Behav Pharmacol. 1994 Feb;5(1):42-51.
Noradrenaline-serotonin interactions in the anxiolytic effects of 5-HT(1A) agonists.

Lopez-Rubalcava C, Fernandez-Guasti A.

Seccion de Terapeutica Experimental, Departamento de Farmacologia y Toxicologia, CINVESTAV and Division de Investigaciones en Neurociencias, Instituto Mexicano de Psiquiatria, Ap. Postal 22026, Mexico 14 000 D.F., Mexico.

The purpose of this study was to analyse adrenergic and serotonergic interactions in the anxiolytic effects of several 5-HT(1A) agonists including ipsapirone, buspirone, indorenate and 8-OH-DPAT. To this end, the effects of different doses of the adrenergic compounds clonidine (0.015-0.0625mg/kg), yohimbine (0.125-0.5mg/kg), prazosin (0.5-2.0mg/kg), pindolol (1.55-6.2mg/kg) and practolol (0.25-1.0mg/kg) on defensive burying behaviour were established. Clonidine (0.015-0.0625mg/kg), prazosin (1.0 and 2.0mg/kg), pindolol (1.55 and 6.2mg/kg) and all 5-HT(1A) agonists reduced burying behaviour by themselves. In contrast, yohimbine (0.250 and 0.5mg/kg) increased, while practolol did not modify, this behaviour. Additionally, the actions of yohimbine (0.125mg/kg), prazosin (0.5mg/kg), pindolol (3.1mg/kg) and practolol (0.5mg/kg) on the effects of ipsapirone (5.0mg/kg), buspirone (5.0mg/kg), indorenate (5.0mg/kg) and 8-OH-DPAT (0.25mg/kg) were examined. Prazosin enhanced the effects of ipsapirone, indorenate and buspirone, while yohimbine antagonized the actions of indorenate and 8-OH-DPAT. Pindolol enhanced the effects of indorenate while practolol antagonized the actions of ipsapirone, buspirone and 8-OH-DPAT. Only buspirone (5.0mg/kg) affected motor coordination, an effect that was not counteracted by the antagonists. Based on these data an interaction between 5-HT(1A) agonists and the noradrenergic system in the regulation of anxiety is proposed.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11224250&dopt=Abstract buspirone Buspar




Behav Pharmacol. 1994 Jun;5(3):255-264.
Serotonin involvement in the discriminative stimulus effects of mu and kappa opioids in rats.

Powell KR, Picker MJ, Dykstra LA.

Department of Psychology, University of North Carolina, Chapel Hill, NC 27599-3270, USA.

The role of serotonin (5-HT) in the discriminative stimulus effects of opioids was examined using a two-lever, food-reinforced drug discrimination procedure. The effects of the 5-HT(1A) full agonist 8-OH-DPAT, the 5-HT(1A) partial agonist buspirone and the 5-HT(2) antagonist ketanserin were evaluated in rats trained to discriminate the mu opioid agonist morphine, or the kappa opioid agonist U50, 488 from saline. In rats trained to discriminate 5.6mg/kg of morphine from saline, morphine dose-dependently substituted (produced >/= 80% morphine-appropriate responding) for the morphine stimulus. In contrast, U50,488, 8-OH-DPAT and ketanserin did not substitute for morphine, and buspirone produced only a small degree of substitution (approx. 40% morphine-appropriate responding). When administered in combination with morphine, 8-OH-DPAT, but not buspirone and ketanserin, attenuated the discriminative stimulus effects of higher doses of morphine. In rats trained to discriminate 5.6mg/kg of U50, 488 from saline, U50, 488 dose-dependently substituted for the U50, 488 stimulus. When administered alone, 8-OH-DPAT and buspirone partially substituted (produced between 40% and 79% U50, 488-appropriate responding) for the U50,488 stimulus, whereas morphine and ketanserin did not substitute for U50,488. The opioid antagonist naltrexone failed to antagonize the effects of 8-OH-DPAT and buspirone suggesting that the effects of these drugs in U50,488-trained rats were not mediated by opioid receptors. When administered in combination with U50,488, 8-OH-DPAT, but not buspirone or ketanserin, attenuated the discriminative stimulus effects of the training dose of U50,488. These results suggest that the 5-HT system is involved in the discriminative stimulus e




Behav Pharmacol. 1994 Jun;5(3):315-325.
Triazolam discrimination by humans under a novel response procedure: effects of buspirone and lorazepam.

Kamien JB, Bickel WK, Oliveto AH, Smith BJ, Higgins ST, Hughes JR, Badger GJ.

Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA.

