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

Abstract

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 Ca 2+ mediated acetylcholine release can be restored by the ionophore A23187, it was of interest to determine if age-related decrements in Ca 2+ 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 Ca 2+ mobilizing agents A23187 or inositoltrisphosphate (IP 3) 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 IP 3 were utilized to enhance the K +-evoked release of DA. Other control experiments indicated that these Ca 2+ mobilizing agents were not effective in promoting DA release from striatal tissue from either young or old animals in the presence of 2.5 mM KCl. Thus, the observed enhancement of K +-evoked release of DA by these agents only occurred during depolarization, and was probably not the result of direct toxic effects allowing DA to ‘leak’ from the terminal. Since age-differences in enhancement of K +-evoked release of DA were only seen with the muscarinic agonists and not with either IP 3 or A23187, these findings indicate that there may be an age-related deficit in Ca 2+ mobilization that may find its locus at the muscarinic receptor-ligand interface. Once this interface is bypassed, and Ca 2+ mobilized intracellularly the age-differences in enhancement are not seen.