DTG and (+)-3-PPP inhibit a ligand-activated hyperpolarization in mammalian neurons

DH Bobker, KZ Shen, A Surprenant and JT Williams

Vollum Institute, Oregon Health Sciences University, Portland.

The effects of three compounds with high affinity for the haloperidol- sensitive alpha-binding site were studied with intracellular recordings in the vitro neuronal preparations of the rat locus ceruleus, rat dorsal raphe and the guinea pig submucous plexus. Both (+)-3-(3- hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] and 1,3-di-o- tolylguanidine (DTG) inhibited the hyperpolarization induced by a ligand-activated potassium conductance. In the locus ceruleus, (+)-3- PPP and DTG produced a maximal 40 to 45% inhibition of the [Met5]enkephalin hyperpolarization, and had EC50 values of 6.6 and 2.2 microM, respectively. In the submucous plexus, the two compounds had a similar action on the alpha-2 adrenoceptor agonist UK14304 hyperpolarization, producing a maximal 50% inhibition with EC50 values of 140 and 32 nM, respectively. In addition, DTG inhibited the alpha-2- mediated inhibitory postsynaptic potential in both preparations. In contrast, (+)-3-PPP increased and prolonged the inhibitory postsynaptic potential. This action is qualitatively similar to the actions of cocaine on locus ceruleus and submucous plexus neurons. Haloperidol (1- 10 microM) shared none of these actions. It is concluded that DTG and (+)-3-PPP are inhibitors of the opiate and alpha-2-mediated hyperpolarization at a postreceptor site, possibly the potassium channel. In addition, (+)-3-PPP, but not DTG, inhibits norepinephrine reuptake. None of these effects appear to be related to the sigma - binding site, because haloperidol acted as neither an agonist nor an antagonist.

Volume 251, Issue 3, pp. 840-845, 12/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics