Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological, and biochemical correlates

Abstract

We have compared the time course of the behavioral manifestations of opiate withdrawal to the in vivo activity of locus coeruleus (LC) neurons and to increases in the levels of G-proteins, adenylate cyclase, and cAMP-dependent protein kinase known to occur in the LC in opiate-dependent animals. Rats were given morphine by daily subcutaneous implantation of morphine pellets for 5 d. On the sixth day, morphine withdrawal was induced by subcutaneous administration of naltrexone, an opiate receptor antagonist, with additional doses given 6 and 24 hr later, conditions that resulted in sustained, maximal levels of withdrawal over the duration of the experiment. We found a striking parallel between the time courses of the behavioral signs and the increased activity of LC neurons during withdrawal, both of which appeared to follow 2 phases. There was an early, rapid phase, during which withdrawal signs and increased LC activity became most pronounced within 15–30 min after naltrexone administration, and then recovered rapidly by over 50% within 4 hr of withdrawal. Subsequently, there was a slower phase, during which the persisting withdrawal signs and elevated LC activity remained roughly constant from 4 to 24 hr and did not recover completely until after 72 hr of continuous withdrawal. Adenylate cyclase and cAMP-dependent protein kinase activities in isolated LC subcellular fractions, both elevated in dependent animals, recovered to control levels after 6 hr of withdrawal, in parallel with the rapid phase of withdrawal. Levels of G1 and Go, also elevated in dependent animals, remained only slightly elevated at 6 hr and returned to normal by 24 hr. Taken together, these data suggest that increased neuronal activity in the LC is associated temporally with the behavioral morphine withdrawal syndrome and that increased levels of G- proteins and an up-regulated cAMP system may contribute to the early withdrawal activation of these neurons.

Opposite Modulation of Opiate Withdrawal Behaviors on Microinfusion of a Protein Kinase A Inhibitor Versus Activator into the Locus Coeruleus or Periaqueductal Gray

“…7 legend). This is consistent with the robust increase in cAMP-dependent protein phosphorylation known to occur in the LC on precipitation of opiate withdrawal (Guitart et al, 1990(Guitart et al, , 1992Rasmussen et al, 1990). Thus, the 92% increase in tyrosine hydroxylase back phosphorylation (i.e., the 92% decrease in phosphorylation state in vivo) elicited by Rp-cAMPS infusion in withdrawing animals indicates that Rp-cAMPS is effective at blocking the withdrawal-induced increase in PKA-mediated protein phosphorylation.…”

“…Thus, chronic morphine administration increases levels of adenylyl cyclase and protein kinase A (PK A) in the LC (Duman et al, 1988;Nestler and Tallman, 1988;Matzuoka et al, 1994). These adaptations have been shown to increase the electrical excitability of LC neurons (Alreja et al, 1991;Kogan et al, 1992;Shiekhattar and AstonJones, 1993) and appear to contribute to activation of the LC seen on precipitation of withdrawal (Rasmussen et al, 1990;Kogan et al, 1992).…”

Upregulation of Galanin Binding Sites and GalR1 mRNA Levels in the Mouse Locus Coeruleus Following Chronic Morphine Treatments and Precipitated Morphine Withdrawal

“…treatment results in compensatory upregulation of these systems in the nAc and LC (Nestler 1992), resulting in increased firing of LC neurons, opiate dependence, and the expression of withdrawal symptoms (Nestler et al 1993;Rasmussen et al 1990). In the current study, we show that galanin receptor levels do not change significantly during chronic morphine treatment alone.…”

Modulation of Anxiety-Like Behavior and Morphine Dependence in CREB-Deficient Mice

“…The firing rate of LC neurons was strongly increased during spontaneous and antagonist-precipitated morphine withdrawal, which seems to contribute to the behavioral expression of the somatic signs of abstinence (Rasmussen and Aghajanian, 1989;Rasmussen et al, 1990). Moreover, the LC was the most sensitive brain structure to precipitate the somatic signs of morphine withdrawal by microinjection of opioid antagonists (Maldonado et al, 1992a, b), and its electrolytic lesion strongly inhibited opioid abstinence (Maldonado and Koob, 1993).…”