Pharmacol Biochem Behav. 1993 Dec;46(4):905-10.
Acute and chronic administration of buspirone fails to yield anxiolytic-like effects in a mouse operant punishment paradigm.

Martin JR, Moreau JL, Jenck F, Cumin R.

Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Drug-naive mice failed to exhibit antipunishment effects of ascending doses of buspirone (1-30 mg/kg, PO) in an operant punishment paradigm; however, these same mice subsequently exhibited increased punished responding after diazepam (10 mg/kg, PO). In a separate group of drug-naive mice, diazepam (1-30 mg/kg, PO)produced a robust antipunishment effect under identical experimental conditions, but crossover to buspirone (10 mg/kg, PO) failed to enhance punished responding. In a further experiment using this conflict model, two groups of benzodiazepine-experienced mice received daily oral administration of either vehicle or buspirone (5 mg/kg) for four weeks followed by a test with buspirone; neither group exhibited an antipunishment effect. Two other groups of benzodiazepine-experienced mice received either oral vehicle or diazepam (5 mg/kg) daily for four weeks followed by a test with diazepam; both groups exhibited a clear antipunishment effect. Finally, a group of benzodiazepine-experienced mice given vehicle daily for four weeks followed by a test with vehicle failed to exhibit an antipunishment effect. Thus, despite the attempt to optimize some important experimental conditions in this mouse conflict paradigm, buspirone still failed to produce an antipunishment effect. In contrast, diazepam consistently exhibited a robust anxiolytic-like effect under the same experimental conditions.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7906039&dopt=Abstract buspirone Buspar




Eur J Pharmacol. 1993 Jan 5;230(1):41-6.
Comparison of the effect of buspirone and 1-(2-pyrimidinyl)-piperazine on cerebral glucose utilization in the rat.

Grasby P, Sharp T, Moorman J, Grahame-Smith D.

M.R.C. Unit, Radcliffe Infirmary, Oxford, UK.

The novel anxiolytic and antidepressant, buspirone, and its main metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), which is pharmacologically active, were examined for their effect on regional cerebral glucose utilization in awake rats using quantitative 2-deoxyglucose autoradiography. At a dose of 1 mg/kg, buspirone reduced glucose utilization in the hippocampus by approximately 15%, whilst 1-PP at the same dose had no effect. In comparison, at a higher dose, 10 mg/kg of both buspirone and 1-PP decreased glucose utilization in the hippocampus by 20% and 27%, respectively. In addition, widespread reductions in local cerebral glucose utilization were noted with this higher dose of 1-PP; such generalized effects are compatible with those reported for alpha 2 adrenoceptor antagonists. Buspirone at 1 and 10 mg/kg increased glucose utilization by 40% and 65%, respectively, in the lateral habenular nucleus, whilst 1-PP at 1 and 10 mg/kg had no effect. The findings suggest that buspirone's effects on glucose utilization cannot be attributed to 1-PP, unless high doses of buspirone are administered.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8094054&dopt=Abstract buspirone Buspar




Pharmacol Biochem Behav. 1993 Mar;44(3):633-41.
Combination of buspirone and other drugs with beta-CCE in monkeys: effects on respiration and behavior.

Wettstein JG, Teeple ES, Morse WH.

Harvard Medical School, Boston, MA 02115.

The respiratory and behavioral effects of the benzodiazepine receptor (BZR) inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) were determined alone and in combination with buspirone, lorazepam, flumazenil, and SR 95195 in rhesus monkeys. For the respiratory studies, one group of monkeys inhaled either air or 5% CO2 mixed in air according to a fixed alternating schedule; respiratory frequency and minute volume were monitored. For the behavioral studies, another group of monkeys responded under a fixed-ratio (FR 30) schedule of food presentation. The respiratory stimulant effects of beta-CCE in both air and 5% CO2 were enhanced by prior treatment with the 5-hydroxytryptamine1A (5-HT1A) partial agonist buspirone (0.03 and 0.3 mg/kg) and a weak BZR inverse agonist, SR 95195 (10.0 mg/kg). Coadministration of buspirone (0.1 and 0.3 mg/kg) also potentiated the rate-decreasing effects of beta-CCE under the FR schedule. The BZR agonist lorazepam (3.0 mg/kg) and BZR antagonist flumazenil (1.0 mg/kg) attenuated the effects of beta-CCE on respiratory frequency and minute volume particularly under the 5% CO2 condition, and lorazepam (0.1 and 0.3 mg/kg) and flumazenil (0.1 and 0.3 mg/kg) attenuated the effects of beta-CCE on FR responding. These latter results show that the respiratory and behavioral effects of beta-CCE in rhesus monkeys are at least in part due to effects at BZRs. Moreover, the findings suggest either that coactivation of benzodiazepine and 5-HT1A sites lead to a greater than additive effect or that beta-CCE and buspirone share a common mechanism of action that is unrelated to the receptor at which BZR inverse agonists act.

