Morphine acutely and persistently attenuates nonvesicular GABA release in rat nucleus accumbens

Withdrawal from repeated exposure to morphine causes a long-lasting increas e in the reactivity of nucleus accumbens nerve terminals towards excitation . The resulting increase in action potential-induced exocytotic release of neurotransmitters, associated with behavioral sensitization, is thought to contribute to its addictive properties, We recently showed that activation of N-methyl-D-aspartate (NMDA) as well as dopamine (DA) D1 receptors in rat striatum causes tetrodotoxin-insensitive transporter-dependent GABA releas e. Since sustained changes in extracellular GABA levels may play a role in drug-induced neuronal hyperresponsiveness, we examined the acute and long-l asting effect of morphine on this nonvesicular GABA release in rat nucleus accumbens slices. The present study shows that morphine, through activation of mu -opioid receptors, reduces nonvesicular NMDA-induced [H-3]GABA relea se in superfused nucleus accumbens slices. Moreover, prior repeated morphin e treatment of rats (10 mg/kg, se, 14 days) caused a reduction in NMDA-stim ulated [H-3] GABA release in vitro until at least 3 weeks after morphine wi thdrawal. This persistent neuroadaptive effect was not observed studying do pamine D1 receptor-mediated [H-3] GABA release in nucleus accumbens slices. Moreover, this phenomenon appeared to be absent in slices of the caudate p utamen. Interestingly, even a single exposure of rats to morphine (>2 mg/kg ) caused a long-lasting inhibition of NMDA-induced release of GABA in nucle us accumbens slices. These data suggest that a reduction in nonvesicular GA BA release within the nucleus accumbens, by enhancing the excitability of i nput and output neurons of this brain region, may contribute to the acute a nd persistently enhanced exocytotic release of neurotransmitters from nucle us accumbens. neurons in morphine-exposed rats. (C) 2001 Wiley-Liss, Inc.