Modulation of mesoprefrontal dopamine neurons by central benzodiazepine receptors. I. Pharmacological characterization.
The benzodiazepine (BZ) recognition sites on the gamma-aminobutyric acid receptor/chloride ionophore complex have been suggested to be involved in the modulation of mesoprefrontal dopamine (DA) neurons. We have examined further the effects of different classes of BZ receptor ligands on DA metabolism in the prefrontal cortex. The anxiogenic inverse agonist FG 7142 elevated selectively 3,4-dihydroxyphenylacetic acid (DOPAC) levels and DO-PAC/DA ratio in the prefrontal cortex in a dose- and time-dependent manner. The activating effect was not, however, observed in any other mesocortical, mesolimbic or nigrostriatal DA terminal fields examined. Pretreatments with BZ agonists such as diazepam, flurazepam, lorazepam and CGS 9896 and BZ antagonists such as Ro15-1788 and CGS 8216 and barbiturates such as pentobarbital, significantly antagonized the beta-carboline-induced elevation of prefrontal DOPAC levels. Furthermore, a significant correlation was found between the pharmacological profile of different BZ receptor ligands on prefrontal DA metabolism and their profiles in behavioral, electrophysiological and receptor binding studies. Agonists increased DA levels and consequently decreased DOPAC/DA ratio in the prefrontal cortex. Inverse agonists, on the other hand, significantly elevated prefrontal DOPAC levels and DOPAC/DA ratio in a dose-dependent manner. Antagonists such as Ro15-1788 and CGS 8216, at low doses, did not alter mesoprefrontal DA metabolism, but at higher doses did elevate DOPAC/DA ratio in the prefrontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D058787:GABA-A Receptor Antagonists; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D001067:Appetite Depressants; D002243:Carbolines; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D015102:3,4-Dihydroxyphenylacetic Acid; C035874:FG 7142; D010424:Pentobarbital; D004298:Dopamine