J Pharm Pharmacol. 1988 Jul;40(7):494-500.
Actions of buspirone in a putative model of anxiety in the mouse.

Costall B, Kelly ME, Naylor RJ, Onaivi ES.

Postgraduate School of Studies in Pharmacology, University of Bradford, UK.

In a two-compartment box divided into a dark area and a brightly illuminated white area, mice taken from a dark environment showed aversion to the light and exhibited preference for exploratory rearings and line crossings in the black area. The peripheral administration of buspirone, and its injection into the dorsal raphe nucleus, lead to an increased time spent in the white area associated with enhanced exploratory behaviour with a decreased incidence of rearings and line crossings in the black section. In contrast, the injection of 5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine into the dorsal raphe nucleus increased exploratory behaviour in the black section with decreased activity in the white area: the effects of 2-methyl-5-hydroxytryptamine were antagonized by buspirone administered peripherally. Ritanserin, methysergide, metergoline and cyproheptadine failed, in non-sedative doses, to influence exploratory behaviour in the two-compartment system and ritanserin and methysergide also failed to antagonize the effects caused by 2-methyl-5-hydroxytryptamine. It is concluded that in the mouse model the ability of buspirone to reduce the aversive response to a brightly illuminated area may reflect an anxiolytic action, that the dorsal raphe nucleus may be an important locus of action, and that the effects of buspirone may reflect an interaction at 5-hydroxytryptamine receptors.

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Life Sci. 1988;43(25):2095-102.
Different effects of intracerebral and systemic administration of buspirone in the forced swimming test: involvement of a metabolite.

Cervo L, Grignaschi G, Samanin R.

Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.

Buspirone, a drug with high affinity for serotonin1A receptors, was studied for its ability to reduce rats' immobility in the forced swimming test when injected systemically or into the nucleus raphe dorsalis (DR). Between 0.1 and 10 mg/kg buspirone had no effect on rats' immobility when injected systemically as a single dose or as a 3-injection course during 24 hours. Direct injection of 1 and 5 mu/0.5 microliter buspirone in the DR significantly reduced the duration of immobility without changing rats' activity in an open field. The anti-immobility effect of 1 microgram/0.5 microliter buspirone in the DR was completely prevented by injecting 2.5 micrograms (-)-propranolol in the same area. Oral administration of 0.3-1.0 mg/kg 1-(2-pyrimidinyl)piperazine (1-PP), one of the main metabolites of buspirone, and 0.3-3.0 mg/kg s.c. idazoxan, two substances with alpha 2 adrenergic blocking properties, completely antagonized the effect of 0.25 mg/kg s.c. 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), an agent with selective affinity for serotonin1A receptors. The anti-immobility effect of an infusion of 1 microgram/0.5 microliter buspirone or 8-OH-DPAT in the DR was also antagonized by 1 mg/kg p.o. 1-PP. The results suggest that buspirone possesses potential antidepressant properties but its effects may be masked in certain tests by its metabolite, 1PP, through its alpha 2 adrenergic blocking activity.

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Pharmacol Biochem Behav. 1988 Jul;30(3):723-7.
Effects of buspirone differ from those of gepirone and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on unpunished responding of pigeons.

Barrett JE, Fleck-Kandath C, Mansbach RS.

Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.

Under several behavioral procedures, such as punished responding and drug discrimination, the effects of the atypical anxiolytic buspirone are similar to those of its analogue gepirone, and to those of the 5-HT1A receptor agonist 8-OH-DPAT. Similarities in the effects of these compounds occur despite the fact that buspirone produces strong dopaminergic actions, whereas both gepirone and 8-OH-DPAT effects mainly appear to be serotonergically mediated. When keypeck responding of pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixed ratio schedule of food presentation, responding under both the fixed-interval and fixed-ratio schedules was decreased over a range of buspirone doses (0.3-5.6 mg/kg). As has been reported with many antipsychotic compounds, performance under the fixed-interval schedule was more sensitive to the rate-decreasing effects of buspirone. In contrast, both gepirone (0.03-3.0 mg/kg) and 8-OH-DPAT (0.03-1.0 mg/kg) increased responding under the two schedules. Differences in the effects of buspirone from the other compounds in this study, compared to the similar effects of these drugs obtained using other procedures, emphasize the importance of the specific behavior as a determinant of drug action. The multiple fixed-interval, fixed-ratio schedule may be useful for delineating the relative balance of dopaminergic and serotonergic effects produced by drugs that are less apparent using other behavioral procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

