLR could be induced by subcutaneous injection of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), buspirone, ipsapirone or RU 24969. Inactive were the putative 5HT1B,1C agonist 1-(3'chlorophenyl)-piperazine (mCCP), the 5HT2,1C agonist (dl)-1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5HT reuptake inhibitors citalopram and paroxetine and the 5HT-releasing compounds parachloroamphetamine (PCA) and fenfluramine. 5-Methoxy-N,N-dimethyltryptamine (5-MeODMT) induced lower lip retraction after pretreatment with metergoline, cyproheptadine or ritanserin but not by itself. 8-OH-DPAT-induced LLR could be antagonised by the direct and indirect 5HT agonists mCPP, DOI, 5-MeODMT, PCA, fenfluramine and high doses of paroxetine, but not by the 5HT antagonists metergoline, methysergide, mesulergine, GR38032F, xylamidine or pirenperone. The dopamine agonists apomorphine and pergolide antagonised 8-OH-DPAT-induced LLR, whereas SKF 38393 was weakly active. No significant antagonism was found with the dopamine antagonists haloperidol and spiperone, the alpha 2 agonist clonidine and the alpha 1 antagonist prazosin and the alpha 2 antagonist idazoxan. Also inactive were the antihistaminic mepyramine, the anticholinergic atropine, the opiate antagonist naloxone and the anxiolytic chlordiazepoxide. The results suggest that, in vivo, functional interactions take place between the various 5HT receptors. The hypothesis that lower lip retraction is induced by compounds directly and selectively stimulating 5HT1A receptors is discussed.     

Antimyoclonic properties of S2 serotonin receptor antagonists in the rat

The capacity of the putative S2 serotonin receptor antagonists, pirenperone, pipamperone, ketanserin and cinanserin, to block the myoclonic syndrome produced by 30 mg/kg of L-5-hydroxytryptophan (5-HTP) [after lesioning 5-hydroxytryptamine (serotonin, 5-HT)-containing neurons with 5,7-dihydroxytryptamine (DHT)] or 15 mg/kg of fenfluramine (FF) or p-chloroamphetamine (PCA) was tested in adult male Sprague-Dawley rats. S2 antagonists inhibited limb (arrhythmic and asynchronous) and axial (truncal) myoclonus in a dose-dependent manner in the rank order of potency: pirenperone greater than pipamperone greater than ketanserin = cinanserin. Abnormal movements (myoclonus, lateral head weaving) of the myoclonic syndromes were better antagonized than postural abnormalities (hindlimb abduction, hunching of back). Centrally acting drugs, selective for S2 receptors (pirenperone, pipamperone), exhibited greater antimyoclonic properties than the non-selective 5-HT antagonist methysergide, which was as effective as ketanserin and cinanserin. Significant non-specific reduction in myoclonus without the improvement of other behavioral responses followed treatment with sedative/neuroleptic drugs, such as haloperidol (but not the non-neuroleptic dopamine antagonist sulpiride), clonazepam and diazepam. The anticonvulsants valproic acid (100 and 300 mg/kg), adrenocorticotrophic hormone (ACTH; 100 and 300 U/kg), diphenylhydantoin (15 mg/kg), and phenobarbital (20 mg/kg) and drugs which do not act principally at S2 receptors were ineffective in these models. These data support the hypothesis that myoclonus in behavioral models induced by 5-HT is S2 receptor mediated. S2 antagonists could have a role in the treatment of human myoclonus.     

Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist

YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, showed a high affinity for cloned human 5-HT(2C) receptors (K(i): 0.89 nM). The functional selectivity for 5-HT(2C) receptors in the 5-HT(2) receptor family was the highest among 5-HT(2C) receptor agonists, including m-chlorophenylpiperazine (mCPP) and Ro60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine). Oral administration of YM348 induced penile erections and hypolocomotion in rats, being completely inhibited by a selective 5-HT(2C) receptor antagonist, SB242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline). The dose-response curve for penile erections, unlike that for hypolocomotion, was an inverted U-shape in the dose range of 0.0677-2.03 mg/kg. A selective 5-HT(2A) receptor antagonist, MDL100907 (R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol), and a selective 5-HT(2B) receptor antagonist, RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine), had no effect on the decline in penile erection frequency at 2.03 mg/kg of YM348. YM348 did not affect blood pressure at 2.03 mg/kg. In conclusion, YM348 is a novel, potent and orally active 5-HT(2C) receptor agonist, and neither the activation of 5-HT(2A) or 5-HT(2B) receptors nor a cardiovascular effect is likely to contribute to the inverted U-shape dose-response curve for penile erections.     

