Alcohol dependence: molecular and behavioral evidence

Abstract

Alcohol dependence is a complex condition with clear genetic factors. Some of the leading candidate genes code for subunits of the inhibitory GABAA and glycine receptors. These and related ion channels are also targets for the acute actions of alcohol, and there is considerable progress in understanding interactions of alcohol with these proteins at the molecular and even atomic levels. X-ray structures of open and closed states of ion channels combined with structural modeling and site-directed mutagenesis have elucidated direct actions of alcohol. Alcohol also alters channel function by translational and post-translational mechanisms, including phosphorylation and protein trafficking. Construction of mutant mice with either deletion of key proteins or introduction of alcohol-resistant channels has further linked specific proteins with discrete behavioral effects of alcohol. A combination of approaches, including genome wide association studies in humans, continues to advance the molecular basis of alcohol action on receptor structure and function.

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

“…Ethanol enhances the function of recombinant (Trudell et al, 2014) and native brain GlyRs (Badanich et al, 2013;Maguire et al, 2014). The work of Badanich et al (2013) emphasized a selective effect of GlyRs in ethanol action in lateral orbitofrontal cortex neurons.…”

Glycine and GABAAUltra-Sensitive Ethanol Receptors as Novel Tools for Alcohol and Brain Research

“…The resultant lack of a high-affinity structure-activity relationship precludes the classic approach of using specific agonists and antagonists to identify the sites and mechanisms of ethanol action (Deitrich et al, 1989;Little, 1991). This problem is further complicated by the multiple receptor subunit combinations affected by ethanol and the complex acute and chronic mechanisms of ethanol action (Trudell et al, 2014).…”

“…Current strategies that knock out (KO) receptor subunits or knock in (KI) mutant ethanol-insensitive receptors have provided important insights (Blednov et al, 2003(Blednov et al, , 2010Chandra et al, 2008;Liang et al, 2008;Moore et al, 2010;Trudell et al, 2014). However, these studies involving functional deletion or reduction in receptor sensitivity to ethanol require the use of relatively high ethanol concentrations (10-50 mM) Blednov et al, 2010Blednov et al, , 2011) that may affect other native receptor systems and signaling pathways that modulate additional physiologic processes Harris et al, 2008;Liang et al, 2008;Kumar et al, 2009;Howard et al, 2011;Kelm et al, 2011).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Although many drug targets have been revealed by using high-affinity (nanomolar) radiolabel binding to brain membranes or recombinant receptors, with ethanol this approach has not been possible because of its 1000-or even 100,000-fold lower affinity. However, there is accumulating evidence that ethanol has a few well-defined molecular targets (Trudell et al, 2014). At intoxicating ethanol concentrations, from low to approximately 100 mM, the most important targets of ethanol include ion channels, neurotransmitter receptors, and intracellular signaling molecules.…”