Cholinergic lesions of mouse striatum induced by AF64A alter D2 dopaminergic behavior and reduce D2 dopamine receptors and D2 dopamine receptor mRNA

Abstract

To determine whether dopamine receptors are expressed in acetylcholine-containing neurons intrinsic to the striatum, and to study further the interactions between the dopaminergic and cholinergic systems, the irreversibly acting cholinergic neurotoxin, ethylcholine mustard aziridinium ion (AF64A), was injected unilaterally into the mouse corpus striatum, and rotational behavior induced by dopamine agonists and certain molecular events associated with this lesion were determined 7 days after lesioning. Brains were analyzed for D2 dopamine receptors by autoradiography, using [3H](-)sulpiride as a ligand, and for D2 dopamine receptor mRNA and glutamic acid decarboxylase mRNA by Northern blot analysis, using selective radiolabelled oligonucleotide probes. Choline uptake sites were determined by binding assays using [3H]hemicholinium-3, a selective choline reuptake blocker, as a ligand. Mice with intrastriatal injections of AF64A showed ipsilateral rotational responses to the non-selective dopamine agonist apomorphine and to the D2 dopamine agonists, pergolide and quinpirole, but not to the D1 dopamine agonist SKF 38393. This was associated with a significant reduction in D2 dopamine receptors in the ipsilateral striatum and a significant decrease in the amount of D2 dopamine receptor mRNA. That AF64A produced a relatively selective cholinergic deficit was supported by the evidence showing that AF64A lesions significantly reduced [3H]hemicholinium-3 binding sites but did not alter glutamic acid decarboxylase (GAD) mRNA. Further, hemicholinium-3, prevented the AF64A-induced changes in rotational behavior. These results suggest that striatal cholinergic interneurons contain D2 dopamine receptors and express the D2 dopamine receptor gene, and that these interneurons are involved in dopamine-mediated rotational behavior.