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Jpn J Pharmacol. 1993 Feb;61(2):115-21.
Anxiolytic activity of SC-48274 compared with those of buspirone and diazepam in experimental anxiety models.

Ogawa N, Hara C, Takaki S.

Department of Pharmacology, Ehime University School of Medicine, Japan.

The present study was performed to assess the anxiolytic activity of the novel anxiolytic SC-48274 in comparison with those of buspirone and diazepam. Drugs were administered p.o. The experimental anxiety models included gastric lesions of mice induced by socio-psychological stress in the communication box (CB) and the passive avoidance paradigm in rats. In the CB experiments, non-foot-shocked mice (responder) exposed to the emotional responses of foot-shocked mice (sender), 3 hr per day for 3 days, developed gastric lesions. Single treatments of diazepam (1, 2, 5 mg/kg) and SC-48274 (25, 50 mg/kg) prevented gastric lesion formation, but buspirone at 2.5-10 mg/kg did not. A 3-day treatment with SC-48274 at doses over 5 mg/kg prevented gastric lesions; and a 3-day treatment with buspirone at 2, 5 and 10 mg/kg prevented the lesions with a U-shaped dose-response. Diazepam also prevented gastric lesion formation at the doses of 1 and 2 mg/kg. In the passive avoidance response study, rats which had a single acquisition trial for 2 days were used. The step-down latency for rats to enter from the illuminated compartment to the dark one was recorded. Single treatments of SC-48274 (25 mg/kg), diazepam (5, 10 mg/kg) or buspirone (25 mg/kg) shortened the delayed latency. These results suggest that SC-48274 has anxiolytic activity of the same potency as buspirone and repeated-dose administration is needed to induce anxiolytic activity.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8096257&dopt=Abstract buspirone Buspar




Jpn J Pharmacol. 1993 Apr;61(4):311-7.
Comparison of the anticonflict effect of buspirone and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats.

Amano M, Goto A, Sakai A, Achiha M, nee Hara, Takahashi N, Hara C, Ogawa N.

Pharmacology Laboratory, Bristol-Myers Squibb K.K., Aichi, Japan.

The anxiolytic effects of buspirone and its major metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP) have been investigated with a conflict (shock-induced suppression of drinking) paradigm in rats. Buspirone (10 mg/kg, p.o.) showed an anticonflict activity with a bell-shaped dose-response relationship without any effect on spontaneous water consumption. Higher doses of buspirone reduced the punished response. Diazepam (20 and 40 mg/kg, p.o.) also showed an anticonflict activity in a dose-dependent manner, but animals with diazepam showed an increase in spontaneous water consumption at these doses. On the other hand, 1-PP (6.25-200 mg/kg, p.o.) showed a weak anticonflict activity with a significant effect at 25 mg/kg without any effect on spontaneous water consumption. In the 7-day treatment test, buspirone (5 and 10 mg/kg, p.o.), 1-PP (5 and 25 mg/kg, p.o.) and diazepam (10 and 40 mg/kg, p.o.) did not develop the tolerance to the anticonflict activity. Conversely, the anticonflict activity of diazepam was increased by the repeated treatment. Diazepam (10 mg/kg, p.o.) showed an anticonflict activity without any effect on spontaneous water consumption in this test. These results demonstrated that buspirone clearly exhibited an anticonflict effect similar to that of diazepam in a Vogel-type conflict test, and its real anxiolytic effect may not be always based on 1-PP, the main metabolite of buspirone.

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J Clin Psychopharmacol. 1993 Jun;13(3):204-9.
Buspirone in the treatment of tardive dyskinesia.

Moss LE, Neppe VM, Drevets WC.

Washington University School of Medicine, Department of Psychiatry, St. Louis, MO 63110.

Eight patients with mild to severe tardive dyskinesia (TD) were treated for 12 weeks with buspirone in dosages of up to 180 mg/day in an open-label study. Changes in TD severity were assessed by the Abnormal Involuntary Movement Scale. The rater was blind to buspirone dosage. Buspirone was well tolerated by most subjects. A within-subjects comparison of pretreatment and post-treatment Abnormal Involuntary Movement Scale scores revealed a mean improvement of 4.4 (p < 0.01). Improvement was also observed in neuroleptic-induced extrapyramidal side effects such as parkinsonism and akathisia. Scores on the Hamilton Rating Scale for Anxiety and the Brief Psychiatric Rating Scale did not change during the 12-week study. The results of this open-label pilot study suggest that relatively high doses of buspirone may be efficacious in the treatment of TD.

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Br J Pharmacol. 1993 Aug;109(4):1046-52.
The effects of alpha 2-adrenoceptor antagonists on the inhibition of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shakes by 5-HT1A receptor agonists in the mouse.

Dursun SM, Handley SL.

Pharmaceutical Sciences Institute, Aston University, Birmingham.

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), gepirone, buspirone and ipsapirone dose-dependently antagonized the head-shakes induced by 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane hydrochloride (DOI) (1.0 mg kg-1) in mice, when these agents were given i.p. 10 min beforehand. 2. para-Chlorophenylalanine (pCPA) abolished the effect of 8-OH-DPAT (0.1 mg kg-1) and of buspirone (1.0 mg kg-1). (+/-)-Pindolol (5.0 mg kg-1) also antagonized the effect of 8-OH-DPAT (0.1 mg kg-1). 3. The alpha 2-adrenoceptor antagonists, RX811059 (1.0 mg kg-1), idazoxan (0.5 mg kg-1), yohimbine (1.0 mg kg-1) and 1-(2-pyrimidinyl)-piperazine (1-PP) (2.0 mg kg-1) i.p. prevented the antagonistic effect of 8-OH-DPAT (0.1 mg kg-1) on DOI-head-shakes. 4. Orally-administered buspirone, given 60 min beforehand, only reduced DOI-head-shakes at doses of 60 mg kg-1 and above. However, when buspirone (1.0 mg kg-1) was administered orally twice daily for 21 days, DOI-head-shakes were significantly reduced when tested 60 min after the first daily dose on days 5, 12 and 21 and 48 h after withdrawal. 5. A single oral dose of buspirone (1.0 mg kg-1) strongly antagonized DOI-head-shakes when given 24 h after the last of 4 daily doses of 1-PP (2.0 mg kg-1, p.o.) but had no effect on DOI-head-shakes 24 h after the last of 4 daily doses of water (p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

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Pharmacol Biochem Behav. 1994 Jan;47(1):153-9.
Perceptual masking of the chlordiazepoxide discriminative cue by both caffeine and buspirone.

Gauvin DV, Peirce JM, Holloway FA.

Department of Psychiatry & Behavioral Sciences, University of Oklahoma Health Sciences Center, Oklahoma City 73190.

Twelve male Sprague-Dawley rats were trained to discriminate between the interoceptive stimulus attributes of 5 mg/kg chlordiazepoxide (CDP) and saline in a two-lever operant task under a fixed-ratio 10 (FR-10) schedule of food reinforcement. Caffeine, buspirone, and Ro 15-1788 failed to engender complete generalization when tested in combination with saline. In drug interaction test sessions caffeine (56 mg/kg) blocked the discriminative stimulus properties of the training dose of CDP and shifted the CDP discriminative dose-response function to the right. This rightward shift in CDP discriminative function was paralleled by a concomitant downward shift in the rate-of-responding dose-response function. Drug interaction test sessions conducted with 3.2 mg/kg of buspirone in combination with various doses of CDP engendered a downward shift in both the discriminative and rate-of-responding dose-response functions. Because 3.2 mg/kg buspirone in combination with the training dose of CDP resulted in complete response rate suppression, additional combination tests were conducted with 3 mg/kg CDP, a dose which reliably engendered > 90% CDP-appropriate responding, and various doses of buspirone. Similar to the CDP-caffeine interactions, buspirone blocked the cueing properties of 3 mg/kg CDP with a parallel reduction in response rates. Interaction test sessions conducted with Ro 15-1788 and CDP resulted in rightward shifts in both the discriminative and rate functions of CDP. We suggest that the interactions between CDP and both caffeine and buspirone resulted from the perceptual masking of the interoceptive (subjective) effects of CDP, whereas the interaction between Ro 15-1788 and CDP reflect pharmacological an