Functional acetaldehyde blockade selectively prevents ethanol-induced increase in mesolimbic dopaminergic system activity. In vivo microdialysis

Acetaldehyde (ACD) is the first metabolite of ethanol (EtOH), mainly produced by alcohol dehydrogenase (ADH) in the gastric system. Owing to the aversive “flushing syndrome” caused by ACD accumulation, this molecule formed the rationale for the use of disulfiram to prevent EtOH abuse in alcoholics. Conversely, recent evidences suggest that ACD may be involved in the neurochemical basis of the reinforcing effects of EtOH (1). In fact, ACD is self-administrated in experimental animals, stimulates mesolimbic dopaminergic neuronal firing, and its blockade by D-penicillamine (DP) or by ADH competitive inhibition with 4-methylpyrazole (4MP) prevents several EtOH-induced behaviors (2,3,4). In this study we used in vivo microdialysis to measure DA extracellular levels in the Nucleus accumbens shell (NAcbs) after a challenge with ACD and EtOH in control and DP- or 4MP-treated male albino Wistar rats. Moreover, to verify the selectivity of ACD blockade, we studied the effects of morphine (MOR) administration using the same experimental paradigm. ACD (20 mg/kg) and EtOH (1.0 g/kg) where administered by gavage in order to mimic the route of administration used by humans; MOR (25 mg/kg) was administered intra peritoneum. Our data show that pretreatment with 4-MP and DP prevents EtOH-induced DA outflow in the NAcbs without interfering with MOR-induced DA release. These findings provide further support to the hypothesis that EtOH-induced increment in DA outflow in the shell of the NAcb mainly occurs by an action of its first metabolite ACD, thereby suggesting that ACD plays a key role in the EtOH-induced stimulation of mesolimbic pathway and possibly in its affective/motivational properties. 1) Quertemont et Al., TIPS 25(3):130-4, 2004 2) Rodd-Henricks et Al., PBB 72:55-64, 2002 3) Foddai et Al., Neuropsych. 29(3): 530-6, 2004 4) Font et Al., Neuropsych. 184(1): 56-64, 2005