Alterations in muscarinic control of striatal dopamine autoreceptors in senescence: a deficit at the ligand-muscarinic receptor interface?

Research has indicated that the release of striatal dopamine (DA) is controlled by inhibitory DA autoreceptors which are in turn regulated by inhibitory muscarinic inhibitory cholinergic heteroreceptors (HTRs) located in close vicinity to the autoreceptors. Muscarinic activation enhances K+-evoked release of DA from striatal slices from mature but not senescent rats. Since it has been shown that age-dependent declines in Ca2+ mediated acetylcholine release can be restored by the ionophore A23187, it was of interest to determine if age-related decrements in Ca2+ mobilization might contribute to the alterations in muscarinic control of the striatal DA autoreceptors seen in senescence. Cross-cut striatal tissue slices obtained from two age-groups (6 and 24 months) of Wistar rats were superfused with a modified Krebs-Ringer medium containing 2.5 mM KCl. After a 30-min equilibration period, a 5-min baseline fraction was collected. The medium was then switched to one which contained 30 mM KCl and, depending upon the experiment, the muscarinic agonists carbachol, or oxotremorine or the Ca2+ mobilizing agents A23187 or inositoltrisphosphate (IP3) and enhancement of K+-evoked release of DA was examined. Six 5-min fractions were collected. DA release was determined by HPLC coupled to electrochemical detection. Results indicated that although deficits were seen in oxotremorine and carbachol enhancement of K+-evoked release of DA, these decrements were not observed when either A23187 or IP3 were utilized to enhance the K+-evoked release of DA.(ABSTRACT TRUNCATED AT 250 WORDS)