A novel action of morphine in the rat locus coeruleus: persistent decrease in adenylate cyclase.
This study describes a novel action of morphine on adenylate cyclase activity in the rat locus coeruleus (LC). We have previously shown that acute in vitro morphine inhibits adenylate cyclase activity in isolated LC membranes, whereas chronic in vivo morphine treatment increases enzyme activity in this brain region. We now report that acute in vivo morphine treatment produces a 25-30% decrease in adenylate cyclase activity in the LC, which persists in in vitro assays in the absence of opiates. This in vivo effect is clearly distinct from the acute inhibition of adenylate cyclase observed during exposure of isolated LC membranes to opiates in vitro. The in vivo effect was not reversed by the inclusion of naloxone, an opiate receptor antagonist, in the assay, and acute in vitro opiate inhibition of the enzyme was the same in LC membranes isolated from control and morphine-treated rats. Thus, the in vivo effect does not appear to be due to residual morphine retained in the membrane preparation. This persistent decrease in adenylate cyclase was found to occur in a dose-dependent manner and to be mediated through the actions of morphine at opiate receptors, inasmuch as the inhibition was prevented by concomitant in vivo administration of naltrexone, a long-acting opiate receptor antagonist. This effect was also specific to the LC, in that it was not observed in the other brain regions examined, which included the dorsal raphe, neostriatum, and frontal cortex. Acute in vivo clonidine, an alpha 2-adrenergic receptor agonist known to have actions in the LC similar to those of morphine, produced a similar persistent decrease in adenylate cyclase activity in this brain region. In contrast, other drugs with different actions on the LC failed to produce this effect. This decrease in adenylate cyclase activity induced by acute in vivo morphine or clonidine, which persists in isolated membranes after the removal of the drugs, may be an early step in the sequence of events that leads to the development of opiate or clonidine addiction in the LC.
Beitner
D B
DB
Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
Duman
R S
RS
Nestler
E J
EJ
D000262:Adenylyl Cyclases / Q000032:analysis*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D019204:GTP-Binding Proteins / Q000502:physiology; D008125:Locus Coeruleus / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009293:Opioid-Related Disorders; D051381:Rats; D011919:Rats, Inbred Strains
D009270:Naloxone; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D003000:Clonidine