A rodent model of phenotypic variation in sweet preference, addiction vulnerability, and pharmacological treatment sensitivity

Abstract

Sweet preference is a stable, genetically-mediated trait that is associated with vulnerability to drug dependence in both human and non-human animals. For instance, rats that have been selectively bred for high intake of a saccharin solution (HiS) are more drug-prone than rats bred for low saccharin intake (LoS). The experiments detailed in this review investigated whether the HiS and LoS phenotypes would display differential effects of pharmacological agents on cocaine self-administration and cocaine-seeking behavior. Treatment effects (e.g., baclofen, progesterone, allopregnanolone, or histamine) were examined between the HiS and LoS rats during the following phases: escalation during long access (LgA) to the drug [Experiments 1 (baclofen) and 3 (progesterone)], including pre- and post-escalation short-access (ShA) periods, dose-response assessment, and cocaine-primed reinstatement of extinguished drug-seeking behavior [Experiments 2 (baclofen) and 4 (allopregnanolone)]. The last experiment investigated the effect of pharmacological treatment of steady-state cocaine self-administration; specifically, we used a punishment paradigm in which histamine was added to the i.v. cocaine self-administration solution (Experiment 5). We found that baclofen and progesterone decreased cocaine intake in LoS animals but increased cocaine intake in HiS animals. Baclofen attenuated cocaine-primed reinstatement of drug-seeking behavior in both HiS and LoS rats equally. In contrast, allopregnanolone potentiated low-dose cocaine-primed reinstatement in LoS rats, whereas it attenuated this response following moderate-dose cocaine priming injections in the HiS rats. Histamine was equally effective in punishing cocaine self-administration in both phenotypes; however, LoS rats exhibited a delay in reaching baseline levels of self-administration following histamine punishment. By demonstrating that phenotypic variance in sweet preference can predict treatment sensitivity in substance-dependent individuals, these data can inform more effective, personalized treatment strategies.