Six healthy human volunteers (ages 18 to 24) acquired a triazolam (0.32mg/70kg) vs placebo discrimination under a standard, two-response drug discrimination procedure. Dose-effect curves were then determined for triazolam (0.1-0.56mg/70kg), lorazepam (0.75-3.0mg/70kg) and buspirone (7.5-30mg/70kg) under a novel response procedure that provided a response alternative for drugs unlike triazolam or placebo (i.e. a novel-appropriate response). Triazolam dose-dependently increased triazolam-appropriate responding but did not occasion any novel-appropriate responding. Lorazepam dose-dependently increased triazolam-appropriate responding in four of six subjects, but at least one dose also occasioned novel-appropriate responding in three subjects. Buspirone dose-dependently increased novel-appropriate responding, although three of six subjects also made triazolam-appropriate responses following some dose(s). All three drugs comparably increased self-reported sedation. Self-reported effects did not differentiate triazolam from lorazepam whereas only buspirone increased "bad" self-reports, and did not increase "liking" and "good" self-reports. The results suggest that the novel response procedure enhanced the pharmacological selectivity of human benzodiazepine discrimination and may help interpret partial generalization under two-choice drug discrimination procedures. The results also add to the evidence of a close relationship between the discriminative stimulus and self-reported effects of drugs.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11224281&dopt=Abstract buspirone Buspar




Pharmacol Biochem Behav. 2001 Feb;68(2):255-62.
Behavioral effects of buspirone in the marmoset employing a predator confrontation test of fear and anxiety.

Barros M, Mello EL, Huston JP, Tomaz C.

Primate Center and Department of Physiological Sciences, Institute of Biology, University of Brasilia, Brazil, CEP 70910-900, DF, Brasilia, Brazil.

In order to further validate the recently developed marmoset (Callithrix penicillata) predator confrontation model of fear and anxiety, we investigated the behavioral effects of buspirone with this method. The apparatus consisted of three parallel arms connected at each end to a perpendicular arm, forming a figure-eight continuous maze. A taxidermized wild oncilla cat (Felis tigrina) was positioned facing a corner of the parallel arms, alternating between the left or right side of the maze among animals tested. All subjects were first submitted to seven 30-min maze habituation trials (HTs) in the absence of the predator, and then to five randomly assigned treatment trials (TTs) in the presence of the predator: three buspirone sessions (0.1, 0.5 and 1.0 mg/kg), saline and sham injection controls. Twenty minutes after treatment administration, the animal was released into the maze and had free access to the apparatus for 30 min. All trials were taped for later behavioral analysis. Buspirone significantly decreased the frequency of scent marking, while increasing the time spent in proximity to the 'predator' stimulus, indicating an anxiolytic effect. Neither locomotor activity, exposure to a novel environment, stimulus location and habituation, nor gender influenced the effects of the drug treatments. These results further validate this method and demonstrate the potential usefulness of this ethologically based paradigm to test anxiety and fear-induced avoidance in nonhuman primates and its susceptibility to anxiolytic pharmacological manipulations.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11267630&dopt=Abstract buspirone Buspar




Bioorg Med Chem. 2001 Apr;9(4):881-95.
Molecular dynamics of buspirone analogues interacting with the 5-HT1A and 5-HT2A serotonin receptors.

Bronowska A, Les A, Chilmonczyk Z, Filipek S, Edvardsen O, Ostensen R, Sylte I.

Department of Chemistry, University of Warsaw, Poland.

Three-dimensional (3-D) models of the human serotonin 5-HT1A and 5-HT2A receptors were constructed, energy refined, and used to study the interactions with a series of buspirone analogues. For both receptors, the calculations showed that the main interactions of the ligand imide moieties were with amino acids in transmembrane helix (TMH) 2 and 7, while the main interactions of the ligand aromatic moieties were with amino acids in TMH5, 6 and 7. Differences in binding site architecture in the region of highly conserved serine and tyrosine residues in TMH7 gave slightly different binding modes of the buspirone analogues at the 5-HT1A and 5-HT2A receptors. Molecular dynamics simulations of receptor-ligand interactions indicated that the buspirone analogues did not alter the interhelical hydrogen bonding patterns upon binding to the 5-HT2A receptor, while interhelical hydrogen bonds were broken and others were formed upon ligand binding to the 5-HT1A receptor. The ligand-induced changes in interhelical hydrogen bonding patterns of the 5-HT1A receptor were followed by rigid body movements of TMH2, 4 and 6 relative to each other and to the other TMHs, which may reflect the structural conversion into an active receptor structure.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11354671&dopt=Abstract buspirone Buspar




Gen Pharmacol. 2000 May;34(5):357-62.
Buspirone, a 5-HT(1A) receptor agonist, dilates the perfused rat uterine vascular bed through alpha(1)-adrenoceptor blockade.

Adeagbo AS, Kadavil EA, Yousif M, Oriowo MA.

Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA.

