ELECTROPHYSIOLOGICAL EFFECTS OF PUTATIVE AUTORECEPTOR-SELECTIVE DOPAMINE AGONISTS ON A10 DOPAMINE NEURONS

The dopamine (DA) hypothesis of schizophrenia proposes hyperactivity o f the mesocorticolimbic DA system, originating within the A10 DA cells of the ventral tegmental area (VTA), as a pathophysiological mechanis m. Thus, reduction of activity in this system, including that produced by putative ''autoreceptor-selective'' DA agonists, may be of clinica l utility. The present studies compared the ability of eight D2 DA rec eptor agonists to inhibit the firing of rat A10 DA neurons after i.v. administration. Both -propyl-N-phenylethyl-p(3-hydorxyphenyl)ethylamin e hydrochloride (RU 24213) and lyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5 -d]-azepine dihydrochloride (B-HT 920) were potent, high-efficacy agon ists which completely inhibited the firing of A10 DA cells. The putati ve autoreceptor-selective DA agonists phenyl-1,2,3,6-tetrahydropyridyl -(1)-butyl)-indole hydrochloride (EMD 23,448) and (+)-3-(3-hydroxy-phe nyl)-N-n-propylpiperidine [(+)-3-PPP] were considerably weaker than RU 24213 and B-HT 920, but also exhibited ''full'' efficacy (i.e., they completely suppressed cell firing). The putative autoreceptor agonist preclamol [(-)-3-PPP] and its trans-fused congener (-)-HW 165 were wea k partial agonists that failed to completely inhibit A10 DA cells. The new putative autoreceptor agonist ro-6-methylergoline-8-yl]-2,2-dimet hylopropanamide (SDZ 208-911) was also a weak partial agonist that exh ibited partial antagonist effects (reversed inhibition produced by the D2 agonist quinpirole), whereas its structural analog ro-6-methylergo line-8-yl]-2,2-dimethylopropanamide (SDZ 208-912) was nearly inactive as an agonist, but was an effective antagonist. If it is the case that drugs having low activity at DA autoreceptors possess an autoreceptor -selective profile of action, then the present results suggest that pr eclamol, (-)-HW 165, SDZ 208-911 and SDZ 208-912 may have utility as a ntipsychotic drugs.