Psychopharmacology (Berl). 1988;94(1):14-20.
Serotonin does not mediate anxiolytic effects of buspirone in the fear-potentiated startle paradigm: comparison with 8-OH-DPAT and ipsapirone.

Davis M, Cassella JV, Kehne JH.

Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven 06508.

The present study evaluated the role of various neurotransmitter systems in mediating buspirone's blockade of the fear-potentiated startle effect, where acoustic startle amplitude is normally increase in the presence of a light previously paired with a shock. Large lesions of the dorsal and median raphe nuclei or IP injections of the serotonin antagonists cinanserin (10 mg/kg) or cyproheptadine (5 mg/kg) did not alter fear-potentiated startle, nor did these treatments prevent buspirone (5 or 10 mg/kg SC) from blocking fear-potentiated startle. The 5-HT 1A agonist 8-OH-DPAT (2.5-10.0) did not block fear-potentiated startle even at doses that produced a marked "5-HT syndrome". Another 5-HT 1A agonist, ipsapirone (10-20 mg/kg), blocked potentiated startle only at a very high dose (40 mg/kg). p-Chlorophenylalanine and p-chloroamphetamine did not alter fear-potentiated startle. Finally, pretreatment with the benzodiazepine receptor antagonist RO-15-1788 (1 mg/kg); the opiate antagonist naloxone (2 mg/kg) or the alpha 2-adrenergic antagonist yohimbine (5 mg/kg) did not reduce fear-potentiated startle, nor did they prevent buspirone from blocking fear-potentiated startle. Taken together, the data do not support the hypothesis that buspirone's anxiolytic effects are mediated by actions at 5-HT 1A receptors and more generally indicate that serotonergic neurons do not play an important role in fear-potentiated startle.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2894698&dopt=Abstract buspirone Buspar




Psychopharmacology (Berl). 1988;94(1):8-13.
Anxiolytic effects of buspirone and gepirone in the fear-potentiated startle paradigm.

Kehne JH, Cassella JV, Davis M.

Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven 06508.

Fear potentiation of the acoustic startle reflex was produced by eliciting startle responses in the presence of a light that had been previously paired with a shock. Buspirone (0.6-5.0 mg/kg) and gepirone (1.25-10.0 mg/kg), but not their common metabolite, 1-PP (0.5-40 mg/kg), produced a dose-dependent reduction of fear-potentiated startle. These doses of buspirone and gepirone slightly increased baseline startle levels. Reduction of fear-potentiated startle appears to involve supraspinal sites of action, since intraventricular but not intrathecal administration of buspirone (200 micrograms) reduced fear-enhanced startle. Both buspirone and gepirone were highly efficacious in this model compared to other animal tests that are used to study anxiolytic compounds.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2894703&dopt=Abstract buspirone Buspar




Jpn J Pharmacol. 1987 Dec;45(4):493-500.
Pharmacological properties of SM-3997: a new anxioselective anxiolytic candidate.

Shimizu H, Hirose A, Tatsuno T, Nakamura M, Katsube J.

Research Laboratories, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.

Pharmacological properties of SM-3997 (3a alpha,4 beta,7 beta,7a alpha-hexahydro-2-(4-(4-(2-pyrimidinyl)-1- piperazinyl)-butyl)-4,7-methano-1H-isoindole-1,3(2H)-dione dihydrogen citrate) have been examined in rats and mice. SM-3997 showed a dose-related anticonflict activity in rats in a water lick conflict paradigm, and it had no effect on water consumption in a spontaneous water drinking test. The potency of SM-3997 appeared to be equal to that of buspirone and about one-half that of diazepam. No tolerance to the anticonflict activity of SM-3997 was observed following 5 and 10 consecutive days of treatment. Unlike diazepam, SM-3997 had no anticonvulsant effect and had very weak muscle relaxant and hypnotic effects. On the other hand, SM-3997 and buspirone exhibited dopamine antagonistic action, although the potency of SM-3997 was less than one fourth that of buspirone. These results show that SM-3997 is a new anxioselective anxiolytic agent which is weaker than buspirone in the dopaminergic neuron system.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2895201&dopt=Abstract buspirone Buspar




Life Sci. 1990;47(11):961-9.
Effects of systemically administered monoamine reuptake blocking agents on patterns of buspirone-induced analgesia in rats.

