In vitro down-regulation predicts agonist efficacy at central muscarinic cholinergic receptors.

ABSTRACT

Agonist induced short-term down-regulation of central muscarinic cholinergic receptors in mechanically dissociated cells of the mouse brain has been shown to predict the efficacy of agonists at muscarinic receptors. Pretreatment of cells with full agonists such as carbachol or oxotremorine M resulted in a loss of available muscarinic cholinergic receptors of about 30% using [3H]N-methylscopolamine [( 3H]NMS) as radioligand, whereas a second group of agonists e.g. RS 86 were only weakly active in this regard producing a significantly smaller loss of cell surface muscarinic cholinergic receptors. The magnitude of down-regulation of muscarinic receptors induced by pretreatment with several cholinergic drugs correlates fairly well with their ability to stimulate the phosphatidylinositol turnover. It seems that the agonist induced down-regulation of muscarinic cholinergic receptors on mechanically dissociated neurons of the mouse brain is a simple screening method to test for centrally acting cholinergic agonists.