Implications of Genome Wide Association Studies for Addiction: Are Our a Priori Assumptions All Wrong?

Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?

Pharmacol Ther. 2013 Jul 18;
Hall FS, Drgonova J, Jain S, Uhl GR

Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS. HubMed – addiction

Nicotinic Receptor Partial Agonists Modulate Alcohol Deprivation Effect in C57BL/6J Mice.

Pharmacol Biochem Behav. 2013 Jul 17;
Sajja RK, Rahman S

Relapse is a core feature of alcohol addiction and hinders the pharmacotherapy of alcohol use disorders. Pre-clinical and clinical studies have shown that neuronal nicotinic acetylcholine receptor (nAChR) partial agonists such as cytisine and its derivative, varenicline, reduce alcohol (ethanol) consumption and seeking behavior. However, the effects of these ligands on ethanol relapse are little understood. In the present study, we examined the effects of varenicline and cytisine on alcohol deprivation effect (ADE) – a validated model for relapse-like ethanol drinking in C57BL/6J mice. After habituation to 15% (v/v) ethanol intake using a continuous free-choice procedure, mice were exposed to alternating cycles of ethanol deprivation (5 days) and re-exposure (2 days). At the end of third deprivation cycle, animals received repeated intraperitoneal injections of saline, varenicline (0.5 or 3.0 mg/kg) or cytisine (0.5 or 3.0 mg/kg) and fluid intake was measured post 4 h and 24 h ethanol re-exposure. Repeated ethanol deprivation and re-exposure cycles significantly produced a robust and transient increase in ethanol (ADE). Pretreatment with varenicline (0.5 or 3.0 mg/kg) or cytisine (0.5 or 3.0 mg/kg) significantly reduced the expression of ADE at 4 h and 24 h after ethanol re-exposure. The results from this study indicate that nAChR partial agonists reduce the expression of ADE in mice and further suggest the involvement of nAChR mechanisms in ADE, a relapse-like ethanol drinking behavior. HubMed – addiction

Therapeutic potential of GABAB receptor ligands in drug addiction, anxiety, depression and other CNS disorders.

Pharmacol Biochem Behav. 2013 Jul 17;
Kumar K, Sharma S, Kumar P, Deshmukh R

Glutamate and ?-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitter systems, respectively in the central nervous system (CNS). Dysregulation, in any of these or both, has been implicated in various CNS disorders. GABA acts via ionotropic (GABAA and GABAC receptor) and metabotropic (GABAB) receptor. Dysregulation of GABAergic signaling and alteration in GABAB receptor expression has been implicated in various CNS disorders. Clinically, baclofen-a GABAB receptor agonist, is available for the treatment of spasticity, dystonia etc. associated with various neurological disorders. Moreover, GABAB receptor ligands has also been suggested to be beneficial in various neuropsychiatric and neurodegenerative disorders. The present review is aimed to discuss the role of GABAB receptors and the possible outcomes of GABAB receptor modulation in CNS disorders. HubMed – addiction

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