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

D. H. Bobker, K. Z. Shen, A. Surprenant, J. T. Williams

Research output: Contribution to journalArticle

16 Scopus citations


The effects of three compounds with high affinity for the haloperidol-sensitive σ-binding site were studied with intracellular recordings in the in 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 μM, 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 μM) 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 σ-binding site, because haloperidol acted as neither an agonist nor an antagonist.

Original languageEnglish (US)
Pages (from-to)840-845
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1989

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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