Eur J Pharmacol. 1993 Aug 3;239(1-3):69-73.
Sustained 5-hydroxytryptamine release-inhibitory and anxiolytic-like action of the partial 5-HT1A receptor agonist, buspirone, after prolonged chronic administration.

Soderpalm B, Lundin B, Hjorth S.

Department of Pharmacology, University of Goteborg, Sweden.

The effect of prolonged administration of high doses of buspirone on its 5-hydroxytryptamine (5-HT) release-inhibitory and anxiolytic-like properties was investigated. The 5-HT release-inhibitory effect of a challenge dose of buspirone (0.5 mg/kg, s.c.) was identical in rats chronically treated with vehicle or buspirone (10 mg/kg, b.i.d. for 10 weeks), as estimated by in vivo microdialysis in the ventral hippocampus. In the same set of animals there was a significant anxiolytic-like effect in the elevated plus-maze after 5 weeks of treatment with buspirone. The results indicate that the functional capacity of 5-HT release-controlling 5-HT1A autoreceptors is retained upon chronic administration of buspirone, and that this effect may well be associated with the anxiolytic-like action of the compound.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7901030&dopt=Abstract buspirone Buspar




Eur J Pharmacol. 1993 Sep 14;241(2-3):141-8.
Pharmacological evidence for interactions between 5-HT1A receptor agonists and subtypes of alpha 1-adrenoceptors on rabbit aorta.

Castillo C, Ibarra M, Marquez JA, Villalobos-Molina R, Hong E.

Departamento de Farmacologia y Toxicologia, Centro de Investigacion y Estudios, Avanzados del I.P.N., Mexico, D.F.

This study was designed to determine if alpha 1-adrenoceptors are involved in the vascular responses to 5-HT1A receptor agonists. Buspirone (3.1 x 10(-7)-3.1 x 10(-5) M) and 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT; 3.1 x 10(-6)-10(-4) M) elicited contractions of rabbit aorta rings which were blocked by prazosin (10(-9)-5.6 x 10(-9) M), but which were unaffected by reserpine pretreatment (1 mg/kg i.p.). 5-Methylurapidil (10(-7) and 10(-6) M) blocked contractions elicited by 8-OH-DPAT and by buspirone, whereas chloroethylchonidine (10(-5) and 10(-4) M) inhibited only the effect of buspirone. In addition, these 5-HT1A receptor agonists relaxed arteries precontracted with alpha-adrenoceptor agonists in a similar range of concentrations in which they elicited contraction. Moreover, 8-OH-DPAT and buspirone protected the alpha-adrenoceptors from the irreversible blockade provoked by phenoxybenzamine (10(-7) M), as judged by the norepinephrine contraction and stimulated phosphatidylinositol labeling. According to these results the contractile and relaxant effects elicited by 5-HT1A receptor agonists are a consequence of a direct interaction with alpha 1-adrenoceptors. The contraction elicited by 8-OH-DPAT may be mediated by alpha 1A-adrenoceptors, whereas both alpha 1A- and alpha 1B-adrenoceptors may mediate the effect of buspirone in rabbit aorta.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7902287&dopt=Abstract buspirone Buspar




Naunyn Schmiedebergs Arch Pharmacol. 1993 Oct;348(4):339-46.
Effect of acute and repeated administration of 5-HT1A receptor agonists on 5-HT release in rat brain in vivo.

Sharp T, McQuade R, Bramwell S, Hjorth S.

MRC Clinical Pharmacology Unit, Radcliffe Infirmary, Oxford, UK.

1. Electrophysiological measurements of 5-HT neuronal activity report that repeated administration of 5-HT1A receptor agonists leads to desensitization of the 5-HT1A autoreceptor but this has not yet been detected in measurements of brain 5-HT synthesis or metabolism. Here we have determined the effect of repeated administration of 5-HT1A receptor agonists on brain 5-HT release using microdialysis. 2. Acute administration of the 5-HT1A receptor agonists buspirone (0.1-5 mg/kg s.c.) and ipsapirone (0.03-3 mg/kg s.c.) caused a dose-dependent decrease in 5-HT output in ventral hippocampus of the chloral hydrate anaesthetized rat. 3. The 5-HT response to buspirone (0.1 and 0.5 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was significantly inhibited by pre-treatment with the 5-HT1/beta-adrenoceptor antagonist pindolol (8-16 mg/kg s.c.). The 5-HT response to buspirone (0.1 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was not blocked by pretreatment with a combination of the beta 1 and beta 2-adrenoceptor antagonists metoprolol and ICI 118,551 (4 mg/kg s.c.). 4. The effect of an acute challenge of buspirone (0.5 mg/kg s.c.) on 5-HT output in ventral hippocampus was not attenuated in rats treated twice daily for 14 days with 0.5 or 5 mg/kg s.c. buspirone compared to saline-injected controls. Similarly, the decrease in 5-HT induced by an acute challenge of ipsapirone (0.5 mg/kg s.c.) was not attenuated in rats treated twice daily for 14 days with 5 mg/kg s.c. ipsapirone.(ABSTRACT TRUNCATED AT 250 WORDS)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7904048&dopt=Abstract buspirone Buspar




Neuropsychobiology. 1992;26(1-2):89-99.
Comparative study on the behavioral and EEG changes induced by diazepam, buspirone and a novel anxioselective anxiolytic, DN-2327, in the cat.

