Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal

The activity of mesolimbic dopaminergic neurons was investigated in rats at various times after a chronic regimen of morphine, which produced, upon su spension, a marked somatic withdrawal syndrome. Single-cell extracellular r ecording techniques, coupled with antidromic identification from the nucleu s accumbens, were used to monitor neuronal activity while behavioural obser vations allowed quantification of the somatic signs of morphine withdrawal. Temporal correlation of electrophysiological indices, such as firing rate and burst firing, with scores obtained through behavioural assessments prov ed negative, in that somatic signs were pronounced at 24 h after suspension of treatment and then subsided to control values at 72 h after the last mo rphine injection. In contrast, the firing rate and burst firing of mesolimb ic dopaminergic neurons were found to be reduced at 1, 3 and 7 days after m orphine withdrawal. After 14 drug-free days, electrophysiological analysis revealed an apparent normalization of various parameters. However, at this time, intravenous administration of morphine produced an increment of elect rical activity which was significantly higher than that obtained in control (saline treated) rats. Further, administration of the opiate antagonist na ltrexone, administered without prior morphine, at 3, 7 and 14 days after th e last morphine administration, failed to alter dopaminergic neuronal activ ity. The results indicate: (i) that the activity of mesolimbic dopaminergic neurons remains reduced well after somatic signs of withdrawal have disapp eared; (ii) after 14 days of withdrawal, the augmented magnitude of the ele ctrophysiological response to exogenous morphine suggests an increased sens itivity of opiate receptors; and (iii) the lack of relationship between dop aminergic activity and somatic signs of withdrawal corroborates the notion that dopaminergic activity in the mesolimbic system does not participate in the neurobiological mechanisms responsible for somatic withdrawal. The pre sent results may be relevant to the phenomenon of drug addiction in humans and consequent relapse after drug-free periods.