Pharmacological Research Communications, Vol. 20, Supplement//, 1988

POTENTIATION OF D! AND D2 RECEPTOR ANTAGONISTS: BEHAVIORAL STUDIES

R. Dall'Olio, O, Gandolfi, A. Vaccheri, P. Roncada and N. Montanaro

Institute of Pharmacology, University of Bologna

Key words: DI and D2 receptors, neuroleptic activity, behavior, rat

While several lines of evidence suggest that DI and D2 receptors interact

for the full expression of dopamine-mediated behavior, conflicting observa-

tions are available regarding the role of the two classes of dopamine rece-

ptors in the activity of neuroleptics: D2 dopamine receptors have been pro-

posed as the site mediating the antidopaminergic activity of these drugs as

all clinically effective neuroleptics are mixed DI/D2 or selective D2 anta-

gonists. Nevertheless, the DI blocker SCH 23390 inhibits agonist-induced

stereotypy and hyperactivity whereas the D2 antagonist (-)-sulpiride weakly

inhibits dopamine-mediated behaviors. Aim of the present study was to asce- rtain if the administration o~ the DI blocker SCH 23390 at a dose ineffec-

tive per se would enable the D2 selective antagonist sulpiride to fully ex-

press a neuroleptic activity.

Rats ~fere treated with different doses of (-)-sulpiride and SCH 23390 and

evaluated for their exploratory motility, apomorphine-induced stereotyped

behavior and hypermotility elicited by the D2 agonist LY 171555. This ap- proach allowed us to choose the doses of the two antagonists ineffective in

each behavioral trial; such doses were concomitantly injected in the same

animal and the abovementioned behavioral responses were assayed.

The results showed that (-)-sulpiride (I0 - 20 - 40 mg/kg) did not affect

exploratory motility and apomorphine-induced stereotypy when administered

alone, whereas the DI blpcker SCH 23390 reduced these behaviors at 0.01 and

0.02 mg/kg, and was ineffective at 0.05 mg/kg. When (-)-sulpiride was admi-

nistered in combination with 0.005 mg/kg SCH 23390 both exploratory motili-

ty and apomorphine-induced stereotyped responses were significantly inhibi-

ted. As far as the effect of the two antagonists on the D2 receptor media-

ted responses, only the very low doses of (-)-sulpiride and SCH 23390 admi-

nistered alone (2.5 and 0.0025 mg/kg, respectively) were ineffective in

blocking hypermotility elicited by LY 171555; the combination of the same

ineffective doses of the two antagonists significantly reduced rat locomo-

tor response to the D2 stimulation. The results support the view of a strict correlation between the DT and the

D2 dopamine receptors and suggest that the blockade of both receptors is ne-

cessary for the full antidopaminergic activity of the neuroleptics.

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