In the perfused rat uterine vascular bed, 5-hydroxytryptamine (5-HT) produced dose-dependent vasoconstrictor responses. Buspirone, a selective 5-HT(1A) receptor agonist, was not effective at low doses but produced a response at high doses. When perfusion pressure was raised with phenylephrine, responses to 5-HT were enhanced while buspirone produced dose-dependent vasodilator responses. Buspirone did not produce vasodilation when perfusion pressure was raised with vasopressin or U46619. Buspirone-induced vasodilator responses were not affected by selective 5-HT(1A) receptor antagonists, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]-decane-7,9-dione (BMY 7378) and N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpropanamide (WAY 100478), indicating that specific 5-HT(1A) receptors might not be involved in buspirone-induced vasodilation. Buspirone (3 x 10 (-5) M) and prazosin (3 x 10(-9) M) antagonized noradrenaline-induced constriction with dose ratios of 19.1+/-2.9 and 11.7+/-2.1, respectively. The dose ratio of these antagonists in combination was 46.6+/-8.1. Since the combination ratio is closer to the sum of their individual dose ratios less 2 (i.e. DR(p)+DR(b)-2) than it is to the product of their individual dose ratios, our data suggest an interaction of buspirone with alpha(1)-adrenoceptors. Buspirone also protected adrenoceptors against inactivation by phenoxybenzamine confirming that buspirone interacted with alpha(1)-adrenoceptors. We concluded that buspirone-induced vasodilation of the perfused rat uterine vascular bed is mediated through blockade of alpha(1)-adrenoceptors rather than through 5-HT(1A) receptors.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11368892&dopt=Abstract buspirone Buspar




Brain Res Dev Brain Res. 2001 Jun 29;128(2):157-64.
Potential involvement of S100B in the protective effects of a serotonin-1a agonist on ethanol-treated astrocytes.

Eriksen JL, Druse MJ.

Division of Molecular & Cellular Biochemistry, Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA.

Previously, this laboratory found that the offspring of rats that consumed ethanol on a chronic basis prior to parturition exhibited a significant reduction in serotonin (5-HT) neurons and in astrocytes proximal to these neurons. This laboratory also showed that maternal treatment with a 5-HT(1A) agonist during the latter part of gestation prevented the reduction of 5-HT neurons and most of the astrocyte abnormalities. The present in vitro studies extended our prior in vivo work by examining the potential involvement of S100B with the protective effects of a 5-HT(1A) agonist, i.e., buspirone, on astrocytes. Astrocyte cultures were either maintained in chemically defined media in the presence and absence of ethanol and buspirone or in conditioned media that was generated by ethanol- and buspirone-treated astrocytes. A mouse monoclonal antibody to S100B was used to assess the potential involvement of S100B with the protective effects of buspirone. Additional in vitro studies measured the direct effects of S100B and ethanol on astrocyte proliferation. These investigations demonstrate that in vitro ethanol exposure reduces the number of astrocytes, and that treatment with the 5-HT(1A) agonist buspirone prevents the ethanol-associated reduction in astrocyte number. The protective effects of buspirone appear to be mediated by factors that are secreted by astrocytes; such factors likely include S100B. In addition, added S100B prevents an ethanol-associated reduction in [(3)H]-thymidine incorporation into proliferating astrocytes.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11412901&dopt=Abstract buspirone Buspar




J Psychopharmacol. 1998;12(4):380-4.
The novel buspirone analogue, 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)[butyl]-8-azaspiro [4.5 ]decane-7,9-dione, with anxiolytic-like and antidepressant-like effects in rats.

Deren-Wesolek A, Tatarczynska E, Chojnacka-Wojcik E.

Institute of Pharmacology, Polish Academy of Sciences, Krakow.

In the conflict drinking test, used as a model to examine anxiolytic-like activity, the novel buspirone analogue 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl)-8-azaspiro[ 4.5]decane-7,9-dione (MM199) (0.62-2.5 mg/kg) and buspirone (0.62-5 mg/kg), significantly increased the punished drinking in water-deprived rats, without affecting water consumption or perception of the stimulus. The anticonflict activity of MM199 (1.25 mg/kg) was blocked by (S)-WAY 100135 (20 mg/kg), a 5-hydroxytrypatmine1A (5-HT1A) receptor antagonist. In the forced swimming test, used as a model to examine the antidepressant-like activity, MM199 (5-20 mg/kg) reduced the immobility time, while buspirone (5-20 mg/kg) had no such effect. The reduced immobility induced by MM199 (20 mg/kg) was antagonized by (S)-WAY100135 (10 mg/kg). The above findings suggest that MM199 possesses potent anxiolytic- and antidepressant-like properties which are mediated by activation of 5-HT1A receptors.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10065913&dopt=Abstract buspirone Buspar