title: Morphine acutely and persistently attenuates nonvesicular GABA release in rat nucleus accumbens.
abstract: Withdrawal from repeated exposure to morphine causes a long-lasting increase 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 release. Since sustained changes in extracellular GABA levels may play a role in drug-induced neuronal hyperresponsiveness, we examined the acute and long-lasting 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 [(3)H]GABA release in superfused nucleus accumbens slices. Moreover, prior repeated morphine treatment of rats (10 mg/kg, sc, 14 days) caused a reduction in NMDA-stimulated [(3)H]GABA release in vitro until at least 3 weeks after morphine withdrawal. This persistent neuroadaptive effect was not observed studying dopamine D1 receptor-mediated [(3)H]GABA release in nucleus accumbens slices. Moreover, this phenomenon appeared to be absent in slices of the caudate putamen. Interestingly, even a single exposure of rats to morphine (>2 mg/kg) caused a long-lasting inhibition of NMDA-induced release of GABA in nucleus accumbens slices. These data suggest that a reduction in nonvesicular GABA release within the nucleus accumbens, by enhancing the excitability of input and output neurons of this brain region, may contribute to the acute and persistently enhanced exocytotic release of neurotransmitters from nucleus accumbens neurons in morphine-exposed rats.
authors.affiliation: Drug Abuse Program, Research Institute Neurosciences Vrije Universiteit, Department of Pharmacology, Free University Medical Center, Amsterdam, The Netherlands. ANM.Schoffelmeer.Pharm@med.vu.nl
authors.forename: A N
authors.initials: AN
authors.lastname: Schoffelmeer
authors.forename: G
authors.initials: G
authors.lastname: Wardeh
authors.forename: L J
authors.initials: LJ
authors.lastname: Vanderschuren
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism / Q000503:physiopathology; D016202:N-Methylaspartate / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D014316:Tritium / Q000493:pharmacokinetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000700:Analgesics; D044482:Benzeneacetamides; D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D011759:Pyrrolidines; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D009020:Morphine; C045444:U 69593; D004298:Dopamine