Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol

Abstract

The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a “pro-drug” is not new. Alcohol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine). Recent experiments have established that numerous metabolites of alcohol have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds. The data indicate that there is a positive relationship between alcohol and alcohol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to alcoholism.

Reinforcing Properties and Neurochemical Response of Ethanol within the Posterior Ventral Tegmental Area Are Enhanced in Adulthood by Periadolescent Ethanol Consumption

“…1-3). The reinforcing properties of drugs of abuse within the pVTA are thought to be dependent on the stimulation of VTA DA neurons and DA release in the AcbSh (c.f., Deehan et al, 2013). The current data sets indicate a convergence of the effects of adolescent EtOH consumption on the self-infusion of EtOH directly into the pVTA and the ability of EtOH microinjected into the pVTA to stimulate DA release in the AcbSh.…”

Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line

“…These findings, together with microdialysis studies (Melis et al, 2007; Deehan et al, 2013a,b) show that local administration of acetaldehyde into the posterior VTA leads to increases in dopamine release in nucleus accumbens further suggesting that the reinforcing effect of acetaldehyde is mediated by activation of dopaminergic neurons. Thus, the effect of acetaldehyde on dopamine release mimics the effects of many drugs of abuse (Di Chiara and Imperato, 1988).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Although there are many demonstrations of the reinforcing actions of acetaldehyde in the brain, either by experimenter-or self-administered acetaldehyde (Deehan et al, 2013), the mechanisms of action remain to be clarified. Converging evidence suggests that acetaldehyde could contribute to ethanol's stimulatory action on the VTA DA neurons.…”

“…Role of Acetaldehyde in Ethanol's Reinforcing Actions. Although it is widely believed that the actions of the ethanol molecule itself are responsible for ethanol reinforcement, there is evidence to suggest that ethanol metabolism and its products, particularly acetaldehyde, could have a role in ethanol consumption and abuse (reviewed in Quertemont, 2004;Deng and Deitrich, 2008;Deehan et al, 2013). The bulk of ethanol is metabolized in the liver by alcohol dehydrogenase and aldehyde dehydrogenase (ALDH) enzymes.…”

“…However, the DAreleasing effect of ethanol in the NAc is not mediated by acetaldehyde . It is also to be noted that acetaldehyde is a highly reactive molecule that interacts with many endogenous substances in the brain to form additional biologically active products (Deehan et al, 2013). …”