Endothelin mechanisms in the central nervous system: A target for drug development

Behavioral and electrophysiological methods were used to study the role of 5-hydroxytryptamine (5-HT) receptors on bladder and erectile function in the male rat. Postulated 5-HT_1A [p-aminophenylethyl-m-trifluoromethylphenylpiperazine (PAPP), 5-methoxydimethyltyramine (5-MeODMT)] and 5-HT_1C/2 [MK212, m-trifluoromethylphenylpiperazine (TFMPP)] agonists did not consistently alter sensitivity voiding frequency (VF) in awake rats or affect micturition threshold (0.4 vs. 0.3 cc) in anesthetized rats. The 5-HT_1B agonist Organon 6997 (ORG 6997) had no effect on pelvic nerve-induced detrusor contraction or evoked responses in bladder nerves. 5-HT_1C/2 agonists abolished reflexly evoked bladder contractions by inhibiting efferent firing in the pelvic nerve. 5-HT_1C/2 agonists also produced penile erections (2–5/30 min) via firing in cavernous nerves mediated by preganglionics in the pelvic nerve. Neural activity in the cavernous nerves following administration of MK212 and TFMPP was abolished by the 5-HT_1C/2 antagonist mianserin. 5-HT_1A, 5-HT_1B, 5-HT_1C/2 agonists failed to influence synaptic transmission in the pelvic ganglion. These data support a functional diversity of 5-HT receptor subtypes with selective excitation or inhibition of central autonomic pathways regulating pelvic visceral function. These observations suggest that 5-HT_1C/2 agonists could be clinically useful for managing impotence or urinary incontinence. © 1992 Wiley-Liss, Inc.     

5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists

The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4–5] décane-7,9 dione), is a high affinity full 5-HT_1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10^–8 M affinity for D₂ dopamine (DA) receptors, 100 fold lower than for 5-HT_1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 µg/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT_1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT_1A receptor antagonist tertatolol (2–5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT_1A agonist property opposes to that of D₂ dopamine receptor stimulation with regard to yawning and penile erections.     

Post-synaptic 5-HT1A receptor involvement in yawning and penile erections induced by apomorphine,physostigmine and mCPP in rats

Apomorphine and mCPP induced yawning associated with penile erections in rats, whereas physostigmine induced only yawns. Apomorphineinduced yawning and penile erections were antagonized by low doses of raclopride, whereas physostigmineinduced yawning and mCPP-induced effects were only partly inhibited at high doses of raclopride. Scopolamine as well as clozapine antagonized yawning and penile erections induced by apomorphine, mCPP and physostigmine. Similarly, the 5-HT_1A agonists 8-OH-DPAT and S 14506 inhibited yawning and penile erections induced by apomorphine, mCPP and physostigmine, and at similar doses induced lower lip retraction and hyperreactivity to handling. The /5-HT_1A antagonist tertatolol reversed the inhibitory effects of 8-OH-DPAT and S 14506 on drug-induced yawning and penile erections and increased apomorphine-and physostigmine-induced yawn frequency but not penile erection frequency. Like tertatolol, propranolol increased apomorphine- and physostigmine-induced yawn frequency, whereas ICI 118551 increased only physostigmine-induced yawning. 8-OH-DPAT-and S 14506-induced lower lip retraction and hyperre-activity to handling were also significantly antagonized by tertatolol. Finally,p-chlorophenylalanine pretreatment produced about 95% depletion in 5-HT in hypothalamus, hippocampus, striatum and frontal cortex and modified neither the responses of the inducing drugs nor the inhibitory effects of 8-OH-DPAT and S 14506 on drug-induced yawning and penile erections. These data suggest (i) that a final cholinergic mechanism blocked by scopolamine and clozapine is involved in drug-induced yawning and penile erections, (ii) that the effects of S 14506 depend upon stimulation of 5-HT_1A receptors, (iii) that the inhibitory effects of 5-HT_1A agonists on yawning and penile erections probably occurred at final steps on the pathways involved in the expression of yawning and penile erections and that these effects could be related to other effects of the 5-HT_1A agonists, (iv) that a tonic inhibitory influence could interfere with the expression of yawning but not with that of penile erections and (v) that presynaptic 5-HT_1A receptors do not seem to play an important role in the inhibitory effects of 5-HT_1A agonists on drug-induced yawning and penile erections in rats.     