Rogers LW, Giordano J.

Neuropharmacology Laboratory, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA 50311.

We have recently shown the serotonin 5-HT1A receptor agonist buspirone to produce analgesia in several pain tests in rats. As a 5-HT1A agonist, buspirone may change serotonergic (5-HT) tone to alter the balance of central monoaminergic (MA) systems that function in analgesia. MA-reuptake blocking drugs have been shown to produce analgesia, both when given alone and in combination with a variety of other agents, presumably via their action upon MA neurochemistry. The present study was undertaken to examine the effect of systemic administration of the 5-HT-reuptake blocker amitriptyline (AMI: 10 mg/kg), NE-reuptake blocker desipramine (DMI: 10 mg/kg) or DA-reuptake blocker GBR-12909 (7.5 mg/kg) on patterns of analgesia produced by buspirone (1-5 mg/kg) in thermal and mechanical pain tests in rats. Neither reuptake blocking agents or buspirone, when administered alone or in combination, produced overt changes in motor activity at the doses tested. AMI alone was not analgesic in either thermal or mechanical pain tests. In both assays, AMI reduced the analgesic action of buspirone, with greater effects seen in the thermal test. When administered alone, DMI produced significant analgesia against thermal and mechanical pain. DMI significantly attenuated the analgesic action of all doses of buspirone in both pain tests. Alone, GBR-12909 did not affect nociception in thermal or mechanical tests. GBR-12909 decreased buspirone-induced analgesia at all doses in the thermal test, while having no effect on buspirone-induced analgesia against mechanical pain. These results demonstrate that facilitation of 5-HT, NE and DA function with reuptake blocking drugs did not enhance the analgesic action of buspirone. Thes




Eur J Pharmacol. 1988 Mar 15;147(3):343-50.
Blockade of alpha 2-adrenoceptors by 1-(2-pyrimidinyl)-piperazine (PmP) in vivo and its relation to the activity of buspirone.

Bianchi G, Garattini S.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

The effect of 1-(2-pyrimidinyl)-piperazine (PmP) and the parent drug, buspirone in counteracting the behavioral and biochemical effects of clonidine were evaluated in the rat. Intraperitoneal or oral administration of PmP, buspirone and yohimbine, but not of prazosin, antagonized the slowing of gastrointestinal motility induced by subcutaneous clonidine (0.1 mg/kg). The doses that inhibited the effect of clonidine on the transit time by 50% were 0.5 mg/kg i.p. and 0.7 mg/kg p.o. for PmP, 7 mg/kg i.p. and 9 mg/kg p.o. for buspirone and 0.5 mg/kg i.p. for yohimbine. PmP (0.5 mg/kg) did not block the antitransit effect of clonidine when administered by intracerebroventricular injection. The antitransit effect of a low dose of morphine (0.05 mg/kg i.p.) was not blocked by PmP (2 mg/kg i.p.). The prolongation of the hexobarbital-induced loss of the righting reflex that occurs after clonidine (0.25 mg/kg i.p.) administration was inhibited by pretreatment with PmP (0.1-2 mg/kg p.o.) or yohimbine (1 mg/kg i.p.) but not by pretreatment with prazosin (2 mg/kg i.p.). Buspirone (1-20 mg/kg) also reduced the effect of clonidine after oral administration, with a maximal effect at 5 mg/kg, whereas the same dose administered i.v. had less effect. PmP (2 mg/kg) and buspirone (15 mg/kg) raised the levels of total 3-methoxy-4-hydroxyphenylgycol (MHPG) in rat cerebral cortex, and prevented the decrease in MHPG induced by clonidine. These findings show that buspirone, in doses at which it is active as an anxiolytic, suppresses the central and peripheral effects of clonidine. This action occurs through alpha 2-adrenoceptors and is mediated primarily by the metabolite, PmP.

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Pharmacol Biochem Behav. 1988 Apr;29(4):711-5.
5-Hydroxytryptamine1A receptor-mediated effects of buspirone, gepirone and ipsapirone.

