Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system

Abstract

Ethanol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered to be responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend, at least partially, on the activation of the mesolimbic dopaminergic system. However, acetaldehyde (ACD), the first metabolite of EtOH, has been classically considered to be aversive and useful in the pharmacological therapy of alcoholics. Here we show that EtOH-derived ACD is necessary for EtOH-induced place preference, a pre-clinical test with high predictive validity for reward liability. We also found that ACD is essential for EtOH-increased microdialysate dopamine (DA) levels in the rat nucleus accumbens and that this effect is mimicked by intra-ventral tegmental area (VTA) ACD administration. Furthermore, in vitro, ACD enhances VTA DA neuronal firing through action on two ionic currents: reduction of the A-type K+ current and activation of the hyperpolarization-activated inward current. EtOH-stimulating properties on DA neurons are prevented by pharmacological blockade of local catalase, the main metabolic step for biotransformation of EtOH into ACD in the central nervous system. These results provide in-vivo and in-vitro evidence for a key role of ACD in the motivational properties of EtOH and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD, by increasing VTA DA neuronal activity, would oppose its well-known peripherally originating aversive properties. Careful consideration of these findings could help in devising new effective pharmacological therapies aimed at reducing EtOH intake in alcoholics.

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

“…In addition, the authors blocked ACD-induced excitation with two specific ion channel blockers: 4-aminopyridine (10 mM) which blocks A-current and ZD7288, which blocks h-current. Both agents apparently blocked the ACDinduced excitation of the VTA neurons (Melis et al, 2007). The firing rate was increased by 4-aminopyridine alone, and no further increase in firing was observed with the addition of ACD.…”

“…Despite the finding in one study that suggested that EtOH excitation of dopaminergic VTA neurons of mice could be blocked with ZD7288 (Okamoto et al, 2006), additional studies of this phenomenon indicate that apparent reduction of EtOH excitation was more likely due to effects of ZD7288 that are not related to its action on h-channels (McDaid et al, 2008). The role of h-current in modulating the firing frequency of dopaminergic neurons of the VTA may differ in different preparations and in different rodents, as ZD7288 alone produces a decrease in firing rate in some studies (Melis et al, 2007;Okamoto et al, 2006), but not in others (Appel et al, 2003) except at high concentrations (Seutin et al, 2001). Under conditions and in species in which ZD7288 does not affect the firing rate, it also does not affect EtOH action.…”

“…On the other hand, hcurrent is a characteristic current of dopaminergic VTA neurons that is activated at membrane potentials about 20 mV negative to the resting membrane potential; it may contribute to the spontaneous firing rate of dopaminergic VTA neurons from mice (Okamoto et al 2006;McDaid et al 2008) but not those from rats (McDaid et al 2008;Appel et al 2003), but its major role is likely to be in the regulation of excitability and synaptic signal integration in dopaminergic VTA neurons (Inyushin et al 2010). The authors noted a rightward voltage shift produced by ACD on I A (Melis et al, 2007). Also noted was a significant increase in h-current produced by acutely applied ACD; this is consistent with an effect of EtOH, which has been shown to acutely increase I h of VTA neurons in brain slices (Brodie and Appel, 1998;Okamoto et al, 2006).…”

“…ACD-induced excitation of dopaminergic VTA neurons appears to be mediated by effects on h-current and A-current (Melis et al, 2007). EtOH excitation in dopaminergic neurons of the rat has been shown to be blocked by quinidine, but not by blockers of h-current (Appel et al, 2003).…”

“…Furthermore, EtOH applied in the presence of a catalase inhibitor, 3-aminotriazole (1 mM), failed to produce its characteristic excitation of the VTA neurons in this study. In exploring the mechanism of ACD excitation of VTA neurons, Melis et al (2007) examined the effect of ACD on two ion currents, Acurrent and h-current. An A-current represents a rapidly-inactivating potassium current that can contribute to spike after hyperpolarization and is involved in the regulation of firing frequency of dopaminergic VTA neurons (Koyama and Appel, 2006a).…”