In humans, adolescence is a period of heightened propensity to develop cocaine addiction. It is unknown whether this is attributable to greater access and exposure to cocaine at this age, or whether the adolescent brain is particularly vulnerable to the addictive properties of cocaine. Here, we subjected male adolescent (P42) and adult (~P88) rats to a wide range of cocaine self-administration procedures. In addition, to determine whether behavioral differences are associated with developmental differences in dopaminergic activity, we examined and manipulated the activity of dopamine neurons. Relative to adults, adolescent rats took cocaine more readily, were more sensitive to lower doses, showed greater escalation of cocaine intake, and were less susceptible to increases in price (i.e., were more “inelastic”). In parallel, adolescents also showed elevated activity of ventral tegmental area dopamine neurons, a feature known to be associated with increased self-administration behavior. Pharmacological manipulation of dopamine D2 receptor function with quinpirole (agonist) or eticlopride (antagonist), to alter dopamine neuron activity, eliminated age differences in cocaine self-administration. These data suggest a causal relationship between behavioral and electrophysiological determinants of cocaine addiction liability. In conclusion, adolescents show behavioral and electrophysiological traits of heightened addiction liability.
Adolescent rats take cocaine more readily than adults, are more sensitive to lower doses of the drug, and work harder for it. It remains unknown if adolescent-onset of cocaine use has long-term consequences on adult relapse liability. Therefore, we tested if self-administering cocaine during adolescence impacts subsequent stress-induced reinstatement to cocaine seeking and taking, after a prolonged drug-free period. Adolescent (~P42) or adult (P88) rats self-administered cocaine (0.6 or 1.2 mg/kg/infusion) for 7 or 10 days. Then, they underwent a prolonged drug-free period (21–40 days), after which they were tested for reinstatement of cocaine-seeking (i.e. responding in the absence of cocaine) induced by the stress hormone corticosterone, the pharmacological stressor yohimbine, or electric footshock. Studies employed either single extinction session (within-session extinction/reinstatement) or repeated extinction prior to reinstatement (between-session extinction/reinstatement). Finally, in a separate set of experiments, rats underwent a prolonged drug-free period (~40 days) and were then allowed to self-administer cocaine again, using progressive-ratio procedures that appraise the reinforcing efficacy of cocaine. Rats with adolescent-onset of cocaine use showed greater stress-induced reinstatement of cocaine seeking than rats with adult-onset of cocaine use. This was observed across conditions, providing external validity to these results. Groups did not differ on drug taking in progressive-ratio tests. Our studies indicate that experiencing cocaine during adolescence renders subjects particularly responsive to the subsequent effects of stress on drug seeking. This heightened propensity for reinstatement puts adolescent-onset drug users at heightened risk for relapse.
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