Involvement of 5-HT1C-receptors in drug-induced penile erections in rats

Drug-induced penile erections (PE) were initially suggested to be 5-HT_1B receptor mediated. However, since the discovery of the 5-HT_1C receptor a number of compounds, considered to be 5-HT_1B selective, appear to bind more strongly to the 5-HT_1C receptor and this prompted a re-evaluation of the receptor subtype involved in PE induction. PE could be induced by the 5-HT agonists mCPP (0.22–2.2 mg/kg), TFMPP (0.46–1.0 mg/kg) and MK 212 (0.1–1.0 mg/kg). The 5-HT agonist DOI (0.022–0.22 mg/kg) did not induce PE in placebo-pretreated rats but in rats pretreated with various 5-HT₂ antagonists it did. These compounds have in common a strong affinity for the 5-HT_1C receptor. mCPP (0.46 mg/kg)-induced PE could be antagonized by the 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin, ritanserin and ketanserin. Their ED₅₀s were 0.04, 0.4, 0.03, 0.06, 0.4 and 2 mg/kg, respectively. The potency of both the agonists to induce, and the antagonists to inhibit, PE was found to be dependent on their selectivity for the 5-HT_1C receptor versus the 5-HT₂ receptor. Spiperone (0.1–1.0 mg/kg) and GR 38032F (1–10 mg/kg) did not antagonise mCPP-induced PE. 8-OH-DPAT and 5MeODMT counteracted mCPP (0.46 mg/kg)-induced PE. Their ED₅₀s were 0.03 and 0.4 mg/kg, respectively. DOI counteracted mCPP induced PE only at doses above 1 mg/kg, whereas CGS 12066B (1.0–10 mg/kg) was inactive. The results suggest that PE are induced by activation of the 5-HT_1C receptor and are functionally inhibited by activation of 5-HT_1A or 5-HT₂ receptors.     

DOI-induced inhibition of copulatory behavior in male rats: reversal by 5-HT2 antagonists.

Relatively little is known regarding the role of 5-HT2 receptor activity in male rat sexual behavior. Previous work has yielded equivocal results, and both facilitation and inhibition of copulation have been reported to follow administration of selective 5-HT2 antagonists. In the present series of experiments, the ability of a variety of 5-HT2 antagonists to block inhibition induced by the 5-HT2/5-HT1C agonist DOI was examined. Systemic ritanserin, pirenperone and ketanserin all potently blocked DOI-induced (1.0 mg/kg SC) inhibition of mounts, intromissions and ejaculations. None of these drugs influenced the sexual behavior of the male rats when given alone in doses that effectively blocked DOI-induced inhibition. In addition, unlike ritanserin and ketanserin, pirenperone produced a biphasic effect on DOI-induced inhibition, exhibiting a diminished blockade at higher doses. This may be due to activity at receptors other than 5-HT2. Overall, the present data suggest that activity at 5-HT2 receptors mediates an inhibition of male rat sexual behavior.     

Stimulation of corticosterone secretion by the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the rat

The selective 5-HT1A receptor agonist 8-OH-DPAT increased serum corticosterone concentration in rats in a dose-dependent manner. The synthetic corticoid dexamethasone lowered the serum corticosterone level and abolished its rise induced by 8-OH-DPAT. The corticosterone response to 8-OH-DPAT was also antagonized by spiperone, (+/-)- and (-)-pindolol and (+/-)-propranolol, all of which have been shown to have a high affinity for 5-HT1A receptors, though in most cases no complete blockade was found. A partial antagonism of the response was also observed after flumazenil, a benzodiazepine antagonist. On the other hand, the 5-HT1B receptor antagonist 21009, the 5-HT2 receptor antagonists ketanserin and pirenperone, the 5-HT3 receptor antagonist ICS 205-930, the alpha 2-adrenoceptor antagonists yohimbine and idazoxan, the beta-adrenoceptor blocker with no affinity to 5-HT1 receptors, atenolol, the dopaminergic antagonist pimozide, the histamine receptor blocker chloropyramine and the opiate receptor antagonist naloxone did not affect the hormonal response to 8-OH-DPAT. The 8-OH-DPAT-induced corticosterone secretion was not affected either in rats pretreated with p-chlorophenylalanine (PCPA, an inhibitor of tryptophan hydroxylase) or p-chloroamphetamine (PCA, a drug-inducing lesion of serotonergic nerve terminals). It is concluded that 8-OH-DPAT-induced increase in serum corticosterone concentration results from its action at a site different than the adrenal cortex and is mediated by postsynaptic 5-HT1A receptors, whereas other subtypes (5-HT1B, 5-HT2, 5-HT3) of 5-HT receptors do not participate in this response.(ABSTRACT TRUNCATED AT 250 WORDS)     

The 5HT(7) receptor subtype is involved in the regulation of female sexual behaviour in the rat

