Animal Models of the Preoccupation/Anticipation Stage of the Addiction Cycle

Cue-Induced Reinstatement

Environmental cues paired with drug self-administration can also reliably and robustly reinstate responding after extinction. In this procedure, animals are trained to self-administer drugs of abuse using an operant response procedure, usually lever pressing. A cue, such as a tone or light, precedes the drug delivery. When the animal acquires stable responding, it is then subjected to extinction, in which further lever presses do not deliver any drugs or cues. After responding is extinguished, reinstatement sessions are conducted. The cue by itself is presented, and the animal is allowed to press the lever (Figure 3.13). The cue then elicits vigorous lever pressing. This procedure is widely used to explore the neurobiological substrates of relapse (Shaham et al., 2003). Place conditioning can also be used as a model of cue-induced reinstatement. A place preference is induced by a drug, followed by extinction sessions. Conditioned place preference can then be induced again by a cue presentation.

FIGURE 3.11 Escalation of drug intake with extended access. (Cocaine) Effect of drug availability on cocaine intake. In long-access (LgA) rats with 6 h access (n = 12) but not short-access (ShA) rats with 1 h access (n = 12), the mean total cocaine intake began to increase significantly from session 5 (p < 0.05; sessions 5 to 22 compared with session 1) and continued to increase thereafter (p < 0.05; session 5 compared with sessions 8–10, 12, 13, and 17–22). (Heroin) Effect of drug availability on total intravenous heroin self-infusions. During the escalation phase, the rats had access to heroin (40 μg per infusion) for 1 h (ShA rats, n = 5–6) or 11 h per session (LgA rats, n = 5–6). Regular 1-h (ShA rats) or 11-h (LgA rats) sessions of heroin self-administration were performed for 6 days per week. The dotted line indicates the mean ± SEM number of heroin self-infusions in LgA rats during the first 11-h session. ∗p < 0.05, different from the first session. (Methamphetamine) Effect of extended access to intravenous methamphetamine on self-administration as a function of daily sessions in rats trained to self-administer 0.05, 0.1, and 0.2 mg/kg/infusion of intravenous methamphetamine during the 6 h session. ShA, 1 h session (each unit dose, n = 6). LgA, 6 h session (0.05 mg/kg/infusion, n = 4; 0.1 mg/kg/infusion, n = 6; 0.2 mg/kg/infusion, n = 5). ∗p < 0.05, ∗∗p < 0.01, compared with day 1. (Nicotine) Nicotine intake in rats that self-administered nicotine under a fixed-ratio (FR) 1 schedule in either 21 h (long-access [LgA]) or 1 h (short-access [ShA]) sessions. LgA rats increased their nicotine intake on an intermittent schedule with 24–48 h breaks between sessions, whereas LgA rats on a daily schedule did not. The left shows the total number of nicotine infusions per session when the intermittent schedule included 24 h breaks between sessions. The right shows the total number of nicotine infusions per session when the intermittent schedule included 48 h breaks between sessions. #p < 0.05, compared with baseline; ∗p < 0.05, compared with daily self-administration group (n = 10 per group). (Ethanol) Ethanol self-administration in ethanol-dependent and nondependent animals. The induction of ethanol dependence and correlation of limited ethanol self-administration before and excessive drinking after dependence induction following chronic intermittent ethanol vapor exposure is shown. ∗∗∗p < 0.001, significant group × test session interaction. With all drugs, escalation is defined as a significant increase in drug intake within-subjects in extended-access groups, with no significant changes within-subjects in limited-access groups.

[Cocaine: Taken with permission from Ahmed SH, Koob GF. Transition from moderate to excessive drug intake: change in hedonic set point. Science, 1998, (282), 298–300.]

[Heroin. Taken with permission from Ahmed SH, Walker JR, Koob GF. Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology, 2000, (22), 413–421.]

[Methamphetamine. Taken with permission from Kitamura O, Wee S, Specio SE, Koob GF, Pulvirenti L. Escalation of methamphetamine self-administration in rats: a dose-effect function. Psychopharmacology, 2006, (186), 48–53.]

[Nicotine. Taken with permission from Cohen A, Koob GF, George O. Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence. Neuropsychopharmacology, 2012, (37), 2153–2160.]

[Ethanol. Taken with permission from Edwards S, Guerrero M, Ghoneim OM, Roberts E, Koob GF. Evidence that vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-dependent rats. Addiction Biology, 2011, (17), 76–85.]

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