Neuropharmacology. 1995 Oct;34(10):1305-10.
The effect of 5-HT1A receptor ligands in a chronic mild stress model of depression.

Przegalinski E, Moryl E, Papp M.

Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Antidepressant properties of 5-HT1A receptor ligands (the full agonist 8-OH-DPAT, the partial agonists ipsapirone and buspirone, and the selective antagonist WAY 100135) were studied in a chronic mild stress model of depression. In this model, rats subjected to a variety of mild stressors for a prolonged period of time show a substantial decrease in the consumption of a 1% sucrose solution (anhedonia), an effect being sensitive to repeated treatment with antidepressant drugs. In the present study we found that the stress-induced deficit in the sucrose intake was gradually reversed by chronic (3-5 weeks) administration of buspirone (2.5 and 5 mg/kg, i.p., b.i.d.) or WAY 100135 (10 mg/kg, s.c., b.i.d.), but not 8-OH-DPAT (0.5 mg/kg, s.c., b.i.d.) or ipsapirone (5 mg/kg i.p., b.i.d.). The magnitude of the effect of buspirone and WAY 100135 was comparable to that observed following similar administration of the antidepressant drugs imipramine (10 mg/kg i.p.) or citalopram (10 mg/kg i.p.). Increases in the sucrose intake following chronic treatment with buspirone, WAY 100135, imipramine and citalopram were specific to the stressed animals; the behaviour of control non-stressed animals was unchanged by any drug. These results suggest that buspirone and WAY 100135 may have antidepressant properties. Possible links between the anti-anhedonic effect of these drugs and their interaction with 5-HT1A receptors and/or the dopamine system are discussed.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8570028&dopt=Abstract buspirone Buspar




Pharmacol Biochem Behav. 1995 Oct;52(2):305-12.
Sleep and waking in 5,7-DHT-lesioned or (-)-pindolol-pretreated rats after administration of buspirone, ipsapirone, or gepirone.

Monti JM, Jantos H, Silveira R, Reyes-Parada M, Scorza C.

Department of Pharmacology and Therapeutics, School of Medicine, Clinics Hospital, Montevideo, Uruguay.

The effects of partial 5-HT1A receptor agonists buspirone (0.010-4.0 mg/kg), ipsapirone (0.010-6.0 mg/kg), and gepirone (0.025-4.0 mg/kg) on sleep and waking were studied in vehicle-treated and 5,7-dihydroxytryptamine (5,7-DHT)-injected rats. 5,7-DHT-treated animals showed a marked and significant serotonin and 5-HIAA depletion in the raphe regions of the pons and upper brain stem, cerebral cortex, hippocampus, and striatum. Subcutaneous administration of the partial agonists to both the vehicle-infused and the 5,7-DHT-treated animals significantly increased waking (W) and reduced light sleep (LS), slow-wave sleep (SWS), and REM sleep (REMS). Pretreatment with (-)pindolol (2.0 mg/kg) reversed the effects of buspirone and gepirone on W and non-REM sleep (LS + SWS) whereas REMS remained suppressed. (-)-Pindolol failed to reverse the effects of ipsapirone on sleep and W. The present results tend to indicate that increased W after acute administration of buspirone, ipsapirone, or gepirone depends upon the activation of postsynaptic 5-HT1A receptors. The well-known anxiolytic action observed after chronic administration of the azapirones seems to be related to mechanisms other that these involved in their stimulant effect.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8577795&dopt=Abstract buspirone Buspar




Arch Med Res. 1995 Autumn;26(3):251-5.
A comparative study of the effects of some 5-HT1A receptor agonists on the blood pressure of pithed rats.

Castillo C, Bobadilla RA, Ibarra M, Castillo EF, Hong E.

Departamento de Fisiologia y Farmacologia de la Escuela Superior de Medicina IPN, Mexico, D.F.