5-Hydroxytryptamine (5-HT) regulates sexual behaviour in the female rat via a number of its receptors. The role of the 5HT(7) receptor was investigated in ovariectomised rats primed with 10 mug oestradiol benzoate (OB) followed at 48 h by 0.5 mg progesterone, which induced receptivity in approximately half of the animals. These animals were treated with three agonists all effective at 5HT(1A) and 5HT(7) receptors; 5-hydroxytryptophan, 8-hydroxy-2-(di-n-propylamino)tetralin 1-Br (8-OH DPAT) and 5-carboxy-aminotryptamine (5-CT) in the presence or absence of selective 5HT(1A) and 5HT(7) antagonists: WAY 100135 and SB 269970-A. The three agonists inhibited lordosis in the receptive group, and this was prevented by both the selective 5HT(1A) and 5HT(7) antagonists. When given alone, both WAY 100135 and SB 269970-A increased the lordosis in the non-receptive rats indicating that endogenous 5-HT acting on 5HT(1A) and 5HT(7) receptors may have a tonic inhibitory effect on receptivity. A comparison of OB priming doses on the effect of serotoninergic agents showed that the higher OB doses attenuated the inhibitory effect of 8-OH DPAT and enhanced the stimulatory effect of WAY 100135, but did not affect the actions of 5-CT or SB 269970-A. The interaction between oestradiol and 5-HT activity on sexual behaviour may therefore be selective to the 5HT(1A) pathway.     

A facilitatory role for serotonin in the sexual behavior of the female rat

The peripheral administration of the serotonin type 2 receptor (5-HT2) antagonist pirenperone inhibited sexual receptivity in ovariectomized female rats primed either chronically with estradiol benzoate (EB), or acutely with EB plus varying doses of progesterone. An inhibition occurred at 50, 100 and 150 but not 25 micrograms/kg pirenperone. Increasing the dose of progesterone did not attenuate the inhibitory effect of pirenperone. Two other 5-HT2 antagonists, ketanserin (2.5 mg/kg) and spiperone (250 micrograms/kg), also inhibited receptivity in females primed with EB and progesterone. The inhibitory effect of pirenperone on receptivity was attenuated by the 5-HT agonist quipazine (3 mg/kg), though quipazine alone had no effect on receptivity. Whereas the 5-HT antagonist methysergide (3 mg/kg) failed to have an effect on receptivity in EB-primed females, methysergide co-administered with quipazine facilitated receptivity. Pirenperone also inhibited proceptivity in females primed with EB and progesterone. Although quipazine did not attenuate the pirenperone-induced inhibition of proceptivity, quipazine alone increased proceptivity. Moreover, quipazine facilitated proceptivity in EB-primed rats whether progesterone was present or absent. The results suggest that 5-HT may serve both a facilitatory and inhibitory role in female sexual behavior, perhaps reflecting 5-HT2 and 5-HT1 receptor activity, respectively.     

2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist

A series of novel 2-[(4-phenylpiperazin-1-yl)methyl]imidazoazines and aza-analogues were prepared and screened at selected dopamine, serotonin, and adrenergic receptor subtypes. 2-Substituted imidazopyridines and pyridazines presented high affinities and selectivities for D4 dopamine receptors. Whereas functional experiments indicated neutral antagonists or weak partial agonist effects for most of the target compounds, the 2-methoxyphenyl substituted 2-piperazinylmethylimidazopyridine 3c (PIP3EA) displayed substantial agonist efficacy in mitogenesis experiments and GTPgammaS binding tests, resulting in EC50 values of 3.0 (46%) and 4.5 nM (57%), respectively. Our D4 agonist 3c induced penile erection in vivo when administered to rats. This effect was inhibited by L-745,870 a D4 selective antagonist, confirming the mechanistic pathway.     

Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists

The effect of the selective 5-HT₃ receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by l-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced l-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by l-5-HTP are mediated by 5-HT₂ receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT₂ receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT.     

The 5HT2 antagonist pirenperone reverses disruption of FR-40 by hallucinogenic drugs

Indolealkylamine and phenethylamine hallucinogens disrupted responding maintained under a fixed-ratio 40 (FR-40) schedule of reinforcement. LSD, DMT, mescaline and DOM produced dose-dependent decreases in number of reinforcers and increases in 10-sec periods of non-responding (pause-intervals). The 5HT agonist quipazine, as well as the LSD congener lisuride, altered response patterns in a similar manner. The effects of these drugs were examined after pretreatment with pirenperone, an antagonist with specificity toward the 5HT2 receptor with reference to the 5HT1 receptor. The dose-response curves for the phenethylamine hallucinogens were shifted significantly to the right and to a greater degree than were those for the indolealkylamine hallucinogens. Pirenperone also antagonized the effects of quipazine to a degree similar to that observed with the phenethylamine-type hallucinogens. Pirenperone did not significantly shift the dose-response pattern to lisuride. These data suggest that the behavioral disruption induced by these hallucinogens and quipazine relates at least in part to an effect on 5HT2 receptors, while the effects of lisuride do not involve a significant interaction at the 5HT2 receptor.     

