Effect of acute and chronic administration of buspirone on serotonin and benzodiazepine receptor subtypes in the rat brain: An autoradiographic study

Gobbi, Marco; Cavanus, S.; Miari, Anna; Mennini, Tiziana

doi:10.1016/0028-3908(91)90055-g

Cited by 28 publications

(13 citation statements)

References 21 publications

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“…As the in vivo affinity of 6-OHbuspirone at the 5-HT 1A receptor is comparable to that of buspirone (Table 5), the contribution of this metabolite in occupying 5-HT 1A receptors in the buspirone experiments is probably low. Although 1-PP was not quantitated in this experiment, it has been shown to have low in vitro affinity and selectivity at 5-HT 1 receptors in rat brain (Caccia et al, 1986;Gobbi et al, 1991) and thus is not likely to contribute significantly to the 5-HT 1A occupancy observed in our studies.…”

Section: Discussionmentioning

confidence: 86%

“…Of these metabolites, 1-PP has been the most extensively investigated in its role as an active metabolite (Caccia et al,1986;Zuideveld et al, 2002). 1-PP behaves as an ␣ 2 -adrenoceptor antagonist with a low affinity to the 5-HT 1A receptor (Caccia et al, 1986;Gobbi et al, 1991) and therefore is unlikely to play an important role in the anxiolytic effects of buspirone. Much less is known about the pharmacological properties of 6-OH-buspirone.…”

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confidence: 99%

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6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Wong

Dockens²,

Pajor³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 ؎ 3.5 ml/min/kg), volume of distribution (2.6 ؎ 0.3 l/kg), and half-life (1.2 ؎ 0.2 h) of 6-OHbuspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT) 1A Buspirone ( Fig. 1) is a potent and selective 5-HT 1A receptor partial agonist that has been prescribed for the treatment of generalized anxiety disorders (Sramek et al., 2002;Blier and Ward, 2003;Goodman, 2004). Although the onset of action of buspirone is relatively slow and the efficacy is only obtained after chronic treatment, therapy with buspirone is not associated with undesirable side effects such as sedation, cognitive impairment, withdrawal symptoms, and potential abuse liability that can occur with benzodiazepine treatment (Eison and Temple, 1986;Tunnicliff, 1991;Argyropoulos and Nutt, 1999). Buspirone has also been suggested to have a role in the treatment of depressive disorders (Thase et al., 1998;Blier and Ward, 2003).Current hypotheses on the clinical mechanisms of action of buspirone focus on its agonist activities on 5-HT 1A receptors (Schreiber and De Vry, 1993;Blier and Ward, 2003). Belonging to the superfamily of G-protein-coupled receptors, 5-HT 1A receptors share a high identity (89%) of their transmembrane-spanning amino acid sequences in humans and rats (Albert et al., 1990). They are abundant as presynaptic (somatodendritic) autoreceptors on serotonergic neurons, primarily in the midbrain dorsal raphe nucleus; activation of the 5-HT 1A autoreceptors inhibits the neuronal activity and results in a reduction of 5-HT release in terminal synapses of the serotonergic neurons (Blier and Ward, 2003). 5-HT 1A receptors are also present as postsynaptic receptors in the forebrain limbic structures; activation of these receptors inhibits activities of postsynaptic neurons innervated by serotonergic axonal terminals. It has been hypothesized that prolonged activation of 5-HT 1A autoreceptors in the dorsal raphe with 5-HT 1A agonists, such as buspirone and its analogs, results in desensitization of the receptors and consequently increases releases of 5-HT in the limbic regions (Blier and Ward, 2003). The enhanced serotonergic functions are believed to be responsible for anxiolytic and antidepressant effects of these agents. Although behavioral/clinical effects of buspirone and other 5-HT 1A agonists are believed to be mediated through occupying and acting on 5-HT 1A receptors, the level of 5-HT 1A receptor occupancy required for the effects has not been well investigated. In two human positron emission tomography studies, little or no occupancy of 5-HT 1A receptors has been observed after administration of clinically efficacious doses of buspirone (Rabiner et al., 200...

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Wong

Dockens²,

Pajor³

et al. 2007

Drug Metab Dispos

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“…It is not clear whether repeated administration of 8-OH-DPAT may desensitize the responses mediated by 5-HT 1A autoreceptors by reducing the density of 5-HT 1A receptors in the raphe nuclei. The density of 5-HT 1A receptors in the dorsal raphe nucleus, as determined by [ 3 H]8-OH-DPAT binding, has been shown to be reduced following treatment for 21 days with the 5-HT 1A receptor agonists buspirone (Gobbi et al, 1991), gepirone (Welner et al, 1989), and ipsapirone (Fanelli and McMonagle-Strucko, 1992). Interestingly, the latter study found that repeated treatment with ipsapirone did not alter the density of 5-HT 1A receptors in the median raphe nucleus (Fanelli and McMonagleStrucko, 1992).…”

Section: Discussionmentioning

confidence: 97%

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei

Kreiss

Lucki

1997

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The present study investigated alterations of the regulation of serotonin (5-hydroxytryptamine; 5-HT) release by 5-HT1A autoreceptors following single and repeated treatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). Rats were pretreated with 8-OH-DPAT (1.0 mg/kg, s.c.) for 1, 7, or 14 days. The ability of an acute challenge administration of 8-OH-DPAT (1.0 mg/kg, i.p.) to decrease 5-HT release in the ventral striatum and the ventral hippocampus of rats maintained under chloral hydrate anesthesia was examined 24 h after the last pretreatment injection using in vivo microdialysis. The decrease of 5-HT release in the striatum produced by the challenge dose of the 5-HT1A receptor agonist was diminished following 7 and 14 days of pretreatment, but not after 1 day of pretreatment, with 8-OH-DPAT. In contrast, decreases of 5-HT release in the hippocampus by the 8-OH-DPAT challenge were not altered after 1 or 7 days of pretreatment, and only a trend for attenuation appeared after pretreatment for 14 days. The results of the present study indicate that desensitization of 5-HT1A autoreceptors regulating 5-HT release in different brain regions by repeated treatment with 8-OH-DPAT occurs at different rates.

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“…Because not all of the subjects had recent exposure to antidepressant medications, it appears that the increase in serotonin-1A receptors is related to the depression and/or suicide. Furthermore, chronic treatment of rats with SSRIs, monoamine oxidase inhibitors, or novel anxiolytics with antidepressant qualities either decreases or has no effect on [ 3 H]8-OH-DPAT binding to serotonin-1A receptors in midbrain (Welner et al, 1989;Gobbi et al, 1991;Hensler et al, 1991;Fanelli et al, 1992;Burnet et al, 1994;Le Poul et al, 1995).…”

Section: The Binding Of [mentioning

confidence: 99%

Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity

Stockmeier

Shapiro²,

Dilley³

et al. 1998

J. Neurosci.

384

243

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It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [, an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [ 3 H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [ 3 H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.

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Effect of acute and chronic administration of buspirone on serotonin and benzodiazepine receptor subtypes in the rat brain: An autoradiographic study

Cited by 28 publications

References 21 publications

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei

Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity

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Effect of acute and chronic administration of buspirone on serotonin and benzodiazepine receptor subtypes in the rat brain: An autoradiographic study

Cited by 28 publications

References 21 publications

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1AReceptor Occupancy in Rats

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei

Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity

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6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats