Developing new treatments for substance use disorders depends on understanding the basis of individual differences in susceptibility to addiction and highly comorbid disorders (e.g., anxiety, depression). This issue has been widely studied in humans through the use of Confirmatory Factor Analysis (CFA). CFA identifies latent variables (variables that are not measured directly) reflecting the common variance among a larger number of related measures. These latent variables have greater statistical reliability than individual measures and serve as targets of neurobiological and genetic studies to develop biomarkers and improve treatments. Despite its widespread application in clinical research, CFA has been virtually unused in preclinical studies and has never been applied in animal models of addiction and comorbidity. This proposal will use CFA to identify the latent variable(s) underlying individual differences in propensity for opiate self-administration (SA) in rats, and determine which factors are most closely associated with susceptibility to anhedonia or anxiety elicited during opiate withdrawal. Opiate SA propensity will be assessed through a number of measures of morphine SA including acquisition, demand, and reinstatement. Withdrawal from acute morphine injections will be measured both prior to and at the completion of drug SA testing. Anhedonia will be measured as elevations in intracranial self-stimulation thresholds, and anxiety as potentiation of the startle reflex and freezing. Hypotheses: 1) Variability among different measures of opiate SA will be best accounted for by one or more latent variables of opiate SA propensity; 2) Withdrawal-induced anhedonia and anxiety will be associated with greater opiate SA propensity. This association will be evident even after limited drug exposure, suggesting that negative affective responses during initial drug use reflect an underlying trait predictive of addiction liability; 3) Severity of anhedonia and anxiety during drug withdrawal will also be associated most strongly with separate measures of drug SA (e.g., elasticity of demand versus stress-induced reinstatement). This proposal is entirely innovative in seeking to characterize underlying constructs of disease severity, and their relationships, from multiple preclinical indices of drug SA and withdrawal. Identification of such constructs will provide critical refinements of targets for genetic, molecular, and pharmacological investigations aimed at developing more effective treatments. This proposal is also innovative in characterizing the distinct contributions of anxiety and anhedonia to individual differences in drug SA, and in testing the validity of withdrawal-induced negative affect as an early marker for addiction. By increasing the reliability of measures of drug SA propensity, and by utilizing an approach that is already well established in the human literature, this proposal is expected to provide preclinical models of addiction with greater predictive and construct validity. In sum, in adapting the powerful approach of CFA to identify the most critical variables associated with compulsive drug use and drug withdrawal in rodents, our proposal is highly appropriate to the primary goals of the CEBRA program.
Understanding core factors underlying individual differences in vulnerability to drug addiction and comorbid disorders such as depression and anxiety is essential for developing better treatments. A statistical approach known as Confirmatory Factor Analysis has proven highly effective in identifying these core factors and understanding their relationships in humans. By extending this approach to rodent behavioral models of opiate addiction and depression/anxiety, the proposed studies promise to accelerate identification of relevant genetic and neural substrates of these comorbid diseases.
| Swain, Yayi; Muelken, Peter; LeSage, Mark G et al. (2018) Locomotor activity does not predict individual differences in morphine self-administration in rats. Pharmacol Biochem Behav 166:48-56 |
