DTG and (+)-3-PPP inhibit a ligand-activated hyperpolarization in mammalian neurons.
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.
Bobker
D H
DH
Vollum Institute, Oregon Health Sciences University, Portland.
Shen
K Z
KZ
Surprenant
A
A
Williams
J T
JT
D000818:Animals; D000068438:Brimonidine Tartrate; D015259:Dopamine Agents / Q000494:pharmacology*; D004744:Enkephalin, Methionine / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017480:Receptors, sigma; D012701:Serotonin / Q000494:pharmacology
D015259:Dopamine Agents; D006146:Guanidines; D010880:Piperidines; D011810:Quinoxalines; D011957:Receptors, Opioid; D017480:Receptors, sigma; D012701:Serotonin; D000068438:Brimonidine Tartrate; D004744:Enkephalin, Methionine; C026539:preclamol; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D009638:Norepinephrine