ABSTRACT
BACKGROUND: Although ethanol addiction is believed to be mediated by the mesolimbic dopamine system, originating from the ventral tegmental area (VTA), how acute ethanol increases the activity of VTA dopaminergic (DA) neurons remains unclear. METHOD: Patch-clamp recordings of spontaneous firings of DA and GABAergic neurons in the VTA in acute midbrain slices from rats. RESULTS: Ethanol (20-80 mM) excites DA neurons, and more potently depresses firing of local GABAergic neurons. The ethanol-induced excitation of DA neurons is considerably attenuated by DAMGO (Tyr-d-Ala-Gly-N-Me-Phe-Gly-ol enkephalin), a mu-opioid agonist that suppresses firing of GABAergic neurons, or by naloxone, a general opioid antagonist. The ongoing opioid-induced facilitation of DA cell firing (revealed by naloxone) is enhanced by ethanol, probably by an increase in opioid release or action. CONCLUSION: Ethanol excites VTA DA neurons at least partly by increasing ongoing opioid-mediated suppression of local GABAergic inhibition. This indirect mechanism may contribute significantly to the positively reinforcing properties of ethanol.
Subject(s)
Brain/drug effects , Ethanol/pharmacology , Receptors, Opioid/drug effects , Synaptic Transmission/drug effects , Alcoholism/physiopathology , Animals , Brain/physiology , Dopamine/physiology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/drug effects , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/physiology , GABA Antagonists/pharmacology , Humans , Neurons/drug effects , Neurons/physiology , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Receptors, Opioid/physiology , Synaptic Transmission/physiology , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/physiology , gamma-Aminobutyric Acid/drug effects , gamma-Aminobutyric Acid/physiologyABSTRACT
Previous studies suggested that electroacupuncture (EA) can suppress opioid dependence by the release of endogenous opioid peptides. To explore the site of action and the receptors involved, we tried to inject highly specific agonists for mu-, delta- and kappa-opioid receptors into the CNS to test whether it can suppress morphine-induced conditioned place preference (CPP) in the rat. Male Sprague-Dawley rats were trained with 4 mg/kg morphine, i.p. for 4 days to establish the CPP model. This CPP can be prevented by (a) i.p. injection of 3 mg/kg dose of morphine, (b) intracerebroventricular (i.c.v.) injection of micrograms doses of the selective mu-opioid receptor agonist DAMGO, delta-agonist DPDPE or kappa-agonist U-50,488H or (c) microinjection of DAMGO, DPDPE or U50488H into the shell of the nucleus accumbens (NAc). The results suggest that the release of endogenous mu-, delta- and kappa-opioid agonists in the NAc shell may play a role for EA suppression of opiate addiction.
