In search of predictive endophenotypes in addiction: insights from preclinical research

Abstract

Drug addiction is widely recognized to afflict some but not all individuals by virtue of underlying risk markers and traits involving multifaceted interactions between polygenic and external factors. Remarkably, only a small proportion of individuals exposed to licit and illicit drugs develop compulsive drug-seeking behavior, maintained in the face of adverse consequences and associated detrimental patterns of drug intake involving extended and repeated bouts of binge intoxication, withdrawal and relapse. As a consequence, research has increasingly endeavored to identify distinctive neurobehavioral mechanisms and endophenotypes that predispose individuals to compulsive drug use. However, research in active drug users is hampered by the difficulty in categorizing putatively causal behavioral traits prior to the initiation of drug use. By contrast, research in experimental animals is often hindered by the validity of approaches used to investigate the neural and psychological mechanisms of compulsive drug-seeking habits in humans. Herein, we survey and discuss the principal findings emanating from preclinical animal research on addiction and highlight how specific behavioral endophenotypes of presumed genetic origin (e.g. trait anxiety, novelty preference and impulsivity) differentially contribute to compulsive forms of drug seeking and taking and, in particular, how these differentiate between different classes of stimulant and non-stimulant drugs of abuse.

Addictions Neuroclinical Assessment: A reverse translational approach

“…However, translating findings from animal models to humans, and reverse translating from humans to animal models, is hampered by the etiologic heterogeneity of addiction vulnerability in both humans and the diversity of animal models available (4). In humans, there is wide variation in progression and outcome, and limited ability to stage addiction using measures of progression emergent from studies in animal models.…”

“…The roles of both genetic and environmental factors in interindividual variation in vulnerability and progression can bet traced in both humans and animal models of addiction. In rodents, genetically very similar, or identical (inbred and inbred F1) individuals can be divergent in behaviors such as novelty seeking and novelty-induced hyperlocomotion that predict addiction-like behavior, and, by extension, divergent in outcome (4), and divergent in addiction behaviors that develop subsequent to exposure. Preclinical studies are therefore an avenue to identify domains that are critical for predicting liability and staging response in human patients, provided relevant domains can be measured.…”

“…Historically, most preclinical studies of addiction, including alcohol, have focused on drug reinforcement (4). However, studies in rats and mice have revealed powerful predictors of interindividual variation in liability.…”

Determinants of choice, and vulnerability and recovery in addiction

“…Additionally, addiction is often characterized by compulsions or inability to stop using drugs, despite the individual expressing a desire to stop (see Belin et al, 2016). Health risk, habitual usage, and compulsion have helped identify addiction as a phenomenon, but the responsible processes remain elusive.…”

Patología dual: integrando la salud mental

“…Ésta no se produce sólo por los efectos reforzantes de las sustancias sobre el Sistema de Recompensa Cerebral, sino por otros mecanismos de vulnerabilidad -aun no suficientemente dilucidados-que separan de forma clara al uso recreativo del uso compulsivo. Por tanto, sólo una minoría de los consumidores de sustancias o personas que "juegan" tiene una adicción y quienes la padece, no la eligen (Belin, Belin-Rauscent, Everitt, & Dalley, 2016).…”