Ethanol interactions with dopamine function in the mesolimbic "reward" pathway
Because ethanol acts as a positive reinforcer, focus on ethanol-induced activation of ventral tegmental area (VTA) dopamine (DA) function in the mesocorticolimbic reward pathway has prevailed. Other drugs of abuse have direct actions at DA synapses, but how ethanol affects this pathway has been a matter of some debate. Ethanol increases the firing of VTA DA neurons (Gessa et al., 1985
; Brodie et al., 1990) through what has been shown recently to be direct excitatory cellular activation (Brodie et al., 1999). Like most drugs of abuse, ethanol elevates extracellular DA concentrations in the NAc (Di Chiara and Imperato, 1988), but recent evidence has linked this effect to direct actions at VTA DA somata rather than NAc DA terminals (Yim and Gonzales, 2000; Budygin et al., 2001).
Is activation of mesolimbic DA transmission a necessary condition for ethanol reward?
Early behavioral evidence (for review, see McBride and Li, 1998
) that microinjection of ethanol into the VTA supports ethanol self-administration, ethanol dose-dependently increases DA release in the NAc in rats self-administering ethanol, and interference with DA transmission by microinjection of pharmacological agents into VTA or NAc reduces ethanol-reinforced responding has provided direct support for a role of DA in the reinforcing actions of ethanol. Manipulations of DA receptor gene expression and receptor knockout (KO) methodologies have supported this position. Mice deficient in DA D1 or D2 receptors and mice lacking DARPP-32, a phosphoprotein regulating D1 receptor function, consume less ethanol and show reduced ethanol-conditioned place preference (El-Ghundi et al., 1998
; Cunningham et al., 2000
; Risinger et al., 2000
, 2001
). Moreover, injection of D2 receptor antisense oligonucleotide into the NAc suppresses alcohol intake and reverses ethanol preference in a genetically selected line of high ethanol preferring rats (Myers and Robinson, 1999
), pointing to the NAc as the critical site for attenuation of ethanol reward associated with DA D2 receptor deficiency.
On the other hand, DA lesion studies with the selective neurotoxin 6-hydroxydopamine (6-OHDA) consistently show that DA denervation of the NAc does not interfere with ethanol consumption or maintenance of ethanol-reinforced responding (Ikemoto et al., 1997; Koistinen et al., 2001). Similarly, elevation of NAc DA levels by a selective DA reuptake inhibitor fails to alter ethanol self-administration (Engleman et al., 2000). These results indicate that ethanol self-administration is not dependent on NAc DA activation. Possibly, compensatory adaptations after 6-OHDA lesions may substitute for loss of DA input to NAc, or, as suggested by imaging studies in rodents (Williams-Hemby and Porrino, 1997), stimulation of NAc DA transmission is necessary for rewarding effects associated with low-dose stimulant actions of ethanol but not essential for other aspects of reinforcing actions of ethanol (e.g., anxiolytic effects). Yet such effects may be sufficient to substitute for ethanol reward derived from its stimulant properties, or they may support ethanol-reinforced behavior in their own right.
Does DA function change with chronic ethanol exposure and withdrawal?
Over the course of chronic ethanol exposure, adaptations develop in mesolimbic DA function to counter sustained stimulation of this system by ethanol. Although ethanol acutely activates mesolimbic DA neurotransmission, withdrawal from chronic ethanol leads to substantial decrements in VTA DA neuron activity (Diana et al., 1992; Shen and Chiodo, 1993) and extracellular NAc DA levels (Rossetti et al., 1992; Weiss et al., 1996), suggesting that chronic ethanol exposure causes mesolimbic DA hypofunction, a condition significant for maintenance of addiction by promoting ethanol intake to compensate for its deceased efficacy on DA release and by motivating resumption of drinking during withdrawal to reverse DA deficits.
Recent findings have shed light on the mechanisms underlying DA dysregulation during chronic intoxication and withdrawal. Overactivity of L-type calcium channels is a possible mechanism for the suppression of DA release during ethanol withdrawal, because pharmacological inhibition of L-type calcium channels selectively blocks this withdrawal consequence (Rossetti et al., 1999). Decreased expression of tyrosine hydroxylase coupled with elevated levels of DA transporter (DAT) in rats maintained chronically on ethanol-containing diets suggests that decreases in DA synthesis and enhanced clearance of synaptic DA may cause DA hypofunction during ethanol dependence (Rothblat et al., 2001). The latter finding contrasts with results from human alcoholics in whom DAT binding is depressed significantly early in withdrawal but returns to normal with sustained abstinence (Laine et al., 1999). However, DAT binding in humans was measured after 4 d of withdrawal, whereas DAT expression in rats was determined before withdrawal. Thus, it remains to be determined whether decreased DAT binding is a consequence of chronic drinking or develops to compensate for reductions in DA release during ethanol withdrawal.
DA deficits in subjects with a history of dependence are not restricted to acute ethanol withdrawal but can be long-lasting, as suggested by reduced activity of VTA DA neurons after 3 d of withdrawal (Diana et al., 1996
). Changes in NAc DA turnover and synthesis indicate that decreased DA release is present as long as 2 months after ethanol withdrawal (Bailey et al., 2000
). The persistence of such abnormalities may have implications for vulnerability to relapse and adverse symptoms associated with protracted ethanol withdrawal. In clinical studies, a slow rate of recovery of DA receptor function predicts relapse and poor treatment outcome (Heinz et al., 1995
). Unfortunately, in both the clinical and preclinical domain, systematic studies linking abnormalities in DA function during protracted withdrawal with ethanol-seeking or other relevant behavioral changes are sparse, but they are needed to understand the behavioral significance of persistent DA dysregulation in the abuse potential of ethanol.
Overall, current evidence suggests that mesolimbic DA transmission represents a substrate for the positive reinforcing actions of ethanol, most notably those associated with the mild stimulant actions of this drug. In addition, counteradaptive changes in mesolimbic dopamine function may provide a mechanism supporting the negative reinforcing aspects of ethanol associated with the dependent state as well as acute and protracted ethanol withdrawal.
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