J Pharm Pharmacol. 1997 Jul;49(7):698-705.
The ligand-binding site of buspirone analogues at the 5-HT1A receptor.

Sylte I, Chilmonczyk Z, Dahl SG, Cybulski J, Edvardsen O.

Department of Pharmacology, Institute of Medical Biology, University of Tromso, Norway.

A three-dimensional model of the 5-HT1A receptor in man was constructed by molecular-modelling techniques and used to study the molecular interactions of a series of buspirone analogues with the 5-HT1A receptor by molecular-mechanical-energy minimization and molecular-dynamics simulations. The receptor has seven trans-membrane alpha helices (TMHs) organized according to the electron-density-projection map of visual rhodopsin, and includes all loops between TMHs and the N- and C-terminal parts. The best fit between the buspirone analogues and the receptor model was obtained with the quinolinyl part of the ligand molecules interacting with amino acids in TMH6, the imide group interacting with amino acids in TMH2, TMH3 and TMH7, and the carbonyl groups hydrogen-bonded with Ser86 and Ser393. The ligand-binding rank order deduced from the experimentally determined inhibition constant was reproduced by calculation of receptor-binding energies of the buspirone analogues. The models suggest that steric hindrance and repulsive forces between the receptor and the imide group of the buspirone analogues are the most important determinants of ligand-binding affinity for discriminating between these ligands.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9255714&dopt=Abstract buspirone Buspar




Pharmacol Biochem Behav. 1997 Aug;57(4):835-41.
5-HT1A agonists induce central cholinergic antinociception.

Galeotti N, Ghelardini C, Bartolini A.

Department of Preclinical and Clinical Pharmacology M. Aiazzi-Mancini, University of Florence, Italy.

The antinociceptive effects of the 5-HT1A agonists buspirone [3 mg/kg intraperitoneally (i.p.)], gepirone (3-6 mg/kg i.p.), and 8-OH-DPAT [3-5 mg/kg i.p.; 1-3 micrograms per mouse intracerebroventricularly (i.c.v.)] were examined in mice by using the hot-plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Buspirone, gepirone, and 8-OH-DPAT produced significant antinociception, which was prevented by atropine (5 mg/kg i.p.), the ACh depletor hemicholinium-3 (1 microgram per mouse i.c.v.), and the 5-HT1A antagonist NAN 190 (0.5 microgram per mouse i.c.v.), but not by naloxone (1 mg/kg i.p.), the GABAB antagonist CGP 35348 (100 mg/kg i.p.), and pertussis toxin (0.25 microgram per mouse i.c.v.). NAN 190 which totally antagonized buspirone, gepirone, and 8-OH-DPAT antinociception, did not modify the analgesic effect of morphine (5 mg/kg subcutaneously). In the antinociceptive dose range, none of the 5HT1A agonists impaired mouse performance evaluated by rota-rod and hole board tests. On the basis of these data, it can be postulated that buspirone, gepirone, and 8-OH-DPAT exert an antinociceptive effect mediated by a central amplification of cholinergic transmission.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9259013&dopt=Abstract buspirone Buspar




Psychopharmacology (Berl). 1997 Jul;132(1):35-43.
On the elevated plus-maze the anxiolytic-like effects of the 5-HT(1A) agonist, 8-OH-DPAT, but not the anxiogenic-like effects of the 5-HT(1A) partial agonist, buspirone, are blocked by the 5-HT1A antagonist, WAY 100635.

Collinson N, Dawson GR.

Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.