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Eur J Pharmacol. 1988 Jul 14;151(3):365-71.
The alpha 2-adrenoceptor antagonist activity of ipsapirone and gepirone is mediated by their common metabolite 1-(2-pyrimidinyl)-piperazine (PmP).

Bianchi G, Caccia S, Della Vedova F, Garattini S.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

Ipsapirone and gepirone, analogs of buspirone, a newly developed antianxiety agent, form 1-(2-pyrimidinyl)-piperazine (PmP) during their biotransformation in rats. After oral administration (10 mg/kg) of a parent drug, e.g. ipsapirone or gepirone, the metabolite appears in significant amounts in plasma, with maximal concentrations of 0.9 and 1.4 nmol/ml respectively. The metabolite half-life ranged from about 140 to 200 min. Ipsapirone is eliminated more slowly than gepirone, with a half-life of about 100 and 30 min, respectively. The metabolite to parent drug ratios for the areas under the plasma concentration-time curve (AUC) were 1 for ipsapirone and 14 for gepirone. PmP (0.5-2 mg/kg p.o), ipsapirone, gepirone and buspirone (5-20 mg/kg p.o.) dose dependently antagonized the slowing of gastrointestinal transit induced by clonidine 0.1 mg/kg s.c. The doses inhibiting the antitransit effect of clonidine by 50% were 0.8 mg/kg for PmP, 14 mg/kg for ipsapirone and 9 mg/kg for both gepirone and buspirone. Analysis of small intestinal longitudinal muscle of rats given the ED50 of PmP, ipsapirone, gepirone, buspirone showed that PmP concentrations in the longitudinal muscle (with attached myenteric plexus) fell within a relatively narrow range and were consistent with the appropriate transit scores. The plasma was also tested for anticlonidine activity. These data indicate that PmP formation is a pharmacologically significant metabolic process for the buspirone-related drugs, ipsapirone and gepirone, and that this metabolite is responsible for the alpha 2-adrenoceptor blocking activity exerted by these drugs in vivo in the rat.

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Brain Res. 1988 Sep 27;461(1):1-9.
Buspirone, 8-OH-DPAT and ipsapirone: effects on hippocampal cerebellar and sciatic fiber excitability.

Hiner BC, Mauk MD, Peroutka SJ, Kocsis JD.

Department of Neurology, Yale University School of Medicine, New Haven, CT 06520.

The effects of serotonin (5-hydroxytryptamine; 5-HT), and the novel anxiolytics buspirone, 8-OH-DPAT (8-hydroxy-2-[N,N-dipropylamino]-tetralin) and ipsapirone (TVXQ 7821, 2-[4-[4-[2-pyrimidinyl]-1-piperazinyl] butyl]-1,2-benzisothiazol-3[2H]one-1,1-dioxide-hydrochloride) on fiber excitability were studied in three axon systems; hippocampal Schaffer collateral fibers, cerebellar parallel fibers, and sciatic nerves. In the hippocampus, application of buspirone, 8-OH-DPAT and ipsapirone resulted in reversible, dose-dependent reductions in the amplitude and conduction velocity of action potentials recorded from presynaptic afferent fibers. Although these agents bind to 5-HT1A receptors, 5-HT application, even at very high (1 mM) concentrations, did not alter axonal responses. This suggests that buspirone, 8-OH-DPAT and ipsapirone exert an action independent of a serotonergic mechanism. Similar effects were observed on the cerebellar parallel fibers although the cerebellum does not have an appreciable number of 5-HT1A receptors. To examine the generalized effects of these agents on nerve excitability, rat sciatic compound action potentials were studied with sucrose gap recordings. Whereas 5-HT, 8-OH-DPAT and ipsapirone had no effects even at high concentrations (1 mM), application of buspirone led to reversible decrement of the responses without appreciable change in membrane potential. These results indicate that buspirone, 8-OH-DPAT and ipsapirone have actions on the excitability of hippocampal and cerebellar neurons independent of serotonergic mechanisms. Moreover, buspirone, but not 8-OH-DPAT or ipsapirone, produces decreased sciatic nerve excitability. NS 20393

