Alcohol reward, dopamine depletion, and GDNF.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Barak et al. In 1985, Dackis and Gold (1985) suggested that cocaine addiction stems from the depletion of synaptic dopamine in the mesolimbic dopamine reward system, leading to a dysphoric withdrawal state that drives cocaine seeking to restore dopamine to normal, drug-naive levels. They further speculated that decreased basal dopamine levels may be an underlying mechanism of addiction to other drugs of abuse. This hypothesis gained empirical support from work showing that withdrawal from cocaine , morphine, amphetamine, and alcohol all reduce nucleus accumbens (NAc) dopamine levels (Rossetti et al., 1992). However, despite the impact that the dopamine-depletion hypothesis and related opponent process theories (Koob et al., 1989) have had in guiding research and theory in the addiction field, it is still unknown whether NAc dopamine depletion is responsible for drug seeking and relapse. For instance, precipitation of opiate drug withdrawal symptoms decreases NAc do-pamine levels without increasing drug seeking (Shaham et al., 1996). Furthermore , manipulations that increase NAc dopamine reinstate drug seeking after extinction, whereas inhibition of NAc do-pamine typically inhibits drug seeking (Stewart, 2000). As with other drugs of abuse, it is currently unclear whether withdrawal-induced decreases in NAc dopamine play a role in alcohol seeking and taking. This question led to a recent study in The Journal of Neu-roscience by Barak et al. (2011), examining the effects of injecting glial cell line-derived neurotrophic factor (GDNF) into the ven-tral tegmental area (VTA, the cell body region of midbrain dopamine neurons) on dopamine levels in the NAc and on alcohol reward in alcohol-dependent rats. GDNF, a growth factor critical for the survival and function of midbrain dopamine neurons, plays a complex role in opiate and psycho-stimulant reward and relapse, with evidence for both inhibitory and facilitatory effects on behavior (Ghitza et al., 2010). In the case of alcohol reward, however, studies by Carni-cella and Ron (2009) demonstrated a clear inhibitory effect of VTA GDNF injections on alcohol reward. In the paper by Barak et al. (2011), the authors assessed whether VTA GDNF injections reverse alcohol withdrawal-induced dopamine depletion in the NAc and inhibit alcohol reward, as …