In the present study we evaluated the effects of the 5-HT(1A) receptor partial agonist, buspirone hydrochloride and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on the elevated plus-maze. In addition, the ability of the 5-HT(1A) receptor antagonist, WAY 100635, to reverse the effects of both compounds was determined. 8-OH-DPAT (0.01 0.3 mg/kg, SC) dose-dependently increased the percent time on, and the number of entries to, the open arms of the maze. In a second experiment, WAY 100635 (0.003 0.3 mg/kg, SC) dose-dependently reversed the anxiolytic-like effects of 8-OH-DPAT (0.3 mg/kg, SC). In a third experiment, buspirone (0.3-4.0 mg/kg, SC) dose-dependently decreased the time spent on the open arms of the maze, indicating that it had anxiogenic-like effects. Buspirone also significantly decreased locomotor activity, which was evident in the decreases in the distance travelled on the open arms, closed arms and on the maze as a whole, the total number of arm entries and the mean speed of the animals. In contrast to its effects on 8-OH-DPAT-induced behaviours in the maze, WAY 100635 (0.003 1.0 mg/kg SC) failed to reverse any of the effects induced by buspirone. Animals treated with high doses of WAY 100635 (0.3 1.0 mg/kg SC) alone did not significantly differ from vehicle-treated animals on any of the measures recorded during elevated plus-maze trials. These data suggest that the anxiolytic-like effects of 8-OH-DPAT, but not the anxiogenic-like effects of buspirone, on the elevated plus-maze are mediated via 5-HT(1A) receptors in the CNS.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9272757&dopt=Abstract buspirone Buspar[PubMed]



Pharmacol Biochem Behav. 1995 Aug;51(4):821-5.
Effects of buspirone on the immune response to stress in mice.

Freire-Garabal M, Nu nez-Iglesias MJ, Balboa JL, Fernandez-Rial JC, Rey-Mendez M.

NIMUS, Department of Pharmacology, School of Pharmacy, University of Santiago de Compostela, Spain.

Several experiments were conducted to evaluate the effects of buspirone, a selective 5-hydroxytryptamine-1A (5-HT1A) anxiolytic, on the immune system of mice exposed to a chronic auditory stressor. Daily injection with 0.5 and 1 mg/kg (intraperitoneally) of buspirone resulted in a dose-dependent reduction in the stress-induced suppression of the natural killer (NK) cell activity and the in vitro and in vivo activity of phagocytosis. Higher doses of buspirone (2.0 mg/kg) showed less robust immunoenhancing effects in stressed mice, and caused a significant suppression of these immune parameters in unstressed mice.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7675864&dopt=Abstract buspirone Buspar




Neuropharmacology. 1997 Aug;36(8):1089-97.
Comparative behavioural profiles of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in the murine elevated plus-maze.

Cao BJ, Rodgers RJ.

Department of Psychology, University of Leeds, U.K.

It has been suggested that in vivo formation of the metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) may be a major drawback in the use of buspirone as an anti-anxiety agent. To test this hypothesis, the effects of buspirone, alone or with proadifen (an inhibitor of liver microsomal enzymes) pretreatment, were contrasted with those of 1-PP in the murine elevated plus-maze test of anxiety. At 3.0 mg/kg (but not lower doses), buspirone per se had modest anxiolytic-like effects (increased percentage of open arm entries; reduced stretched-attend postures and flatback approach) that were associated with increased grooming and immobility. However, in proadifen-pretreated mice, buspirone produced behavioural depression only, with marked effects evident both at 1.0 and 3.0 mg/kg. As proadifen blocks the biotransformation of buspirone to 1-PP, these data suggest that any anxiolytic activity of buspirone in the murine plus-maze may be attributable to its principal active metabolite. Consistent with this hypothesis, 1-PP (0.5-13.5 mg/kg) produced dose-dependent anti-anxiety effects on both conventional and ethological measures that were not confounded by motoric impairment. Results are discussed in relation to biochemical and electrophysiological studies suggesting that 1-PP has a direct action at 5-HT1A receptors.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9294974&dopt=Abstract buspirone Buspar




Pharmacol Biochem Behav. 1997 Oct;58(2):311-5.
Buspirone fails to affect cocaine-induced conditioned place preference in the mouse.

Ali I, Kelly ME.

Postgraduate Studies in Pharmacology, The School of Pharmacy, University of Bradford, West Yorkshire, United Kingdom.

