Identification of genes regulated by trait sensitivity to negative feedback and prolonged alcohol consumption in rats.

BACKGROUND: The results of our previous studies demonstrated that low sensitivity to negative feedback (NF) is associated with increased vulnerability to the development of compulsive alcohol-seeking in rats. In the present study, we investigated the molecular underpinnings of this relationship. METHODS: Using TaqMan Gene Expression Array Cards, we analyzed the expression of the genes related to NF sensitivity and alcohol metabolism in three cortical regions (medial prefrontal cortex [mPFC], anterior cingulate cortex [ACC], orbitofrontal cortex [OFC]) and two subcortical regions (nucleus accumbens [Nacc], amygdala [Amy]). Gene expression differences were confirmed at the protein level with Western blot. RESULTS: Sensitivity to NF was characterized by differences in Gad2, Drd2, and Slc6a4 expression in the ACC, Maoa in the mPFC, and Gria1, Htr3a, and Maoa in the OFC. Chronic alcohol consumption was associated with differences in the expression of Comt and Maoa in the ACC, Comt, Adh1, and Htr2b in the mPFC, Adh1, and Slc6a4 in the Nacc, Gad2, and Htr1a in the OFC, and Drd2 in the Amy. Interactions between the sensitivity to NF and alcohol consumption were observed in the expression of Gabra1, Gabbr2, Grin2a, Grin2b, and Grm3 in the ACC, and Grin2a in the OFC. The observed differences were confirmed at the protein level for MAO-A in the mPFC, and ADH1 in the mPFC and Nacc. CONCLUSIONS: Our findings contribute to a better understanding of the molecular mechanisms underlying the relationship between trait sensitivity to NF and compulsive alcohol consumption.

Trait sensitivity to positive feedback is a predisposing factor for several aspects of compulsive alcohol drinking in male rats: behavioural, physiological, and molecular correlates.

INTRODUCTION: Alcohol use disorder (AUD) is one of the most common psychiatric disorders and a leading cause of mortality worldwide. While the pathophysiology underlying AUD is relatively well known, the cognitive mechanisms of an individual's susceptibility to the development of alcohol dependence remain poorly understood. In this study, we investigated the theoretical claim that sensitivity to positive feedback (PF), as a stable and enduring behavioural trait, can predict individual susceptibility to the acquisition and maintenance of alcohol-seeking behaviour in rats. METHODS: Trait sensitivity to PF was assessed using a series of probabilistic reversal learning tests. The escalation of alcohol intake in rats was achieved by applying a mix of intermittent free access and instrumental paradigms of alcohol drinking. The next steps included testing the influence of sensitivity to PF on the acquisition of compulsive alcohol-seeking behaviour in the seeking-taking punishment task, measuring motivation to seek alcohol, and comparing the speed of extinction and reinstatement of alcohol-seeking after a period of abstinence between rats expressing trait insensitivity and sensitivity to PF. Finally, trait differences in the level of stress hormones and in the expression of genes and proteins in several brain regions of interest were measured to identify potential physiological and neuromolecular mechanisms of the observed interactions. RESULTS: We showed that trait sensitivity to PF in rats determines the level of motivation to seek alcohol following the experience of its negative consequences. They also revealed significant differences between animals classified as insensitive and sensitive to PF in their propensity to reinstate alcohol-seeking behaviours after a period of forced abstinence. The abovementioned effects were accompanied by differences in blood levels of stress hormones and differences in the cortical and subcortical expression of genes and proteins related to dopaminergic, serotonergic, and GABAergic neurotransmission. CONCLUSION: Trait sensitivity to PF can determine the trajectory of alcohol addiction in rats. This effect is, at least partially, mediated via distributed physiological and molecular changes within cortical and subcortical regions of the brain.

Importance of additional behavioral observation in psychopharmacology: a case study on agomelatine's effects on feedback sensitivity in probabilistic reversal learning in rats.

Since the second half of the twentieth century, many important discoveries in the field of behavioral psychopharmacology have been made using operant conditioning cages. These cages provide objective data collection and have revolutionized behavioral research. Unfortunately, in the rush towards automation, many mistakes may have been made that could have been avoided by observing experimental animals. The study described in this paper is an excellent example of how important additional behavioral observation can be for interpreting instrumental data. In this study, we evaluated the effects of single injections of 3 different doses of agomelatine (5, 10, and 40 mg/kg) on feedback sensitivity in rats. To this end, we tested 40 animals in the instrumental probabilistic reversal learning task in a Latin square design. The highest applied dose of agomelatine, prima facie, reduced the sensitivity of rats to negative feedback - an effect that can be considered antidepressant. However, additional behavioral observation dramatically changed the interpretation of the results and revealed that the perceived effect of agomelatine on sensitivity to negative feedback can actually be attributed to drug-induced drowsiness.