Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: electrophysiological and biochemical evidence.

Abstract

Activity of the mesolimbic dopaminergic system was investigated in rats withdrawn from chronic ethanol administration by single-cell extracellular recordings from dopaminergic neurons of the ventrotegmental area, coupled with antidromic identification from the nucleus accumbens, and by microdialysis-technique experiments in the nucleus accumbens. Spontaneous firing rates, spikes per burst, and absolute burst firing but not the number of spontaneously active neurons were found drastically reduced; whereas absolute and relative refractory periods increased in rats withdrawn from chronic ethanol treatment as compared with chronic saline-treated controls. Consistently, dopamine outflow in the nucleus accumbens and its acid metabolites were reduced after abruptly stopping chronic ethanol administration. All these changes, as well as ethanol-withdrawal behavioral signs, were reversed by ethanol administration. This reversal suggests that the abrupt cessation of chronic ethanol adminitration plays a causal role in the reduction of mesolimbic dopaminergic activity seen in the ethanol-withdrawal syndrome. Results indicate that during the ethanol-withdrawal syndrome the mesolimbic dopaminergic system is tonically reduced in activity, as indexed by electrophysiological and biochemical criteria. Considering the role of the mesolimbic dopaminergic system in the reinforcing properties of ethanol, the depressed activity of this system during the ethanol-withdrawal syndrome may be relevant to the dysphoric state associated with ethanol withdrawal in humans.Alcoholism is a major economic, social, and health problem (1). Indeed, alcohol is the most abused substance after nicotine in the Western world, and alcohol abuse and dependence ranked first of all psychiatric disorders in lifetime prevalence rates (2). As for many other abused drugs, this compulsive behavior seems to be elicited and maintained by the powerful reinforcing properties of the drug. Dopamine (DA) is one of the major candidates suggested to mediate reinforcement in animals (3): accordingly, rats will self-stimulate when electrodes are placed near DA neurons in the ventrotegmental area (VTA) (4, 5), and many addicting drugs, including ethanol, increase DA release in the nucleus accumbens (6) and increase DA firing in the VTA (7).The ethanol-withdrawal syndrome begins after cessation of prolonged ethanol administration. A symptom common to withdrawal syndromes, regardless of the substance abused, is the dysphoria associated with absence of the drug. In spite of the evidence linking an increase in dopaminergic transmission to the hedonic properties of ethanol (8), no study has tested in vivo whether the ethanol-withdrawal syndrome is associated with a decline in mesolimbic dopaminergic activity. However, a reduction of DA turnover has been reported The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.(9),...

Repeated Ethanol Intoxication Induces Behavioral Sensitization in the Absence of a Sensitized Accumbens Dopamine Response in C57BL/6J and DBA/2J Mice

“…These studies have consistently shown a profound reduction in the activity of mesolimbic DA neurons that is reversed by resuming ETOH exposure (Rossetti et al, 1992;Diana et al, 1993;Weiss et al, 1996). However, studies examining whether these changes persist beyond the acute withdrawal phase have been lacking.…”

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

“…Activation of the mesolimbic dopamine system is a feature shared by all classes of abused drugs (Di Chiara and Imperato, 1988) and, much like opiate withdrawal, the electrophysiological activity and neurochemical output of dopamine neurons is reduced during withdrawal from ethanol (Rossetti et al, 1991(Rossetti et al, , 1992Diana et al, 1993;Shen 2003;Rada et al, 2004), nicotine (Hildebrand et al, 1998;Rada et al, 2001;Liu and Jin, 2004), and other stimulants (Parsons et al, 1991;Robertson et al, 1991;Rossetti et al, 1992). Furthermore, reduced dopaminergic signaling in the NAc is associated with emotional signs of nicotine withdrawal (Cryan et al, 2003;Paterson et al, 2007).…”

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…Alcohol-dependent rats and mice show a profound reduction of spontaneous firing rate and burst firing of Nacc-projecting VTA DA-containing neurons (Diana et al, 1993;Bailey et al, 2001), resulting in a concomitant reduction of microdialysate DA in the Nacc (Diana et al, 1993). Further, this reduced dopaminergic activity outlasts somatic signs of withdrawal (Diana et al, 1996), thereby suggesting a role for DA in the lasting consequences of alcohol dependence while perhaps excluding the possibility of a DA role in somatic aspects of withdrawal.…”