Apomorphine priming alters the response of striatal outflow pathways to D2 agonist stimulation in 6-hydroxydopamine-lesioned rats.
Chronic treatment with dopaminergic agonists is associated with response fluctuations to L-dihydroxyphenylalanine in Parkinson's disease and enhanced motor activity to D1 and D2 dopamine agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. In dopamine-depleted 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 aspects of priming of D1 agonist-mediated rotation in the 6-hydroxydopamine-lesioned rat have been characterized, but priming of D2-agonist-dependent motor responses has been less thoroughly studied. In this study, examination of rotational behaviour and induction of Fos-like immunoreactivity were used to investigate changes in the striatal outflow systems in response to treatment with the D2 agonist quinpirole in 6-hydroxydopamine-lesioned rats that had been primed with apomorphine. Administration 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 expression of Fos in striatal neurons belonging to the striato-nigro-entopeduncular ("direct") pathway. The increase in contralateral rotation and ipsilateral striatal Fos expression following administration of quinpirole to apomorphine-primed rats was mediated by a D2-like receptor and did not appear to be due to a change in sensitivity of D2 receptors. Apomorphine priming also enhanced the ability of quinpirole to induce Fos expression in the globus pallidus, a target of the striatopallidal ("indirect") pathway. Western blot analysis confirmed that treatment with quinpirole induced the expression of c-Fos protein with no change in the expression of 35-37,000 mol. wt Fos-related antigens in apomorphine-primed rats treated with water or quinpirole. Induction of Fos expression in the striatum generally results from blockade of D2 receptors and the striato-nigro-entopeduncular pathway preferentially expresses D1 receptors. Thus, the quinpirole-dependent induction of striatal Fos in apomorphine-primed 6-hydroxydopamine-lesioned rats represents a qualitative alteration in striatal outflow. These studies demonstrate that pretreatment of 6-hydroxydopamine-lesioned rats with apomorphine increases the activity of the "direct" and "indirect" striatal outflow pathways in response to D2 receptor stimulation. These changes have the net result of enhancing thalamocortical activity and likely underlie the enhanced contralateral rotation produced by quinpirole in apomorphine-primed rats. Changes in striatal outflow, particularly in the striato-nigro-entopeduncular pathway, may contribute to alterations in D2-dependent motor responses observed after chronic dopaminergic stimulation in the dopamine-depleted striatum.
Pollack
A E
AE
Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston 02114, U.S.A.
Turgeon
S M
SM
Fink
J S
JS
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001370:Axonal Transport; D001479:Basal Ganglia / Q000502:physiology; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D007839:Functional Laterality; D017979:Gold Colloid; D008297:Male; D008959:Models, Neurological; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D019257:Quinpirole / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D012399:Rotation; D012457:Salicylamides / Q000494:pharmacology; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate
D001552:Benzazepines; D018491:Dopamine Agonists; D017979:Gold Colloid; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D018998:Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate; D019257:Quinpirole; D016627:Oxidopamine; C045989:eticlopride; D001058:Apomorphine