psico.med.unipi.it

The mode of action of antidepressant drugs may be related to mechanisms of receptor adaptation, involving overall the serotonin 1A (5-HT1A) receptor subtype. However, so far, the clinical effectiveness of selective compounds acting at this level has proved disappointing. This could be explained by the heterogeneity of 5-HT1A receptors within the central nervous system. In animals, two 5-HT1A agonists, flibanserin and buspirone, have shown different pharmacological properties, depending on the brain region. Since no evidence supports this observation in humans, this study sought to investigate whether these two drugs exert different effects on 5-HT1A receptor activation in three different human brain areas: the prefrontal cortex, hippocampus and raphe nuclei. 5-HT1A-mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) was taken as an index of 5-HT1A receptor activation. Flibanserin significantly reduced the activity of AC post-synaptically, i.e. in the prefrontal cortex [EC50 (mean +/- S.E.M.), 28 +/- 10.2 nM; Emax, 18 +/- 2.3%] and in the hippocampus (EC50, 3.5 +/- 3.1 nM; Emax, 20 +/- 4.0%), but had no effect in the raphe nuclei, i.e. at pre-synaptic level. Vice versa, buspirone was only slightly but significantly effective in the raphe (EC50, 3.0 +/- 2.8 nM; Emax, 12 +/- 1.9%). Agonist effects were sensitive to the 5-HT1A antagonists WAY-100135 and pindobind 5-HT1A in the cortex and raphe nuclei, whereas buspirone antagonized flibanserin in the hippocampus. These findings suggest a region-related action of flibanserin and buspirone on forskolin-stimulated AC activity in human brain.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1213553&dopt=Abstract




Ther Drug Monit. 1999 Jun;21(3):317-21.
Determination of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) in human plasma by capillary gas chromatography.

Kivisto KT, Laitila J, Martensson K, Neuvonen PJ.

Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.

Two separate gas chromatographic methods for the determination of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP) in human plasma are described. Both procedures involve solid-phase extraction (the packing material of the cartridges used was C8 for buspirone and a mixed-mode sorbent for 1-PP), injection of the sample into a gas chromatograph equipped with a fused-silica capillary column and a nitrogen-phosphorus detector, and analysis with temperature programming (from 220 degrees C to 285 degrees C for buspirone and from 138 degrees C to 285 degrees C for 1-PP). The coating material of the analytical column was 5% diphenyl dimethyl silicone for buspirone and 50% diphenyl dimethyl silicone for 1-PP. Zolpidem was used as an internal standard in the buspirone assay and 1-phenylpiperazine in the 1-PP assay. Recovery of buspirone and 1-PP averaged 98% and 89%, respectively, and the limit of quantification was 0.2 ng/mL for both compounds. The between-run coefficients of variation ranged from 3.2% to 9.4% and from 2.9% to 8.6% for samples spiked with three different concentrations of buspirone and 1-PP, respectively. The suitability of these assays for pharmacokinetic studies was shown by analyzing timed plasma samples from volunteers after ingestion of a single therapeutic dose of buspirone (10 mg).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10365644&dopt=Abstract buspirone Buspar




J Psychosoc Nurs Ment Health Serv. 2002 Jul;40(7):34-41.
The use of buspirone in primary care.

Khouzam HR, Emes R.

Chemical Dependency Treatment Program, VA Central California Health Care System, 2615 East Clinton Avenue, Fresno, CA 93703-2286, USA.

1. Although clinical trials have demonstrated the effectiveness of buspirone in treating generalized anxiety disorder, more studies are needed to confirm its efficacy in treating other anxiety disorders, depression, behavior disorders, substance abuse disorders, movement disorders, and other medical conditions. 2. Clinicians prescribing buspirone must know its basic pharmacology, adverse effects, and dosing guidelines. 3. Buspirone appears to be an alternative attractive medication to traditional benzodiazepines due to its low addictive potential and lack of lethality.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12136514&dopt=Abstract buspirone Buspar

pharm.umu.se

Buspirone, a 5-HT1A agonist, has been shown to decrease the intake of ethanol when given as a single dose to rats with a psychological dependence induced according to our rat model of alcoholism. The present experiment evaluates the effects different treatments with buspirone have on voluntary ethanol intake in these psychologically dependent rats. As a first treatment, buspirone was given once daily for 23 days at the dose of 20 mg/kg/day. Ethanol was withheld except for the first and the last day of the treatment. On the first day, the buspirone injection decreased ethanol intake from the pretreatment value (1.94+/-0.18 g/kg/day), down to 1.36+/-0.18 g/kg (p < 0.01, n = 12). The rats were again given a choice between water and 10% ethanol after the last injection of buspirone. During the following 24 hr period, the ethanol intake was increased to 3.56+/-0.24 g/kg/day (p < 0.001 vs. the pretreatment intake, n = 12). A loss of correlation with the pretreatment intake of ethanol indicated an altered regulation of ethanol intake for approximately 3 more weeks. Fifteen weeks after the start of the first treatment, buspirone (20 mg/kg) was re-tested as a single dose, with no effect on ethanol intake. Twenty-two weeks after the start of the first treatment, a 1-week treatment with 20 mg/kg/day of buspirone was started. During this treatment, the rats had a continuous choice between 10% ethanol and water. There was, as in the first re-test, no effect on ethanol intake on the first day of the treatment. However, on the last 2 days of the treatment, the ethanol intake was increased to 2.86+/-0.28 g/kg and to 2.89+/-0.26 g/kg respectively (p < 0.05, n = 10 on both days, compared with the pretreatment intake of 1.78+/-0.36 g/kg). Thus, an acut




J Pharmacol Exp Ther. 2002 Dec;303(3):1130-7.
Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats.