Hashimoto T, Hamada C, Wada T, Fukuda N.

Research and Development Division, Takeda Chemical Industries Ltd., Osaka, Japan.

Behavioral and EEG effects of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4)-dioxa-8-(azas piro-[4.5]dec-8- yl)carbonylmethyl]isoindolin-1-one (DN-2327; 1, 5 and 20 mg/kg p.o.) were compared to those of diazepam (0.2 and 1 mg/kg p.o.) and buspirone (1 and 5 mg/kg p.o.) in freely moving cats. DN-2327 did not affect motor coordination or the relative percentages of the three sleep-wakefulness stages. Diazepam (1 mg/kg) increased wakefulness and non-REM sleep, and buspirone (5 mg/kg) also increased wakefulness and decreased REM sleep. In addition, diazepam (1 mg/kg) caused severe motor disturbance, but buspirone did not. The cortical EEG power density spectra during wakefulness were changed almost dose-dependently by DN-2327 (decreased: 2-7.75 Hz; increased: 20-49.75 Hz), and dose-dependently by diazepam (decreased: 2-7.75 Hz; increased 13-49.75 Hz) and buspirone (decreased: 4-9.75 and 13-19.75 Hz). The effect of DN-2327 on the cortical EEG varied with the sleep-wakefulness stage. The power of the 4- to 7.75-Hz frequency (theta) band of the hippocampal EEG during wakefulness was decreased by diazepam and buspirone but not by DN-2327, while the peak frequency of its spectra was decreased only by diazepam. On the other hand, during non-REM sleep, DN-2327 decreased the power of the theta band as did diazepam. These results indicate that the behavioral and EEG effects of DN-2327 differ completely from those of buspirone and considerably from those of diazepam and that the EEG effect of DN-2327 varies with the sleep-wakefulness stage.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1361973&dopt=Abstract buspirone Buspar




Pharmacol Biochem Behav. 1993 Nov;46(3):647-51.
Atypical anxiolytic profile of buspirone and a related drug, SM-3997, in a modified forced swim test employing straw suspension.

Nishimura H, Tanaka M, Tsuda A, Gondoh Y.

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

Previous reports have shown that immobility time increases in the presence of suspended straws in association with an inhibition of straw-climbing behavior after acute administration of a prototypical anxiolytic benzodiazepine (BZD) such as diazepam. In this modified forced swim (MFS) test employing straw suspension, the effects of two new non-BZD compounds were tested and compared with those of diazepam (0.5, 1, and 5 mg/kg, IP) used in a previous MFS test. After a 5-min test of forced swimming, four straws were suspended just above the surface of the water and subsequently the straw-climbing trials were counted for 5 min as an index of escape behaviors induced by negative emotionality (stress and/or anxiety). Rats were injected IP with either saline, buspirone HCl (0.5, 1, and 5 mg/kg), or a related compound, SM-3997 (5, 10, and 20 mg/kg), 30 min before testing. At lower doses, both buspirone (0.5, 1 mg/kg) and SM-3997 (5, 10 mg/kg) reduced the duration of immobility, as opposed to that of diazepam. Conversely, buspirone at the highest dose of 5 mg/kg significantly prolonged the duration of immobility, and SM-3997 at 20 mg/kg also prolonged its duration, indicating a biphasic effects. All doses of buspirone and SM-3997 inhibited straw-climbing counts, in the same manner as diazepam. These results suggest that buspirone may possess relatively weak and/or atypical anxiolytic effects at lower doses, whereas at 5 mg/kg this compound may have an anxiolytic effect. In addition, SM-3997 may be a less potent anxiolytic drug than buspirone in the MFS test following a single-injection protocol.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7904073&dopt=Abstract buspirone Buspar




Eur J Pharmacol. 1993 Nov 16;249(3):341-51.
Neuronal circuits involved in the anxiolytic effects of the 5-HT1A receptor agonists 8-OH-DPAT ipsapirone and buspirone in the rat.

Schreiber R, De Vry J.

Institute for Neubiology, Department of Psychopharmacology, Cologne, Germany.

