Inhibition of ethanol-derived acetaldehyde-induced dopamine release in the mesolimbic system by L-cysteine

Relevant evidence shows that acetaldehyde (ACD) may contribute to the reinforcing effects of ethanol (EtOH) (1). In rodents, ACD induces conditioned place preference (CPP), is self-administered, and stimulates the activity of the mesolimbic dopamine (DA) neurons (2,3,4). We recently reported that inhibition of EtOH metabolism with 4-methylpyrazole (4MP), prevents EtOH- induced CPP and DA release in the Nucleus accumbens shell (NAcs) of the rat (3,4). Consistently, selective ACD sequestering with D-penicillamine (Dp) prevents EtOH-induced stimulation of the mesolimbic DA system (5). Similarly, other thiol compounds, such as the amino acid L-cysteine (L-Cys), can sequester ACD by forming a stable 2-methyl-thiazolidine-carboxylic acid derivative. In this study, we used in vivo microdialysis to measure DA output in the NAcs of male Wistar rats in response to a challenge with ACD and EtOH, after pretreatment with L-Cys. To address the specificity of L-Cys, we also evaluated its effect against morphine (Mor)-induced DA release. Both EtOH (1.0 g/kg) and ACD (20 mg/kg) were administered by gavage (i.g.) to mimic the oral route of administration, Mor (2.5 mg/kg) and L-Cys (30 mg/kg 1 hour before drug challenge) were administered i.p.. EtOH and ACD administration significantly increased DA output in the NAcs (129.44±4.9% and 140.75±9.7% of baseline values respectively, n=6). This effect was prevented by L-Cys pretreatment, while Mor-induced DA release (184.91±19.6% of baseline values, n=4) was unaffected. These findings further highlight the role of ACD in EtOH-induced stimulation of the DA mesolimbic system. Moreover, together with our observations with 4MP and Dp (2,4,5), these data suggest that selective sequestering of ACD prevents the mesolimbic DA potentiating effects of EtOH ingestion. Hence,modulation of EtOH-derived ACD by sequestering agents such as L-Cys, may decrease the motivational effects associated to EtOH intake. 1) Quertemont. TIPS 25:130-4, 2004 2) Peana. ACER 32:249-58, 2008 3) Foddai. Neuropsych. 29: 530-6, 2004 4) Melis. E J Neurosci. 26:2824-33, 2007 5) Mereu. SFN2007 online 609.21/JJ6