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

D. H. Bobker, Ke-Zhong Shen, A. Surprenant, John Williams

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Abstract

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
Volume251
Issue number3
StatePublished - 1989

Fingerprint

Submucous Plexus
Locus Coeruleus
Ligands
Neurons
Haloperidol
Inhibitory Postsynaptic Potentials
Opiate Alkaloids
Binding Sites
Enkephalins
Potassium Channels
Cocaine
Adrenergic Receptors
Norepinephrine
Potassium
Guinea Pigs
preclamol

ASJC Scopus subject areas

  • Pharmacology

Cite this

DTG and (+)-3-PPP inhibit a ligand-activated hyperpolarization in mammalian neurons. / Bobker, D. H.; Shen, Ke-Zhong; Surprenant, A.; Williams, John.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 251, No. 3, 1989, p. 840-845.

Research output: Contribution to journalArticle

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