Chronic morphine treatment increases cyclic AMP-dependent protein kinase activity in the rat locus coeruleus.
We have studied a possible role for cyclic AMP-dependent protein kinase in mediating opiate addiction in the central nervous system by focusing on the rat locus coeruleus. This brain region is well suited for these studies because it is relatively homogeneous and because a wealth of electrophysiological and behavioral data indicate that it plays an important role in mediating the chronic effects of opiates in animals, including humans. It was found that chronic, but not acute, in vivo treatment of rats with morphine increased cyclic AMP-dependent protein kinase activity in the locus coeruleus with a time course that closely paralleled the time course by which locus coeruleus neurons become tolerant to and dependent on opiates, based on electrophysiological studies. Concomitant administration of the opiate receptor antagonist naltrexone was found to block the effect of chronic morphine treatment on protein kinase activity, indicating that the effect is mediated via specific activation of opiate receptors. In contrast, chronic morphine treatment did not alter protein kinase activity in several other brain regions studied, including the neostriatum, frontal cortex, and dorsal raphe. We propose that the observed increase in cyclic AMP-dependent protein kinase activity in the locus coeruleus contributes to the biochemical basis of opiate addiction.
Nestler
E J
EJ
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
Tallman
J F
JF
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008125:Locus Coeruleus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C015482:protein kinase modulator; D009020:Morphine; D011494:Protein Kinases