Local opiate withdrawal in locus coeruleus neurons in vitro

Noradrenergic neurons of the brain nucleus locus coeruleus (LC) become hype ractive during opiate withdrawal. It has been uncertain to what extent such hyperactivity reflects changes in intrinsic properties of these cells. The effects of withdrawal from chronic morphine on the activity of LC neurons were studied using intracellular recordings in rat brain slices. LC neurons in slices from chronically morphine-treated rats exhibited more than twice the frequency of spontaneous action potentials after naloxone compared wit h LC neurons from control rats. However, after naloxone treatment, the rest ing membrane potential (MP) of LC neurons from dependent rats was not signi ficantly different from that in control rats. Neither resting MP nor sponta neous discharge rate (SDR) was altered by naloxone in LC neurons from contr ol rats. Neither kynurenic acid nor a cocktail of glutamate and GABA antago nists (6-cyano-7-nitroquinoxalene-2,3-dione + 2-amino-5-phosphonopentanoic acid + bicuculline) blocked the hyperactivity of LC neurons precipitated by naloxone in slices from morphine-dependent rats. The effects of ouabain on MP and SDR were similar in LC neurons from control and morphine-dependent rats. These results indicate that an adaptive change in glutamatergic or GA BAergic synaptic mechanisms or altered Na/K pump activity does not underlie the withdrawal-induced activation of LC neurons in vitro. Specific inhibit ors of protein kinase A [Rp-cAMPS or N-(2-[p-bromocinnamylamino]ethyl)-5-is oquinolinesulfonamide (H-89)] partially suppressed the withdrawal hyperacti vity of LC neurons, and activators of cAMP (forskolin) or protein kinase A (Sp-cAMPS) increased the discharge rate of LC neurons from control rats. Th ese results suggest that upregulation of cAMP-dependent protein kinase A du ring chronic morphine treatment is involved in the withdrawal-induced hyper activity of LC neurons.