The intention of this study was to supply additional information about direct effects of the 5-HT1A receptor agonist indorenate on the arterial blood pressure. The effects of indorenate were compared with those of buspirone and ipsapirone (all selective 5-HT1A agonists) on the blood pressure of pithed rats. These compounds increased the blood pressure in a dose-dependent fashion. The effects of either ipsapirone or buspirone were clearly inhibited with 100 micrograms/kg of prazosin (selective alpha 1-adrenoceptor antagonist), whereas 1 mg/kg of this blocker elicited only a mild inhibition of the pressor effect of indorenate. Pindolol (100 micrograms/kg; a beta-adrenoceptor and 5-HT1 receptor blocker) was unable to modify the effects of all the 5-HT1A agonists tested. In addition, the 5-HT2 receptor and weak alpha 1-adrenoceptor blocker ketanserin (10-100 micrograms/kg) antagonized the pressor effect of indorenate. Nevertheless, only a mild inhibition was observed in the case of both ipsapirone and buspirone. On the other hand, the latter drugs diminished the blood pressure of pithed rats intravenously infused with norepinephrine, but indorenate was inactive. However, in rats infused with quipazine, all the 5-HT1A agonists failed to reduce blood pressure. These results indicate that buspirone and ipsapirone behaved as partial alpha 1-adrenoceptor agonists. Furthermore, the results show that indorenate-elicited pressor effects are probably due to stimulation of 5-HT2 receptors. Thus, unlike ipsapirone and buspirone, indorenate did not show conclusively activity related with alpha 1-adrenoceptors.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8580676&dopt=Abstract buspirone Buspar




Life Sci. 1996;58(1):63-73.
Role of alpha1-adrenoceptors in the reduction of external carotid blood flow induced by buspirone and ipsapirone in the dog.

Terron JA, Ramirez-San Juan E, Hong E, Villalon CM.

Terapeutica Experimental, CINVESTAV, Mexico.

The effects of the 5-HT1A receptor agonist with anxiolytic properties, buspirone and ipsapirone, in the external carotid bed of anaesthetized dogs were analyzed. Since these agonists produce several vascular effects via activation of both 5-HT receptors and alpha1-adrenoceptors, their effects were compared with those elicited by the 5-HT agonist, quipazine, and the alpha1-adrenoceptor agonist, methoxamine. 1-Min intracarotid (i.c.) infusions of buspirone (300 microgram/min), ipsapirone (40 microgram/min), quipazine (300 microgram/min) and methoxamine (15 microgram/min) produced consistent decreases in external carotid blood flow (ECBF); since these changes in blood flow were not accompanied by modifications in systemic blood pressure, the agonists produced parallel increases in external carotid resistance. After interruption of the sympathetic tone by bilateral cervical vagosympathectomy, the vasoconstrictor responses to all the agonists remained unaffected. The intravenous (i.v.) administration of the nonselective 5-HT1-like receptor antagonist, methiothepin (1-100 microgram/kg), potently and dose-dependently antagonized buspirone-, ipsapirone- and quipazine-induced vasoconstriction; methiothepin similarly antagonized the vasoconstrictor responses to methoxamine. Interestingly, the alpha1-adrenoceptor antagonist, prazosin (1-100 microgram/kg, i.v.), also antagonized the vasoconstrictor responses to buspirone, ipsapirone and methoxamine in a dose-dependent manner. Finally, buspirone (300 microgram/min, i.c.) and ipsapirone (40 microgram/min, i.c.) did not modify the responses to noradrenaline (10 microgram/min, i.c.) or tyramine (100 microgram/min, i.c.). It is concluded that canine external carotid vasoconstriction induced by buspir




J Pharmacol Exp Ther. 1996 Feb;276(2):388-97.
Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT2A/2C antagonist anxiolytics. I. Antipunishment effects in the pigeon.

Kleven MS, Koek W.

Centre de Recherche Pierre Fabre, Castres, France.

A conflict procedure in pigeons was used to characterize the antipunishment effects of the putative mixed 5-hydroxytryptamine (5-HT)1A agonist/5-HT2A/2C antagonists WY 50,324, CGS 18102A, LEK 8804 and FG 5974 and to further investigate interactions between the antipunishment effects of the 5-HT1A agonists buspirone and 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] administered in combination with the mixed 5-HT2A/2C antagonist ritanserin and the alpha 1 antagonist prazosin. The 5-HT1A agonists, buspirone and 8-OH-DPAT, which lack affinity for 5-HT2A/2C receptors, produced dose-related increases in punished responding. Of the compounds with a mixed binding profile, only WY 50,324 showed effects that were comparable to those observed after 8-OH-DPAT, whereas FG 5974 and CGS 18102A exhibited limited effects on punished responding, and LEK 8804 was ineffective. Administration of a relatively low, behaviorally active dose of ritanserin (0.16 mg/kg) significantly enhanced the potency of 8-OH-DPAT and buspirone to increase punished responding from 8 to 50-fold without altering their effects on unpunished responding. Importantly, ritanserin failed to increase the number of doses of 8-OH-DPAT that significantly increased punished responding. In contrast, prazosin (2.5 mg/kg) significantly enhanced the potency and increased the number of doses of buspirone exerting significant effects on punished responding, but did not alter the effects of 8-OH-DPAT. Taken together, the results neither explain the suggested greater efficacy in producing anxiolytic effects of compounds with putative mixed 5-HT1A agonist and 5-HT2A/2C antagonist properties, nor confirm a proposed interaction between alpha1 adrenoreceptors and 5-HT1A agonists in




Psychopharmacology (Berl). 1995 Mar;118(1):93-100.
Minimal changes with long-term administration of anxiolytics on septal driving of hippocampal rhythmical slow activity.