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Eur J Pharmacol. 1988 Oct 18;155(3):279-83.
Strychnine seizure potentiation by azaspirodecanedione anxiolytics in rats.

Anderson MC, Chung E, Van Woert MH.

Department of Neurology, Mt. Sinai School of Medicine, New York, NY 10029.

Buspirone, gepirone and ipsaperone administered intraperitoneally (40 mg/kg) to naive rats were found to be proconvulsive for strychnine-induced seizures. The dose of strychnine required to induce seizures in 50% of test animals (CD50) was 2.18 mg/kg in naive rats, while CD50s for rats treated with the azaspirodecanediones ipsaperone, gepirone and buspirone were 1.65, 0.97 and 0.70 mg/kg respectively. Azaspirodecanediones have high affinity for the 5-HT1A serotonin receptor, however, the specific 5-HT1A agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) had no effect on strychnine seizure in naive rats (CD50 = 2.0 mg/kg). The strychnine specific proconvulsive effects of inferior olive lesions and buspirone were additive, resulting in a CD50 of 0.1 mg/kg. This observation indicates that the buspirone-induced decrease in strychnine seizure threshold does not require intact inferior olive-climbing fiber pathways. Cerebellar sites for possible azaspirodecanedione action are discussed.

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Eur J Pharmacol. 1988 Oct 11;155(1-2):129-37.
Alpha 2-adrenoceptor antagonist activity may account for the effects of buspirone in an anticonflict test in the rat.

Gower AJ, Tricklebank MD.

Merrell Dow Research Centre, Strasbourg, France.

The anxiolytic effects of buspirone, its metabolite, 1-(2-pyrimidyl)piperazine (1-PP) and several alpha 2-adrenoceptor antagonists have been compared in an anticonflict (shock-induced suppression of drinking) paradigm in rats. Idazoxan, WY 26392 and yohimbine had anticonflict effects comparable to those of buspirone and 1-PP, and enhanced the release of suppressed responding induced by buspirone. The response to buspirone was antagonised by the alpha 2-adrenoceptor agonist clonidine. In tests of clonidine-induced mydriasis, the antagonist potencies of buspirone, 1-PP, idazoxan, WY 26392 and yohimbine corresponded closely to the doses of the compounds active in the anticonflict test. Clonidine-induced hypolocomotion was also antagonised by 1-PP, although this response was potentiated by buspirone. The results suggest that the anticonflict effects of buspirone involve an alpha 2-adrenoceptor mechanism.

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Pain. 1989 Feb;36(2):257-61.
Buspirone effect on the development of antinociceptive reactions.

Bragin EO, Korneev AY, Vasilenko GF.

Central Research Institute of Reflex Therapy, Ministry of Health, Moscow U.S.S.R.

The anxiolytic agents, buspirone and diazepam, increase the paw lick latency of rats in the hot plate test, the effect being dose-dependent and exceeding that of morphine. The action of buspirone was not accompanied by ataxic and sedative effects which were observed in rats on diazepam. Buspirone (up to 25 mg/kg) and diazepam (up to 5 mg/kg) neither change the tail flick latency nor potentiate the action of morphine on the test. A buspirone dose of 2 mg/kg administered to animals before foot shock, or the dose of 1.5 mg/kg before cold swimming stress, led to a significant increase in hot plate latency 1 min after stress as compared to the control. The effect of buspirone on the paw lick reaction in rats may be related to the activation of antinociceptive mechanisms and inhibition of an emotional-motivational component of the pain reaction.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2919106&dopt=Abstract buspirone Buspar