SR 58611A, a selective agonist of gut and brown adipose tissue beta 3-adrenoceptors (beta 3 ARs), has been reported to have antidepressant-like activity in rodents, by indicating brain beta 3ARs as the sites of this property. SR 58611A and its acid metabolite SR 58878A, as opposed to BRL 37344, ICI 215,001, and CGP 12177, increased cyclic AMP levels in rat frontal cortex. ICI 215,001, differently from BRL 37344, at concentrations in the millimolar range antagonized norepinephrine- or (-)-isoproterenol-stimulated adenylyl cyclase partially. The increase of cyclic AMP levels induced by SR 58878A was blocked selectively by beta 1AR antagonist CGP 20712A but not by beta 2AR antagonist ICI 118,551. In addition, PCR analysis did not reveal beta 3AR mRNA, and no specific beta 3AR binding sites were detected by [3H]CGP 12177 in rat frontal cortex. When down-regulation of the beta 1AR ligand binding and mRNA levels had been induced in frontal cortex by chronic administration of imipramine, SR 58878A as well as norepinephrine and (-)-isoproterenol inceased the cyclic AMP production less markedly. Our findings indicate that beta 3ARs are absent in the adult rat frontal cortex, and that various beta 3AR agonists differently affect the frontal cortex beta 1ARs, indicating that SR 58611A may exert its putative antidepressant effect acting on the frontal cortex beta 1ARS.