In rats, the 5-HT1A receptor full agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT1A receptor partial agonists ipsapirone and buspirone dose dependently and completely inhibited shock-induced ultrasonic vocalization after systemic injection and after microinjection into the dorsal raphe nucleus, a brain region rich in somatodendritic 5-HT1A receptors. As compared with injection into the dorsal raphe nucleus, ipsapirone and 8-OH-DPAT were significantly less potent after microinjection into the lateral ventricle or the median raphe nucleus. Depletion of brain 5-HT (5-hydroxytryptamine) by means of 5,7-dihydroxytryptamine or parachlorophenylalanine inhibited ultrasonic vocalization. In lesioned rats, however, ipsapirone (i.p. or dorsal raphe nucleus) and 8-OH-DPAT (dorsal raphe nucleus) retained their ability to inhibit ultrasonic vocalization and, in non-lesioned rats, bilateral injection of ipsapirone, buspirone and 8-OH-DPAT into the dorsal hippocampus and the amygdala - two brain regions rich in postsynaptic 5-HT1A receptors - also inhibited ultrasonic vocalization. In a Geller-Seifter conflict test, i.p. and local injection of 8-OH-DPAT in the dorsal raphe nucleus and the hippocampus selectively enhanced punished responding. It is suggested that both presynaptic and (possibly to a lesser extent) postsynaptic 5-HT1A receptors are involved in the anxiolytic effects of ipsapirone, buspirone, and 8-OH-DPAT.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7904566&dopt=Abstract buspirone Buspar




Neuropharmacology. 1993 Oct;32(10):969-75.
Effects of chlordiazepoxide, buspirone and the 5-HT3 receptor antagonist, BRL 46470, on the behaviour of oestrous and dioestrous female mice when encountering male partners.

Gao B, Cutler MG.

Department of Biological Sciences, Glasgow Caledonian University, Scotland.

Ethological procedures were employed to examine the differences in behaviour between oestrous and dioestrous control mice, and to investigate the changes to behavioural responsiveness in oestrous and dioestrous mice induced by treatment with the anxiolytic compounds, chlordiazepoxide (CDP, 21.5 mg/l), buspirone (12.8 mg/l) and the 5-HT3 receptor antagonist, BRL 46470 (40 micrograms/l). Compounds were given in drinking fluid for 6-8 days prior to behavioural observations (average daily intake: CDP--5 mg/kg; buspirone--2.5 mg/kg; BRL 46470--10 micrograms/kg). Behaviour of the females was examined in the "approach-avoidance" situation of 5 min encounters with an unfamiliar male in a neutral cage. Oestrous controls spent more time in social investigation, sniffing of the substrate and scanning than dioestrous controls and spent less time in digging and exploration. Each of the anxiolytic compounds, CDP, buspirone and BRL 46470, significantly raised the duration of social investigation both in oestrous and dioestrous females. Each of these compounds also increased the duration of "digging" by oestrous females, and duration of the social element "investigate" in dioestrous females. Effects on the occurrence of other individual elements within each behavioural category depended on the anxiolytic compound administered and the stage of the ovarian cycle at the time of testing. There were few significant differences between the behaviour of the male partners in each group. It is concluded that in this paradigm both oestrous and dioestrous females are sensitive to the enhancement of social investigation by anxiolytic compounds and that the use of female mice in this tes




Neuropharmacology. 1993 Oct;32(10):977-85.
Serotonergic innervation of the hippocampus and nucleus accumbens septi and the anxiolytic-like action of midazolam and 5-HT1A receptor agonists.

Stefanski R, Palejko W, Bidzinski A, Kostowski W, Plaznik A.

Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, Warsaw, Poland.

An involvement of serotonergic innervation of the hippocampus (HP) and the nucleus accumbens septi (NAS) in anxiolytic activity of benzodiazepine midazolam and 5-HT1A receptor agonists was studied in two different animal models of anxiety. Injection of midazolam (10.0 and 20.0 micrograms) or 8-OH-DPAT (0.5 and 1.0 micrograms) into the hippocampus increased punished consumption of water in the Vogel conflict test. Buspirone given at 0.1, 0.5 and 1.0 microgram was ineffective in the Vogel test, while at 5.0 micrograms it enhanced shock-induced suppression of drinking. In the open-field test midazolam (0.01 and 0.1 microgram), 8-OH-DPAT (0.1, 0.5 and 1.0 microgram) and buspirone (2.5 and 5.0 micrograms) increased the number of entries into the central part of the open-field and the time spent in the central sector. Depletion of 5-HT had no influence on the anxiolytic-like effect in the open-field test of intrahippocampally-administered 8-OH-DPAT (0.5 microgram), but the drug tended to increase motor activity in lesioned animals. Midazolam and buspirone injected into the NAS did not have an anxiolytic effect in the Vogel test. A small increase in punished drinking was observed after 8-OH-DPAT (1.0 and 2.5 micrograms). Following intra-NAS injection, midazolam, 8-OH-DPAT and buspirone all failed to produce any marked anxiolytic-like effect in the open-field test. It appears that the hippocampus, rather than the NAS, is involved in mediating anxiolytic-like effects of 5-HT1A receptor agonists. Hippocampal postsynaptic 5-HT1A receptors may account for the anti-emotional influence of this group of drugs. The results indicate some similarit