Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

Abstract

Drug addiction represents a major social problem where addicts and alcoholics continue to seek and take drugs despite adverse social, personal, emotional, and legal consequences. A number of pharmacological compounds have been tested in human addicts with the goal of reducing the level or frequency of intake, but these pharmacotherapies have often been of only moderate efficacy or act in a sub-population of humans. Thus, there is a tremendous need for new therapeutic interventions to treat addiction. Here, we review recent interesting studies focusing on gamma-aminobutyric acid receptors, voltage-gated ion channels, and transcranial magnetic stimulation. Some of these treatments show considerable promise to reduce addictive behaviors, or the early clinical studies or pre-clinical rationale suggest that a promising avenue could be developed. Thus, it is likely that within a decade or so, we could have important new and effective treatments to achieve the goal of reducing the burden of human addiction and alcoholism.

Opioid antagonists block acetaldehyde-induced increments in dopamine neurons activity

“…Among the therapies available today for alcohol abuse (Leggio et al, 2010;Addolorato et al, 2012), one of the most widely used is NTX and the present results suggest that EtOH-derived ACD may participate in its mechanism of action.…”

Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder

“…Family, twin, and adoption studies have shown that genetic factors have an important role in the etiologies of AD and drug dependence, and these disorders share common genetic risk to some extent (Fu et al, 2002;True et al, 1999;Xian et al, 2008). Variation in the function of the gamma-aminobutyric acid (GABA) receptor subunit genes is hypothesized to have a role in developing the disorders (Addolorato et al, 2012;Davis and Wu, 2001). GABA is the major inhibitory neurotransmitter in mammalian brain, where it acts at GABA A receptors, which are ligand-gated multisubunit chloride channels.…”

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

“…Fortunately, current thoughts and attitudes about alcohol-use disorders are considerably different. Despite some rooted reticence in considering alcoholism strictly as a medical problem, alcohol and other addictive substance disorders are now more widely recognized as brain diseases, similar to other clinical psychiatric disorders (Addolorato et al, 2012). There is an increased awareness about genetic predisposition to alcoholism and long-lasting changes in neurotransmission systems associated with different phases of addiction.…”

“…Although the treatment of alcoholism represents a central aim in public health care, only a few medications are currently approved for this disease, whereas others are still in clinical trials (see Box 1). Another limitation to treatment is the fact that pharmacogenetic studies show that the efficacy of these drugs varies across the heterogeneous clinical population of alcoholics (Addolorato et al, 2012;Anton et al, 2006;Garbutt, 2009;Heilig and Egli, 2006;Leggio and Addolorato, 2010;Volkow and Li, 2005). Therefore, an increase in effective medications for the treatment of alcohol abuse is of critical importance; drug development depends initially on the identification of novel therapeutic targets determined from preclinical research studies.…”

“…Therefore, an increase in effective medications for the treatment of alcohol abuse is of critical importance; drug development depends initially on the identification of novel therapeutic targets determined from preclinical research studies. Because the effects of alcohol involve complex system interactions, numerous neuropharmacological targets associated with these systems are currently under investigation, including the following: neurotransmission systems (a-adrenergic, dopaminergic, endocannabinoid, GABAergic, glutamatergic, nicotinic cholinergic, neuropeptide Y, serotonergic, and substance P), pathways associated with acetaldehyde-related enzymes, corticotropin-releasing factor, feeding-related peptides, neuroinflammation, and nociception, among others (Addolorato et al, 2012;Leggio and Addolorato, 2010;Spanagel, 2009). Advances in highthroughput technologies promise to accelerate the process of pinpointing therapeutic targets and offer invaluable diagnostic and screening potential for a multifaceted disease like alcoholism.…”