Demographic and clinical characteristics of young adults by <i>PER2</i> rs56013859 genotype: means and SE (in parenthesis) adjusted for sex.

1<p>“Enriched” family adversity index as proposed by Rutter and Quinton (1977) measuring the presence of 11 adverse family factors covering characteristics of the parents, the partnership, and the family environment during a period of one year prior to birth;</p>2<p>obstetric adversity score counting the presence of 9 adverse conditions during pregnancy, delivery, and postnatal period such as preterm labor, asphyxia or seizures;</p>3<p>referring to the last 45 days;</p>4<p>number of standard drinks, each containing 10–13 g alcohol.</p

Linear regression models testing the effects of <i>PER2</i> rs56013859 genotype, severe negative life events and their interaction on drinking measures in young adult regular drinkers (n = 131).

<p>Note: All models adjusted for sex and age. Main effects of genotype and severe negative life events were entered in a first step, followed by the interaction term in a second step.</p>1<p>Unstandardized regression coefficients from linear regression (standard errors);</p>2<p>referring to the last 45 days.</p

Spatiotemporal mRNA expression patterns of <i>PER2</i> in humans.

<p>Data were extracted from Brain Span, Atlas of Developing Human Brain.</p

Mean AUDIT scores (SE), adjusted for sex, in young adults grouped by <i>PER2</i> rs56013859 genotype and exposure to negative life events.

<p>Mean AUDIT scores (SE), adjusted for sex, in young adults grouped by <i>PER2</i> rs56013859 genotype and exposure to negative life events.</p

Cocaine effects on mouse incentive-learning and human addiction are linked to a2 subunit-containing GABAA receptors

Because GABAA receptors containing a2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with a2 gene deletion showed reduced synaptic GABAA receptor-mediated responses. Behaviorally, the deletion abolished cocaine’s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of a2-GABAA receptors (a2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In a2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of a2-GABAA receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction