Behavioural sensitization to alcohol: Bridging the gap between preclinical research and human models

Highlights

• Few studies have examined alcohol sensitization in the context of human alcohol research

• There currently lacks a reliable protocol for measuring alcohol sensitization in humans

• We address ways to improve the translation between preclinical and clinical research in alcohol sensitization

• Dose, administration frequency, environmental moderators, and individual characteristics are important factors to consider

Abstract

Alcohol use disorder (AUD) is an increasingly prevalent disorder that contributes significantly to the global burden of disease. According to the incentive sensitization theory (IST) of addiction, repeated alcohol exposure produces persistent neuroadaptations that promote the craving, relapse, and drug-taking characteristic of addiction. Critical to the IST model is the prediction that stimulant or hedonic drug effects become more pronounced with repeated exposure (i.e., sensitization). While there is an extensive body of preclinical alcohol sensitization research, there have been few studies examining this aspect of the incentive sensitization model in human alcohol research. In particular, developmental studies assessing sensitization over time in humans are lacking, due largely to ethical considerations precluding alcohol administration in alcohol-naïve individuals, and the lack of a reliable protocol for the prospective measurement of sensitization. The lack of translation between preclinical and human models of alcohol sensitization presents a significant barrier to further understanding the relevance of IST to the development and progression of AUD. The present review discusses how the gap between preclinical and clinical alcohol sensitization research can be bridged and how animal studies can inform human alcohol sensitization research.

Introduction

The World Health Organization (WHO) estimates that roughly 3.3 million people die per year due to harmful alcohol use (WHO, 2015). In the US alone, more than 15 million people met criteria for alcohol use disorder (AUD) in 2015 (Center for Behavioral Health Statistics and Quality, 2016). Of particular concern are recent data showing a 30% increase in high-risk drinking and a 49% increase in AUD prevalence among U.S. adults over a 10-year period (Grant et al., 2017). Alcohol contributes significantly to the global burden of disease, elevating the risk of medical and psychiatric conditions, injury, and premature death (Rehm et al., 2009). Most who use alcohol do not become addicted, and the mechanisms conferring susceptibility and resistance to addiction are only beginning to be elucidated (Volkow and Baler, 2014). Therefore, understanding the processes that lead from non-problematic use to addiction are crucial first steps in identifying individuals who are at risk and who may benefit from targeted interventions.

Several theories of addiction have been put forth and tested in both animal models and human subjects to further understand the processes underlying the development of AUDs (Bechara, 2005; Bickel et al., 2014; Jentsch and Taylor, 1999; Koob and Volkow, 2010). In this review, we focus on the incentive sensitization theory (IST), one of the more prominent theories of addiction, which posits that addiction develops, in part, from the sensitization of brain reward systems to drugs and drug-associated cues (Berridge and Robinson, 2016). This theory has been seldom studied in humans despite being extensively studied in preclinical models (Robinson and Berridge, 2000), and while some human studies have tested hypotheses derived from IST (Bujarski et al., 2017; Bujarski and Ray, 2014; Hobbs et al., 2005; Ostafin et al., 2010), human studies employing a developmental approach to assess sensitization over time are lacking. As such, the goal of this review is to provide a brief background into the IST and present suggestions for human alcohol studies that might bridge the gap between preclinical research findings and human experiments. The first section of this paper provides a review of the IST, followed by a discussion of available literature on alcohol sensitization in humans. Next, we present several methodological aspects that, based on preclinical research, should be carefully considered when attempting to study alcohol sensitization in humans. To this end, we conducted a selective review of the preclinical and human literatures on alcohol, consulting review papers and primary literature to identify methodological considerations for translational research on alcohol sensitization. Sensitization studies and reviews were identified using the PubMed database and bibliographic searches. Keywords searched included alcohol and related terms (ethanol), sensitization and related terms (behavioural, locomotor, incentive), and terms to identify human laboratory studies (alcohol, ethanol, human, clinical). While we focus primarily on preclinical alcohol sensitization studies, selected psychostimulant or opiate sensitization studies are also referenced when relevant, due to the extensive literature available within these drug categories.