The conditioned place preference (CPP) procedure was employed to examine the effects of the 5-hydroxytryptamine1A (5-HT1A) receptor agonist, buspirone, on cocaine reinforcement. Cocaine (5.0 mg/kg, S.C., 30 min) produced a significant place preference whereas buspirone (0.5-2.0 mg/kg, I.P., 30 min) per se failed to induce a CPP. Buspirone pretreatment (0.5-2.0 mg/kg, I.P.) 30 min prior to cocaine (5.0 mg/kg, S.C., 30 min) conditioning had no effect on the acquisition of cocaine-induced CPP. Pretreatment with buspirone on the postconditioning test day also failed to affect the expression of an already established place preference response to cocaine. These results demonstrate an inability of buspirone to block both the acquisition and the expression of cocaine reward, as modeled in the CPP paradigm.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9300585&dopt=Abstract buspirone Buspar




Alcohol Clin Exp Res. 1997 Oct;21(7):1169-78.
Effects of maternal ethanol consumption and buspirone treatment on 5-HT1A and 5-HT2A receptors in offspring.

Kim JA, Gillespie RA, Druse MJ.

Neuroscience Program, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois 60153, USA.

In utero ethanol exposure results in a decreased concentration of serotonin (5-HT) in brain regions containing the cell bodies of 5-HT neurons and their cortical projections. The concentration of 5-HT reuptake sites is also reduced in several brain areas. The present study extended prior work by evaluating the effects of chronic maternal ethanol consumption and maternal buspirone treatment on 5-HT1A and 5-HT2A receptors in multiple brain areas of offspring. Receptors were quantitated early in postnatal development and at an age when the 5-HT networks are normally well-established. Because fetal 5-HT functions as an essential neurotrophic factor, these studies also determined whether treatment of pregnant rats with buspirone, a 5-HT1A agonist, could overcome the effects of the fetal 5-HT deficit and prevent ethanol-associated receptor abnormalities. The results demonstrated that in utero ethanol exposure significantly alters the binding of 0.1 nM [3H]-8-hydroxy-dipropylaminotetralin to 5-HT1A receptors in developing animals. Ethanol impaired the development of 5-HT1A receptors in the frontal cortex, parietal cortex, and lateral septum; these receptors did not undergo the normal developmental increase between postnatal days 19 and 35. The dentate gyrus was also sensitive to the effects of in utero ethanol exposure. 5-HT1A receptors were increased in this region at 19 days. Maternal buspirone treatment prevented the ethanol-associated abnormalities in 5-HT1A receptors in the dentate gyrus, frontal cortex, and lateral septum. Neither maternal ethanol consumption nor buspirone treatment altered the binding of 2 nM [3H]ketanserin to 5-HT2A receptors in the ventral dentate gyrus, dorsal raphe, parietal and frontal




J Chromatogr B Biomed Sci Appl. 1997 Sep 26;698(1-2):133-45.
Buspirone metabolite structure profile using a standard liquid chromatographic-mass spectrometric protocol.

Kerns EH, Rourick RA, Volk KJ, Lee MS.

Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, NJ 08903-0191, USA.

A rapid and systematic LC-MS protocol is utilized to profile buspirone metabolites. Analysis of rat bile, urine and liver S9 samples using a standard LC-MS method provides structural information for 25 metabolites. The resulting buspirone metabolite structure database contains characteristic retention time, molecular mass and MS-MS product ion information for each compound. Metabolites are categorized according to profile groups, which illustrate that substitution reactions are primarily associated with the azaspirone decane dione and pyrimidine substructures. Structures of new buspirone metabolites are reported and include the despyrimidinyl, despyrimidinylpiperazine, glucuronide, hydroxyglucuronide (four isomers), methoxyglucuronide and hydroxymethoxyglucuronide (two isomers) buspirone metabolites.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9367201&dopt=Abstract buspirone Buspar