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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    771—Neural Mechanisms of Appetitive Behavior

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    771.03: Cocaine self-administration during adolescence results in attenuated drug-primed but exaggerated cue-induced reinstatement compared to adulthood

    Location: Halls B-H

    *I. ZBUKVIC, S. LUIKINGA, C. PERRY, A. LAWRENCE, J. KIM;
    The Florey Inst. of Neurosci. and Mental Hlth., Melbourne, Australia

    Abstract Body: Most lifelong substance abuse begins with drug use during adolescence. Adolescents are not only more likely to initiate and maintain drug use, but once addicted they are also more resistant to treatment interventions and more liable to relapse. Therefore, we examined the acquisition, extinction and reinstatement of cocaine-seeking behaviour in adolescent compared to adult rats using an intravenous-self administration (IVSA) paradigm. Postnatal day (P)34 (±1) and P69 (±1) rats were trained to lever press for cocaine (3mg/kg/infusion) over 10-14 days. Once stable self-administration was established, rats received daily lever extinction sessions, where lever pressing had no programmed consequences. After 7-9 days of lever extinction, rats underwent a single reinstatement session. Experiment 1 examined self-administration in the absence of a drug-associated cue or conditioned stimulus (CS). Drug-primed reinstatement was then assessed by intraperitoneal cocaine injection (10mg/kg) versus saline injection. In experiment 2, all cocaine infusions were coupled with a light CS. After lever extinction, rats underwent a single CS extinction session, consisting of 120 CS-alone presentations with levers retracted, or remained in their home cages. Next day, all rats were tested for CS-induced reinstatement. Results showed no effect of age on acquisition or extinction of lever presses in either experiment (ps > .05). Experiment 1 showed significant reinstatement of lever responses following injection of cocaine compared to saline for all animals (p < .005), however adult rats displayed significantly higher cocaine-induced reinstatement than adolescents (p < .05). In experiment 2, CS extinction significantly reduced CS-induced reinstatement in adult, but not adolescent rats, suggesting CS extinction was less effective in adolescents (ps < .05). Our data suggest that while adolescent drug abuse may lead to lower relapse upon drug exposure compared to adults, it enhances vulnerability to relapse when exposed to drug-associated cues, even following cue extinction. Considering drug experience is inevitably associated with cues in the human situation, enhanced sensitivity to drug-associated cues offers a model for the increased likelihood of addiction when drug use commences during adolescence.

    Lay Language Summary: Our study revealed that drug use beginning in adolescence compared to adulthood leads to a stronger memory associating the cues in the drug-taking environment and the drug experience. This ultimately leads to enhanced vulnerability to relapse, even after extensive cue exposure therapy. These results suggest a difference between adolescents and adults in relapse-like behaviour following cocaine use that may help to explain why adolescents are more susceptible to drug addiction.
    At least 15.3 million people have a substance abuse disorder worldwide, and the majority of addicts report using drugs during adolescence. In fact, adolescence is associated with a greater likelihood of addiction to drugs than any other age. However, current literature on adolescent substance abuse is scarce. One of the defining features of addiction is propensity to relapse, as opposed to the amount of drug taken. Hence we hypothesised that adolescents would take the same amount of drug as adults but show differences in their relapse behaviour. Our group is the first to test this hypothesis in the absence as well as presence of a drug-associated cue.
    Adolescent and adult rats were allowed to self-administer cocaine via a chronic intravenous catheter. When rats pressed a lever, an infusion of cocaine could be delivered via the catheter that was connected to pump. At all stages of self-administration, adolescent and adult rats took the same amount of cocaine per bodyweight. Lever pressing was then extinguished by removing the cocaine infusions, during which adolescents and adults showed an equal reduction in lever pressing behaviour. In our first experiment, relapse-like behaviour was then triggered by an injection of cocaine. This produced a significant increase in lever pressing for all rats. Paradoxically, adults displayed significantly higher relapse-like lever pressing than adolescents, suggesting adolescents are less sensitive to a drug trigger of relapse when there are no cues associated with drug use.
    In our next experiment, a light cue was coupled with cocaine infusions throughout self-administration. Adolescents and adults again consumed similar levels of cocaine, and equally decreased lever pressing when the drug and the cue were removed. Rats then received repeated presentations of the light cue without any cocaine and without the lever, modelling human cue exposure therapy. Relapse of drug-seeking was then triggered by presenting the cue light with the lever. Cue exposure therapy was found to prevent relapse-like lever pressing in adult rats. However, adolescents persisted in their lever pressing regardless of having received cue exposure therapy, and all adolescent rats significantly relapsed when confronted with the drug-associated cue.
    These results suggest that adolescent vulnerability to addiction is critically related to the cues associated with drug experience, rather than their greater ‘liking’ or ‘taking’ of the drug. Without the drug-associated cue during self-administration, adolescents even showed reduced relapse compared to adults. By contrast, adolescents showed compulsive drug-seeking upon re-exposure to the drug-associated cue. Since drug experiences are inevitably associated with cues in the human situation, enhanced propensity to relapse when confronted with drug-associated cues helps to explain the unique vulnerability to addiction following adolescent drug use.
    Our findings suggest that the most effective way to fight addiction is to reduce the significance of cues present at the time of drug experience during adolescence. Because one of the strongest cues related to drug use is often drug-taking friends, re-defining the roles of social circles may be the best approach to combat adolescent drug abuse. Future studies should investigate cognitive enhancers to facilitate such behavioural therapy in adolescence.