Zhu XO, McNaughton N.

Department of Psychology, University of Otago, Dunedin, New Zealand.

In free-moving male rats, the function relating frequency to the threshold current required to drive hippocampal rhythmical slow activity (RSA; "theta") with septal stimulation has a minimum at 7.7 Hz. Classical anxiolytics all increase thresholds in the region of 7.7 Hz, and so does the novel anxiolytic buspirone. However, unlike classical anxiolytics, 2 or 3 weeks are normally required for the onset of the clinical effects of buspirone. This study tested the effects of long-term administration of chlordiazepoxide and buspirone on septal driving of RSA. Separate groups of naive rats received three IP injections per day of chlordiazepoxide (0.4 mg/kg), buspirone (0.1 mg/kg) or saline for 50 days. Both chlordiazepoxide and buspirone increased thresholds at 7.7 Hz, as expected. These acute effects were not significantly changed with chronic administration. Buspirone and chlordiazepoxide produced similar, statistically significant, but small cumulative reductions in thresholds at 6.9 Hz. The present experiments suggest that if the effects of anxiolytic drugs on septally driven RSA provide any basis for their clinical action, then classical anxiolytics may have two actions: an immediate effect on euphoria and tension and a delayed effect on anxiety proper--with buspirone sharing only the latter effect.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7597127&dopt=Abstract buspirone Buspar




J Med Chem. 1996 Mar 1;39(5):1125-9.
8-[4-[2-(1,2,3,4-Tetrahydroisoquinolinyl]butyl-8-azaspiro[4.5]decane-7,9-dione: a new 5-HT1A receptor ligand with the same activity profile as buspirone.

Mokrosz JL, Deren-Wesolek A, Tatarczynska E, Duszynska B, Bojarski AJ, Mokrosz MJ, Chojnacka-Wojcik E.

Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

A new analog of buspirone (1), i.e., 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl]-8-azaspiro- [4.5]decane-7,9-dione (6a), was synthesized. In was demonstrated that buspirone and its analog 6a were equipotent 5-HT(1A) ligands. Several behavioral models showed that 6a had essentially the same functional profile at 5-HT(1A) receptors as buspirone. The obtained results permit a conclusion that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group, of buspirone are directly involved in the formation of the bioactive complex with 5-Ht1A receptors.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8676348&dopt=Abstract buspirone Buspar




Arch Inst Cardiol Mex. 1995 Sep-Oct;65(5):395-402.
[Differences between the effects of indorenate and other 5-HT1A agonists on the rabbit aorta]

[Article in Spanish]

Castillo C, Rosas-Lezama MA, Castillo EF, Larios FJ, Hong E.

Departamento de Fisiologia y Farmacologia, Escuela Superior de Medicina, I.P.N., Mexico, D.F.

The aim of this study was to determine if like buspirone, ipsapirone and 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT), the alpha 1-adrenoceptors are involved in the responses elicited by indorenate in rabbit aorta. Exception made of ipsapirone, all the 5-HT1A agonists above mentioned contracted aortic rings. The contraction elicited by buspirone and 8-OH-DPAT was blocked with prazosin (alpha 1-adrenergic antagonist), whereas the effect of indorenate was unaffected with this blocker but it was inhibited with ritanserin (5-HT2 antagonist). On the other hand, buspirone, ipsapirone and 8-OH-DPAT but not indorenate relaxed arteries precontracted with methoxamine (alpha 1-adrenergic agonist) and none of the agonists relaxed preparations precontracted with acetylcholine or KCl. The results indicate that buspirone and 8-OH-DPAT are partial alpha 1-adrenoceptor agonists since they elicited contractions which are blocked with prazosin and relaxed only rings precontracted with methoxamine. Ipsapirone behaved as an alpha 1-adrenoceptor antagonist since it showed the relaxant but not the contractile effect. Finally, we found no evidence that indorenate has afinity for alpha 1-adrenoceptors. Contraction elicited by this agonist seems to be mediated by 5-HT2 receptors, inasmuch it was blocked with ritanserin.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8678695&dopt=Abstract buspirone Buspar