Antagonistic effects of some metabolites and analogues of mianserin on serotonin and alpha 1- and alpha 2-adrenergic receptors in the flexor reflex model in vivo

Mianserin, its two metabolites desmethylmianserin (Org OH-46) and 8-hydroxymianserin (Org GF-45), and its two analogues R(-)-6-aza-mianserin (Org 44-19) and S(+)-6-aza-mianserin (Org 44-20) were tested for their antagonistic action on the central serotonin (5-HT) receptor and alpha-adrenoceptors in the flexor reflex model in vivo in the spinal rat. The ability to reduce the increase in the flexor reflex activity induced by quipazine (a 5-HT receptor agonist), St 587 (an alpha 1-adrenoceptor agonist), or clonidine (an alpha 2-adrenoceptor agonist) was a measure of their potencies as antagonists of the respective receptors. All the compounds occurred to be potent antagonists of the central 5-HT receptor (S(+)-6-aza-mianserin was most active) and, to a lesser degree, of alpha-adrenoceptors with preferential antagonistic action on alpha 2-subtype.     

四乙铵和4—氨基吡啶增强5—HT3受体介异的离体豚鼠回肠收缩

目的：研究四乙铵（ＴＥＡ）、４－氨基吡啶（４－ＡＰ）对５－ＨＴ３受体介导的豚鼠回肠收缩的影响。方法：等长换能器记录回肠收缩；［＾３Ｈ］ＧＲ６５６３０结合试验测定５－ＨＴ３受体结合特性。结果：ＴＥＡ、４－ＡＰ引起回肠收缩并增强自发活动，被阿托品或ＭＤＬ７２２２阻断，ＴＥＡ、４－ＡＰ增强２－甲基－５－ＨＴ和５－ＨＴ引起的收缩；逆转托烷司琼或Ｂｅｎｅｓｅｔｒｏｎ的抑制作用；不影响卡巴胆碱引起的收缩。ＴＥ     

The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic function

Forepaw treading induced in rats by the 5HT1A agonist 8-OH-DPAT, and head shakes caused by the administration of the 5HT2A receptor against DOI, and by the 5HT precursor (-)5HTP, were significantly increased by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine. Dizocilpine administration also significantly increased the locomotor activity induced by the serotonin agonists. The competitive NMDA receptor antagonist CGP 43487 increased only the head shakes induced by DOI, but did not alter the behavior elicited by 8-OH-DPAT, or (-)5HTP, and did not modify locomotor responses to any of the agonists used. The dizocilpine-induced potentiation of head shakes elicited by DOI and (-)5HTP was inhibited by the 5HT2 agonist ketanserin, but was not modified by the selective dopamine D1 and D2 receptor blockers SCH 23390 and (-)sulpiride. The dopamine receptor antagonists did, however, counteract the dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the locomotor response to all the serotonergic agonists. The results indicate that, unlike competitive NMDA receptor antagonists, the non-competitive antagonists enhanced the expression of serotonergic stimulation, and suggest that a glutamate deficiency could contribute to the pathogenesis of schizophrenia, not only through dopaminergic, but also through serotonergic, hyperactivity.     

Involvement of 5-HT2 receptors in the wet-dog shake behaviour induced by 5-hydroxytryptophan in the rat

The wet-dog shake behaviour induced by 5-hydroxytryptophan (5-HTP) was used as a model of central 5-hydroxytryptamine (5-HT) receptor activity in the rat. The wet-dog shake behaviour induced by 5-HTP was dose-dependent. Selective 5-HT₂ receptor antagonists ketanserin, pirenperone and methysergide (with little selectivity) were administered to rats displaying the wet-dog shake behaviour. The three antagonists produced a rapid and dose-dependent inhibition of wet-dog shakes. Pirenperone was more potent than ketanserin, which was more potent than methysergide at inhibiting wet-dog shake behaviour. Since 5-HT₂ receptor antagonists inhibit the 5-HTP-induced wet-dog shakes it is proposed that the wet-dog shakes induced by 5-HTP are mediated by activation of 5-HT₂ receptors.