Koenig JI, Meltzer HY, Gudelsky GA.

Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH 44106.

The effects of the nonbenzodiazepine anxiolytic agents, buspirone, gepirone and ipsapirone on body temperature and corticosterone secretion were studied in the rat. The administration of buspirone, gepirone and ipsapirone resulted in dose-related decreases in body temperature and increases in the plasma concentration of corticosterone. Spiperone produced a dose-related inhibition of the hypothermic and corticosterone responses to gepirone. Spiperone also inhibited ipsapirone-induced changes in body temperature and hormone secretion. Although spiperone also blocked the buspirone-induced stimulation of corticosterone, it did not attenuate the hypothermic response to buspirone at the dose tested. (-)-Pindolol, a potent 5-HT1A antagonist, prevented gepirone- and ipsapirone-induced hypothermia and corticosterone secretion. (-)-Pindolol also blocked the hypothermic but not the corticosterone response to buspirone. Ketanserin, a 5-HT2 antagonist, did not inhibit the hypothermic or corticosterone responses produced by these novel anxiolytic agents. It is concluded that buspirone, gepirone and ipsapirone produce hypothermia and increase plasma concentrations of corticosterone by activating 5-HT1A receptor mechanisms.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2901112&dopt=Abstract buspirone Buspar




Psychopharmacology (Berl). 1990;102(3):301-8.
Effects of 8-OH-DPAT, buspirone and ICS 205-930 on feeding in a novel environment: comparisons with chlordiazepoxide and FG 7142.

Fletcher PJ, Davies M.

Neuropsychiatric Research Division, University of Saskatchewan, Saskatoon, Canada.

Previously, the 5-hydroxytryptamine (5-HT)1A receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone and the 5-HT3 receptor antagonist ICS 205-930 have been shown to exert anxiolytic-like effects in several animal models. In the experiments reported here the effects of these compounds on feeding behaviour and food preference in a novel environment were examined, and compared with the effects of the anxiolytic drug chlordiazepoxide and the anxiogenic compound FG 7142. Chlordiazepoxide significantly reduced the latency to begin eating and prolonged the total time spent eating; chlordiazepoxide also abolished food neophobia, by significantly increasing the time spent eating novel food items. In contrast, FG 7142 significantly increased eating latency and reduced eating duration. Both 8-OH-DPAT and buspirone significantly enhanced eating duration, but unlike chlordiazepoxide eating was directed only towards the familiar food. In addition buspirone, but not 8-OH-DPAT, reduced eating latency. ICS 205-930 significantly increased eating latency and reduced eating duration; however, these effects were observed only at the lowest dose tested. All of these behavioural effects were observed only when animals were unfamiliar with the testing situation, and cannot be accounted for in terms of changes in mechanisms controlling hunger. The behavioural paradigm used in these experiments may induce a competition between the drives to explore a novel environment and to eat. It is suggested that the tendency of buspirone and 8-OH-DPAT to suppress exploratory activity may thus result in enhanced feeding duration.(ABSTRACT TRUNCATED AT 250 WORDS)

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Eur J Pharmacol. 1988 Jul 7;151(2):341-4.
Behavioral effects of acute and chronic buspirone.

Wettstein JG.

Department of Psychiatry, Harvard Medical School, Boston, MA 02115.

The effects of buspirone were studied in squirrel monkeys trained to lever-press under a fixed-interval schedule involving suppressed responding. Buspirone (0.01-0.1 mg/kg) generally did not increase rates of suppressed responding. Buspirone (0.01-0.1 mg/kg) generally did not increase rates of suppressed responding; 0.3 mg/kg of buspirone decreased rate. In comparison, diazepam (0.1-1.0 mg/kg) and CL 218872 (0.3-3.0 mg/kg) increased responding. Additionally, the effects of buspirone (0.01-0.3 mg/kg) were unchanged over a 12-day period of daily administration. The results show that buspirone has effects on schedule-controlled behavior of squirrel monkeys that differ from those of typical anxiolytic drugs.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2901975&dopt=Abstract buspirone Buspar