Differential response of striatal dopamine and muscarinic cholinergic receptor subtypes to the loss of dopamine: I. Effects of intranigral or intracerebroventricular 6-hydroxydopamine lesions of the mesostriatal dopamine system

Abstract

Quantitative autoradiography was utilized to examine the response of the dopamine (DA) and muscarinic cholinergic system within the striatum to lesions of the mesostriatal DA system following intranigral 6-hydroxydopamine (6-OHDA) injections. In addition, the response of DA system was examined in the striatum of animals treated with low, medium, or high doses of 6-OHDA made intracerebroventricularly (icv). Three weeks following removal of the mesostriatal DA fibers with intranigral 6-OHDA, there was an almost complete depletion of DA and [ 3H]mazindol binding throughout the striatum. The resulting increase in D2 receptors labeled with [ 3H]spiroperidol (27%) was most evident in the lateral striatum and topographically correlated with an increase in choline uptake sites labeled with [ 3H]hemicholinium-3 (20%). There was a smaller but significant decrease in D1 receptors labeled with [ 3H]SCH 23390 (15–18%) that was not topographically related to changes in [ 3H]spiroperidol or [ 3H]hemicholinium-3 binding. All doses of icv 6-OHDA produced a significant loss of DA and of [ 3H]mazindol binding as compared to vehicle injections that was more pronounced in the medial than in the lateral striatum. No increase in D1 receptors was observed with any dose of 6-OHDA and greater than 90% loss of DA and [ 3H]mazindol resulted in an increase in D2 receptors in the lateral striatum and a reduction in D1 receptors in the dorsal striatum. These data are consistent with the evidence that there is independent regulation of the two subtypes of the DA receptor. Moreover, the distribution and regulation of the subtypes of the muscarinic receptor were independent. Muscarinic M2 receptors ([ 3H]- N-methylscopolamine in presence of excess pirenzepine) showed a lateral to medial gradient (highest laterally) that was related to the pattern of choline uptake sites and D2 receptors. Loss of DA resulted in a reduction in M2 receptors (24–30%) that was correlated with the increase in choline uptake sites. In contrast, M1 ([ 3H]pirenzepine) receptors showed a reverse gradient from the M2 receptor and a smaller reduction following loss of DA.