Apparent mediation of the stimulus properties of a low dose of quinpirole by dopaminergic autoreceptors
Widzowski, D.V.; Cory-Slechta, D.A.
Journal of Pharmacology and Experimental Therapeutics 266(2): 526-534
1993
ISSN/ISBN: 0022-3565 PMID: 8355188 Document Number: 405338
This study examined the hypothesis that, if the stimulus properties of the D-2 agonist quinpirole (QUIN) were mediated by autoreceptors, then pharmacological treatments engendering a decline in dopamine (DA) release and consequent decrease in postsynaptic DA receptor stimulation should result in QUINappropriate responding; those that activate postsynaptic receptors should result in saline-appropriate responding. In rats trained to discriminate 0.05 mg/kg of QUIN from saline using standard operant drug discrimination procedures, QUIN (up to the training dose), two other putative D-2 autoreceptor agonists (low-dose apomorphine and N-propylnorapomorphine), the DA depeleter alpha-methyl-p-tyrosine (AMPT) and the D-1 antagonist SCH 23390 all produced primarily QUIN-lever responding. Moreover, coadministration of alpha-methyl-p-tyrosine with QUIN potentiated QUIN-stimulus properties. Higher doses of apomorphine, known to stimulate postsynaptic D-1 and D-2 receptors and pretreatment with the D-2 antagonist haloperidol decreased QUIN-lever responding. Neither the D-1 agonist SKF38393, the indirect D-1/D-2 agonist d-amphetamine, the D-2 antagonist haloperidol or coadministration of SCH 23390 and d-amphetamine substituted for QUIN. Coadministration of either SKF 38393 or d-amphetamine with QUIN decreased levels of QUIN responding. Taken together, the data are consistent with the contention that the stimulus properties of 0.05 mg/kg of QUIN are primarily mediated by D-2-type presynaptic autoreceptors and that these stimulus properties involve a decline in DA release and consequent decreased postsynaptic stimulation. Manipulations directly affecting postsynaptic D-2 receptors (high doses of QUIN, SCH 23390 and damphetamine coadministration) did not affect QUIN responding consistently, suggesting that postsynaptic D-2 receptors play a minor or neutral role in the stimulus properties of 0.05 mg/kg of QUIN.