APOMORPHINE PRIMING ALTERS THE RESPONSE OF STRIATAL OUTFLOW PATHWAYS TO D-2 AGONIST STIMULATION IN 6-HYDROXYDOPAMINE-LESIONED RATS

Chronic treatment with dopaminergic agonists is associated with respon se fluctuations to L-dihydroxyphenylalanine in Parkinson's disease and enhanced motor activity to D-1 and D-2 dopamine agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. In dopamine-d epleted rodents this phenomenon has been referred to as ''priming'' or reverse tolerance. The neurochemical changes that underlie ''priming' ' of dopaminergic agonist responses are poorly understood. Some aspect s of priming of D-1 agonist-mediated rotation in the 6-hydroxydopamine -lesioned rat have been characterized, but priming of D-2-agonist-depe ndent motor responses has been less thoroughly studied. In this study, examination of rotational behaviour and induction of Fos-like immunor eactivity were used to investigate changes in the striatal outflow sys tems in response to treatment with the D-1 agonist quinpirole in 6-hyd roxydopamine-lesioned rats that had been primed with apomorphine. Admi nistration of apomorphine (0.5 mg/kg; three injections at three to six day intervals) permitted an otherwise inactive dose of quinpirole (0. 25 mg/kg) to produce robust contralateral rotation and to induce the e xpression of Fos in striatal neurons belonging to the striato-nigro-en topeduncular (''direct'') pathway. The increase in contralateral rotat ion and ipsilateral striatal Fos expression following administration o f quinpirole to apomorphine-primed rats was mediated by a D-2-like rec eptor and did not appear to be due to a change in sensitivity of D-2 r eceptors. Apomorphine priming also enhanced the ability of quinpirole to induce Fos expression in the globus pallidus, a target of the stria topallidal (''indirect'') pathway. Western blot analysis confirmed tha t treatment with quinpirole induced the expression of c-Fos protein wi th no change in the expression of 35-37,000 mol. wt Fos-related antige ns in apomorphine-primed rats treated with water or quinpirole. Induct ion of Fos expression in the striatum generally results from blockade of D-2 receptors and the striato-nigro-entopeduncular pathway preferen tially expresses D-1 receptors. Thus, the quinpirole-dependent inducti on of striatal Fos in apomorphine-primed 5-hydroxydopamine-lesioned ra ts represents a qualitative alteration in striatal outflow. These stud ies demonstrate that pretreatment of 6-hydroxydopamine-lesioned rats w ith apomorphine increases the activity of the ''direct'' and ''indirec t'' striatal outflow pathways in response to D-2 receptor stimulation. These changes have the net result of enhancing thalamocortical activi ty and likely underlie the enhanced contralateral rotation produced by quinpirole in apomorphine-primed rats. Changes in striatal outflow, p articularly in the striato-nigro-entopeduncular pathway, may contribut e to alterations in D-2-dependent motor responses observed after chron ic dopaminergic stimulation in the dopamine-depleted striatum. (C) 199 7.