Abstract

Comparison of intravenous self-administration of psychostimulants vs. opioids and endogenous opioid system differences in an animal model of internalizing vs externalizing temperament

Emery M, Parsegian A, Koonse S, Chang SE, Turner CA, Hebda-Bauer EK, Flagel SB, Watson SJ, Akil H
51st Annual Meeting of the Society for Neuroscience. 2022.

Abstract

In humans, only a small portion of those who experiment with recreational drug use transition to a substance use disorder (SUD). Multiple factors are thought to underlie this susceptibility, including differences in temperament. Those with externalizing temperaments are hypothesized to approach drugs of abuse from a sensation-seeking pathway, while those with internalizing temperaments appear less likely to approach drugs of abuse for recreational reasons but will in response to triggers such as psychosocial stress. Our lab has used a selective breeding strategy based on degree of exploratory locomotion in a novel environment to derive two lines of rats with distinct behavioral and neurobiological phenotypes, termed selectively-bred high-responders (bHRs) and low-responders (bLRs). We have previously shown that temperamental differences between these rats determines their propensity to seek and take psychostimulants, where sensation-seeking bHRs show a higher basal propensity to take drugs; while internalizing bLRs appear less susceptible at baseline but will seek and take drugs in response to psychosocial stress. However, we hypothesized these differences in baseline drug seeking may be partially drug-specific, where bLRs, who display a higher level of baseline anxiety than bHRs, would have higher preference for anxiolytic opioids than anxiogenic stimulants. Here, we used a free access self-administration paradigm of diacetylmorphine (heroin) or cocaine hydrochloride to determine whether these individual differences result in differential use patterns. For both drugs, we observed the expected phenotype differences, with bHRs seeking and taking more drug than bLRs. However, the differences were less pronounced for opioids than stimulants, implying increased preference for opioids in bLRs relative to stimulants. Interestingly, there appears to be a drug x sex x phenotype interaction where a line-specific (bHRs) effect of sex appears in heroin taking behavior, but not for cocaine. We additionally explored differences in opioid neurobiology between these lines, including opioid gene expression in key brain regions, finding differences in multiple opioid system components that likely contribute to line differences in drug-oriented behaviors. Future experiments will explore the impact of stress on drug preference in bHRs/bLRs, as well as the impact of differential expression of opioid system components to drive these differences. These findings contribute to our understanding of the impact of individual differences as well as a potential interaction between temperament, sex, and drug as antecedents of addiction development.