Reduction of Adult Hippocampal Neurogenesis Confers Vulnerability in an Animal Model of Cocaine Addiction

TLDR

Adult neurogenesis is dynamically regulated by drugs of abuse and the hippocampus is key for drug–context associations, yet a causal link to addiction behaviors remains unclear. The authors hypothesized that suppressing adult hippocampal neurogenesis would heighten addiction vulnerability and relapse, and tested this by using rat intravenous cocaine self‑administration combined with cranial irradiation to inhibit neurogenesis before drug exposure. Cranial irradiation–induced suppression of hippocampal neurogenesis increased cocaine self‑administration, shifted the dose–response curve, and enhanced resistance to extinction, without affecting sucrose intake or locomotion. These results identify reduced hippocampal neurogenesis as a novel risk factor for cocaine addiction and suggest that therapies aimed at increasing or stabilizing neurogenesis could help prevent initial addiction and future relapse.

Abstract

Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug–context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose–response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.