Motivated Binge and High-Intensity Drinking in Selected Rat Lines

项目总结

PROJECT SUMMARY Understanding the neural circuitry that underlies binge and high intensity drinking (BHID) requires an animal model that reliably expresses this behavior voluntarily. The alcohol-preferring P rats and the High Alcohol Drinking HAD rats (both rodent models of a human family history of alcohol use disorder; AUD) have behavioral profiles prior to any alcohol exposure that suggest two different pathways to AUD: the P rats are prone to emit behavior, impulsive, and reinforcer-driven; by contrast the HADs are less likely to emit behavior, not impulsive, and more anxious. In addition, our preliminary data show that the lines and sexes display different BHID-like intake patterns. Therefore, P and HAD rats show distinct phenotypes that correspond with “reward” and “relief” drinking, respectively— two risk phenotypes in humans. The objective of this proposal is to identify hypothesized pathologies in specific neural pathways regulating BHID-like consumption that correspond to circuits thought to support reward and relief drinking (prefrontal cortex to nucleus accumbens; prefrontal cortex to basolateral amygdala). Specifically, this proposal will utilize the combination of (i) animal models of behaviorally divergent AUD risk in which we (ii) employ tract tracing to reveal key differential circuits between the lines (iii) that we will in turn manipulate to bidirectionally drive both behavioral impulsivity and BHID behavior. The significance of this Center Component is that it will discover critical novel mechanisms in the structure and function of the circuitry regulating endophenotypic risk behaviors (using the stop signal reaction time task) and alcohol-seeking and BHID (using the operant seeking/drinking paradigm). Moreover, from these findings, and in conjunction with other IARC projects, we may ultimately learn the underlying mechanisms for these traits that contribute to the progression to an AUD. Particularly in an era of “precision medicine”, where drug efficacy can be dependent upon different genetic profiles and drinking patterns, an understanding of different, genetically-influenced pathways to alcohol dependence must precede development of effective AUD treatment.