Adolescent-onset of cocaine use is associated with heightened stress-induced reinstatement of cocaine seeking

Abstract

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.

Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes

“…Evidence for heightened self-administration in adolescents and females may depend on several methodological factors, such as duration of access, dose, and pubertal status. Typically, when cocaine or amphetamines are available for short periods of time (≤ 2 h), adolescents (Shahbazi et al 2008; Harvey et al 2009; Anker et al 2012; Wong and Marinelli 2015) and females (Reichel et al 2012) self-administer similar amounts of drug as their counterparts. Consistent with findings from the current study, these age and sex differences are dependent on dose (Kantak et al 2007; Shahbazi et al 2008; Wong et al 2013; Schassburger et al 2016).…”

“…In rodent studies, there are mixed findings for age-dependent differences in drug-seeking that may depend on drug class (Doherty et al 2013; Doherty and Frantz 2012; Mayer-Blackwell et al 2014) or other methodological factors. However, it is most frequently the case that drug seeking in adolescents is found to be similar or heightened relative to adults (Shahbazi et al 2008; Anker et al 2012; Wong et al 2013; Wong and Marinelli 2015).…”

Sensitive periods of substance abuse: Early risk for the transition to dependence

“…Animal models, in particular rodents, represent an opportunity to investigate the contribution of behavioral and biological risk factors to substance dependence. Environment, genetics, and neurobiology can be manipulated in laboratory animals to determine mechanistic contributions to individual responses to drugs of abuse ( Anker and Carroll, 2010 , Brenhouse et al, 2008 , Sonntag et al, 2014 , Wong and Marinelli, 2016 ). More broadly, behaviors related to substance dependence can be studied systematically using place conditioning or self-administration paradigms.…”

“…However, in place conditioning drug delivery is non-contingent, i.e., drugs are administered by the experimenter. In contrast, self-administration paradigms allow rodents to respond voluntarily for drugs, allowing assessment of drug-seeking and drug-taking behaviors, but require weeks to months of training ( Anker and Carroll, 2010 , Doherty and Frantz, 2012 , Levin et al, 2003 , Levin et al, 2007 , Perry et al, 2007 , Wong et al, 2013 , Wong and Marinelli, 2016 ). Drug studies in adolescent versus adult rats are reviewed further in Section 5.2.2 .…”

Requisite Role of Basolateral Amygdala Glucocorticoid Receptor Stimulation in Drug Context-Induced Cocaine-Seeking Behavior

“…(0.37mg/kg), but not i.p. or s.c., corticosterone administration is sufficient to reinstate extinguished cocaine-seeking behavior (Deroche et al, 1997; Lee et al, 2003; Graf et al, 2013; Wong and Marinelli, 2016), unless s.c. corticosterone administration is preceded by adolescent cocaine exposure (Wong and Marinelli, 2016). This suggests that rapid increases in corticosterone levels or age-dependent cocaine-induced adaptations are required for glucocorticoid-induced reinstatement.…”