A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

Abstract

The purpose of this review is to present up-to-date pharmacological, genetic and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein we sought to place the P rat’s behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this paper discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general.

Rat animal models for screening medications to treat alcohol use disorders

“…Particularly germane to the present topic, animal models have led to important findings on neural substrates mediating addiction to multiple substances of abuse (c.f., Bell and Rahman, 2016; De Biasi, 2015; Dwoskin, 2014; Ekhtiari and Paulus, 2016a, 2016b; Frascella et al, 2011; Heidbreder, 2008; Koob et al, 2014a; McArthur and Borsini, 2008c; Nader, 2016; Olmstead, 2011) and ethanol in particular (Bell et al, 2005, 2006b, 2012, 2013, 2014, 2016; Ciccocioppo, 2013; Crabbe et al, 2013; Knapp and Breese, 2012; Maldonado-Devincci et al, 2012; McBride and Li, 1998; McBride et al, 2014b; Ramsden, 2015; Ryabinin, 2012). As indicated above, advanced neuroimaging techniques including resting state functional connectivity are being used to develop endophenotypes for medications development targeting AUDs (e.g., Brown et al, 2015; Cui et al, 2015; Ernst et al, 2015; Fedota and Stein, 2015; Gowin et al, 2015; Gullo et al, 2011; Moeller et al, 2016; Muller-Oehring et al, 2015a, 2015b; Schuckit et al, 2016; Squeglia et al, 2014).…”

“…Additional criteria might be the ability to display binge-like drinking, as well as the expression of excessive ethanol consumption during the juvenile, adolescent and emerging adult stages of development (e.g., Bell et al, 2013, 2014). Finally, with a substantial minority of alcoholics engaging in polysubstance use and abuse, perhaps it is time to include this behavior in criteria for an animal model of AUD (e.g., Bell et al, 2016) as well.…”

Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models

“…During this time, a number of SNPs have been identified and associate with various aspects of alcohol drinking and dependence. Because a number of recent reviews have detailed these SNPs [4,[6][7][8], we will briefly highlight a few previously identified SNPs in the human AUD population with druggable targets and discuss how this has informed pharmacothera peutic interventions. The remainder of the review will focus on newly identified pharmacogenetic targets from preclinical models that may provide novel treatment strate gies for AUD.…”

Analytical fusion of multimodal magnetic resonance imaging to identify pathological states in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats

“…Since only two of the two symptoms are sufficient to diagnose alcohol use disorders, clinical population and alcohol-related effects are highly heterogeneous with different behavioral and physical consequences, where several neurobiological systems (cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y) are thought to mediate independently or interactively modulating acute rewarding and cognitive and behavioral effects and neuroadaptations facilitating addiction (8,9).…”

“…This natural behavior positions rats and mice as suitable species to try to understand various aspects of alcohol addiction typical of humans as heavy alcohol consumption. Commonly human alcohol consumption is approached using preference studies in rodent, in which animals can choose freely between water and alcohol solutions and the consumed amounts of each fluid are measured (Two-Bottle Free Choice Drinking Paradigm) or other alcohol self-administration paradigms resulting in pharmacologically relevant BACs (9,15). A subset of this animals present a preference for high alcohol concentrations and this fact allows to researcher to generate pairs of breeds characterized by low or high level alcohol consumption, namely, to classify subjects respect to alcohol preference despite of non-sweet taste.…”