Multiple elements of addiction vulnerability are independently heritable in rats

Abstract

Background:Although cocaine is powerfully rewarding, only a fraction of drug-exposed individuals actually transition to become drug-dependent users, possibly due in part to genetic influences, as addictions are among the most heritable of human neuropsychiatric disorders. Consistent with addiction being a complex disorder, prior studies have noted many factors that predict addiction vulnerability, such as drug-induced aversive effects, behavioral responses to novelty, and sensitivity to punishment. Methods:We tested different inbred strains of rats, as well as selectively bred Sprague-Dawley (SD) or Heterogeneous Stock (HS) rats, on cocaine avoidance, sensitivity to punishment, and locomotor responses to novelty, and calculated heritability estimates of these behaviors. We tested animals on additional control tasks (progressive ratio, shock avoidance) to control for alternate interpretations of addiction-like behaviors. Results:Conditioned avoidance to cocaine varied greatly between individual rats as measured using either the runway operant task or conditioned place aversion (CPA). Cocaine avoidance responded rapidly to selective breeding, yielding heritability estimates of 0.70 and 0.58 in SD and HS rats. Resistance to punishment was also highly heritable in inbred rats (estimated h 2 = 0.62), and varied independently of cocaine avoidance despite both behaviors being mediated by the RMTg. Furthermore, cocaine avoidance correlated positively with cocaine-induced c-Fos induction in the RMTg, negatively with initial rates of acquisition of intravenous cocaine self-administration, and positively with both cued and cocaine-primed reinstatement. Conclusions:Cocaine avoidance and resistance to punishment are strongly and independently heritable behaviors that may both control different aspects of individual propensity to acquire and maintain drugseeking.

Large-scale characterization of cocaine addiction-like behaviors reveals that escalation of intake, aversion-resistant responding, and breaking-points are highly correlated measures of the same construct

“…Such a large-scale behavioral approach is required to unveil the genetic basis of addiction-like behavior. The evaluation of different addiction-like behaviors is important as multiple elements of addiction vulnerability were found to be independently heritable (Eid et al, 2019 ), and likely controlled by distinct genes that remain to be identified. Previous studies have clearly identified strain differences in the propensity for escalation of drug intake, which speaks to its heritability (Meyer et al, 2010 ).…”

Individual differences in oxycodone addiction-like behaviors in a large cohort of heterogeneous stock (HS) rats

“…The evaluation of different addiction-like behaviors is essential as multiple elements of addiction vulnerability were found to be independently heritable (56), and are likely controlled by distinct genes that remain unidentified. Opioid self-administration and the psychoactive effects of opioids in rodents, like opioid use disorder in humans, have a heritable component.…”

Large-scale characterization of cocaine addiction-like behaviors reveals that escalation of intake, aversion-resistant responding, and breaking-points are highly correlated measures of the same construct

“…The evaluation of different addiction-like behaviors is important as multiple elements of addiction vulnerability were found to be independently heritable (Eid, Pullmann, LI, Thomas, & Jhou, 2019), and are likely controlled by distinct genes that remain to be identified. Inbred strains studies have clearly identified massive strain differences in the propensity for escalation of cocaine use, which speaks to its heritability.…”