An in-vivo method for testing drugs that influence striatal dopaminergic functions

Abstract

A procedure is described for evaluating the effects of drugs on dopaminergic function in the striatum of mice. Mice, anesthetized with chloral hydrate are injected with 6-hydroxydopamine into one striatum to destroy dopamine nerve terminals at this site. Several days later, the mice are anesthetized with halothane, and test drugs or saline are injected into the intact striatum either before or after the systemic administration of amphetamine. The effect of these drugs on amphetamine-induced circling behavior is evaluated. Using this model, we have found that pilocarpine and muscimol can inhibit amphetamine-induced circling and their effects are blocked by the systemic administration of scopolamine and picrotoxin, respectively. In addition, ethyleneglycol-bis-(β-amino-ethyl ether) N,N′-tetraacetic acid (EGTA), a calcium chelating agent, inhibited amphetamine-induced circling behavior and this effect is prevented by adding calcium to the EGTA solution. Finally, the intrastriatal administration of prostaglandin E 2 but not its metabolite, 13,14-dihydro-15-keto-prostaglandin 2 inhibited amphetamine-induced circling suggesting a selective effect of the active prostaglandin. These results suggest that this procedure could be used for evaluating both the mechanism of action of drugs in the striatum as well as screening drugs for their therapeutic potential.