Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats

Abstract

Rationale: In human and animal studies, adolescence marks a period of increased vulnerability to the initiation and subsequent abuse of drugs. Adolescents may be especially vulnerable to relapse, and a critical aspect of drug abuse is that it is a chronically relapsing disorder. However, little is known of how vulnerability factors such as adolescence are related to conditions that induce relapse, triggered by the drug itself, drug-associated cues, or stress.

Objective: The purpose of this study was to compare adolescent and adult rats on drug-, cue-, and stress-induced reinstatement of cocaine-seeking behavior.

Methods: On postnatal days 23 (adolescents) and 90 (adults), rats were implanted with intravenous catheters and trained to lever press for i.v. infusions of cocaine (0.4 mg/kg) during two daily 2-h sessions. The rats then self-administered i.v. cocaine for ten additional sessions. Subsequently, visual and auditory stimuli that signaled drug delivery were unplugged, and rats were allowed to extinguish lever pressing for 20 sessions. Rats were then tested on cocaine-, cue-, and yohimbine (stress)-induced cocaine seeking using a within-subject multicomponent reinstatement procedure.

Results: Results indicated that adolescents had heightened cocaine seeking during maintenance and extinction compared to adults. During reinstatement, adolescents (vs adults) responded more following cocaine- and yohimbine injections, while adults (vs adolescents) showed greater responding following presentations of drug-associated cues.

Conclusion: These results demonstrated that adolescents and adults differed across several measures of drug-seeking behavior, and adolescents may be especially vulnerable to relapse precipitated by drugs and stress.

Fig. 1

Mean (± SEM) responses on the drug-paired lever (a) and cocaine (0.4 mg/kg, i.v.) infusions (b) during ten 2-h sessions under the maintenance condition in adolescent (n=14) and adult (n=15) male rats. Adolescent rats earned significantly more infusions than adult rats over the 5 days (†p<0.05)

Fig. 2

Mean (± SEM) responses on the previously drug paired lever during 20 2-h sessions following the removal of cocaine. Adolescents (n=14), compared to adults (n=15), responded significantly more on the previously drug-paired lever over the 10 days (†p<0.05)

Fig. 3

Mean (± SEM) responses on the previously drug-paired lever following saline (SA) or cocaine (COC; 5, 10, and 15 mg/kg) i.p. priming injections, cues, and 2.5-mg/kg yohimbine (YOH) i.p. priming injections during the reinstatement procedure in adolescent (n=8) and adult rats (n=14). Responses during priming sessions were compared to responses during control sessions (striped bars) that occurred that same day. Asterisks indicate significantly greater responding during the priming condition compared to the control condition within groups (*p<0.05). Daggers denote significant group differences in responding during the priming conditions (†p<0.05)