Zuideveld KP, Rusic-Pavletic J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M.

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratories, Leiden, The Netherlands.

The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokinetic-pharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with set-point control. Both buspirone and 1-PP behaved as partial agonists relative to R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine(1A) agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12438536&dopt=Abstract buspirone Buspar

cnyrc.org

Cocaine conditioned stimuli are capable of eliciting cocaine craving in individuals with a history of cocaine use. As a consequence, there have been a number of attempts using animal models to identify pharmacological treatments which can attenuate cocaine conditioned effects. The emphasis in these studies has been to employ drug doses which do not have response effects that could directly alter the conditioned drug response. A drug treatment may not have a response effect but still have drug stimulus effects which could interact with and modify the cocaine conditioned stimulus. In order to experimentally investigate this important issue, two experiments are reported. In one experiment, rats were co-administered 0.1 mg/kg MK-801 either with cocaine (10 mg/kg) or with saline; in the other experiment 3.0 mg/kg buspirone was co-administered with either cocaine (10 mg/kg) or with saline. The MK-801 and buspirone treatments did not affect spontaneous activity levels or alter the unconditioned cocaine stimulant effect. In tests for conditioning, however, the effects of buspirone and MK-801 depended upon their association with cocaine. If MK-801 and buspirone had no association with cocaine then these drugs inactivated the cocaine conditioned stimulant response. If MK-801 and buspirone had been co-administered with cocaine, then, in saline conditioning tests, no cocaine conditioning was observed. If the conditioning tests were conducted following MK-801 or buspirone treatment, however, cocaine conditioning was elicited. Altogether, these studies demonstrate that the stimulus properties of drugs can

rockefeller.univ-lyon1.fr

The aim of the present study was to compare, in chloral-hydrate anaesthetized rats, the alpha(2)-adrenergic properties of the selective 5-HT(1A) receptor agonist, alnespirone (S-20499), with those of buspirone, a 5-HT(1A) receptor agonist exhibiting potent alpha(2)-adrenoceptor antagonist properties via its principal metabolite, 1-(2-pyrimidinyl)-piperazine. Both locus coeruleus spontaneous firing activity and noradrenaline release in the medial prefrontal cortex were potently inhibited by the alpha(2)-adrenoceptor agonist clonidine, at a dose of 40 microg/kg (i.p.). Such an inhibition was neither prevented nor reversed by alnespirone (10 mg/kg, i.p.), while buspirone, at the same dose, potently antagonized the locus coeruleus inhibitory effects of clonidine. These data demonstrate that, in contrast with some aryl-piperazine compounds (such as buspirone), alnespirone, either on its own or via a possible metabolite such as buspirone, is devoid in vivo of significant alpha(2)-adrenoceptor antagonist properties.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12505530&dopt=Abstract buspirone Buspar

hotmail.com

RATIONALE: Previous studies have shown that buspirone, a partial 5-HT(1A) receptor agonist, produces antinociceptive effects in rats and mice; Ca(2+) plays a critical role as a second messenger in mediating nociceptive transmission. 5-HT(1A) receptors have been proven to be coupled functionally with various types of Ca(2+) channels in neurons, including N-, P/Q-, T-, or L-type. It was of interest to investigate the involvement of extracellular/intracellular Ca(2+) in buspirone-induced antinociception. OBJECTIVES: To determine whether central serotonergic pathways participate in the antinociceptive processes of buspirone, and investigate the involvement of Ca(2+) mechanisms, particularly L-voltage-gated Ca(2+) channels and Ca(2+)/caffeine-sensitive pools, in buspirone-induced antinociception. METHODS: Antinociception was assessed using the hot-plate test (55 degrees C, hind-paw licking latency) in mice treated with either buspirone (1.25-20 mg/kg i.p.) alone or the combination of buspirone and fluoxetine (2.5-10 mg/kg i.p.), 5-HTP (25 mg/kg i.p.), nimodipine (2.5-10 mg/kg i.p.), nifedipine (2.5-10 mg/kg i.p.), CaCl(2) (25-200 nmol per mouse i.c.v.), EGTA (5-30 nmol per mouse i.c.v.), or ryanodine (0.25-2 nmol per mouse i.c.v.). RESULTS: Buspirone dose dependently increased the licking latency in the hot-plate test in mice. This effect of buspirone was enhanced by fluoxetine, 5-HTP, nimodipine, and nifedipine. Interestingly, central administration of Ca(2+) reversed the antinociceptive effects of buspirone. In contrast to these, ryanodine or EGTA administered centrally potentiated buspirone-induced antinociception. CONCLUSIONS: Dec