Individual differences in addiction-like behaviors and choice between cocaine versus food in Heterogeneous Stock rats

Abstract

Rationale and objectives: Recent studies reported that when given a mutually exclusive choice between cocaine and palatable food, most rats prefer the non-drug reward over cocaine.However, these studies used rat strains with limited genetic and behavioral diversity. Here, we used a unique outbred strain of rats (Heterogeneous Stock, HS) that mimic the genetic variability of humans.Methods: We first identified individual differences in addiction-like behaviors (low and high). Next, we tested choice between cocaine and palatable food using a discrete choice procedure. We characterized the individual differences using an Addiction score that incorporates key features of addiction: escalated intake, highly motivated responding (progressive ratio), and responding despite adverse consequences (footshock punishment). We assessed food vs. cocaine choice at different drug-free days (without pre-trial cocaine self administration) during acquisition of cocaine self-administration or after escalation of cocaine self-administration. We also assessed drug vs. food choice immediately after 1-, 2-, or 6-h cocaine self-administration.Results: Independent of the addiction score, without pre-trial coccaine (1 or more abstinence days) HS rats strongly preferred the palatable food over cocaine, even if the food reward was delayed or its size was reduced. However, rats with high but not low addiction score modestly increased cocaine choice immediately after 1-, 2-or 6-h cocaine self-administration.Conclusions: Like other strains, HS rats strongly prefer palatable food over cocaine.Individual differences in addiction score were associated with increased drug choice in the presence but not absence (abstinence) of cocaine. The HS strain may be useful in studies on mechanisms of addiction vulnerability.

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

“…This represents a challenge for animal models, where the comparatively limited genetic diversity of research subjects may elide some variability factors. Recent work has made use of “heterogeneous stock” rodents – the product of multiple strain crossings - to increase genetic diversity and investigate individual differences in addiction-like behavior and reward learning in the context of drug use ( Hughson et al, 2019 ; de Guglielmo et al, 2021 ; King et al, 2021 ; Sedighim et al, 2021 ). One such study identified a relationship between gut bacterial content and behavioral features of impulsivity and attention ( Peterson et al, 2020 ).…”

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

“…To evaluate addiction-like behaviors in individual rats, we used an Addiction Index (22, 30–33), which includes different addiction-related behaviors: escalation of oxycodone intake under a fixed-ratio (FR) schedule of reinforcement, motivation to maintain responding under a progressive-ratio (PR) schedule of reinforcement, tolerance to the analgesic effects of oxycodone and withdrawal-induced hyperalgesia. To combine these four behavioral outputs, each measure was normalized into an index using its Z -score where χ is the raw value, μ is the mean of the cohort, and σ is the standard deviation of the cohort.…”

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

“…For the cocaine cohorts, rats were characterized for motivation (progressive ratio responding), compulsive-responding to drug use (contingent footshock), and irritability-like behavior (bottle-brush test). An Addiction Index was computed by integrating all the behavioral measures ( Kallupi et al, 2020 ; Carrette et al, 2021 ; Sedighim et al, 2021 ). HS rats classified as having a high Addiction Index were used for this study.…”