PHARMACOLOGY OF A MIXED 5-HYDROXYTRYPTAMINE(1A) DOPAMINE AGONIST/

U-674138 (4-hydroxydipropylaminodihydrophenalene) bound with high affi nity to both 5-hydroxytryptamine (HT)(1A) and D2-dopamine (DA) recepto r sites. U-674138 depressed 5-HT and DA cell firing rates and depresse d synthesis of both neurotransmitters. The drug depressed mouse body t emperatures by an amount similar to that for buspirone, gepirone and i psapirone, but less than that for 8-hydroxy-N,N-dipropyl-2-aminotetral in. In rats, it produced the 5-HT1A behavioral syndrome. In contrast t o 5-HT1A agonists having DA antagonist effects, U-67413B mildly depres sed rather than stimulated firing rates of noradrenaline (NA) neurons in the locus ceruleus by a non-alpha-2 receptor mechanism. In behavior al tests designed to measure anxiolytic activities, U-67413B was a sli ghtly more effective anxiolytic than standard 5-HT1A anxiolytics (busp irone, gepirone and ipsapirone). The data are consistent with the hypo thesis that effects of 5-HT1A agonists on NA neuron activity are media ted through effects on dopaminergic mechanisms, and that effects on NA neurons could modulate anxiolytic activities of 5-HT1A agonists.