Matthew W. Feltenstein

Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine

Stress and drug-associated cues can trigger drug desire and relapse in abstinent cocaine users. Although the role of these two factors in relapse is well documented, it remains unclear as to whether an interaction between stress and drug-associated cues can lead to an enhancement in cocaine-seeking behavior. Here, we assessed the effects of the anxiogenic alpha2-noradrenergic receptor antagonist, yohimbine, on reinstatement of cocaine-seeking in rats either in the presence or absence of cocaine-associated cues. Yohimbine pretreatment in the absence of cocaine-associated cues or cues by themselves reliably reinstated responding on the previously cocaine-paired lever (3-4 times higher than extinction levels). However, animals showed greatly potentiated responding if yohimbine preceded cue-induced reinstatement (10-13 times higher than extinction levels, or 3-5 times over cues or yohimbine alone). While cocaine self-administration produced a significant increase in plasma corticosterone, plasma corticosterone levels did not show a clear relationship to cocaine-paired lever responding during cue and/or yohimbine-induced reinstatement. These results demonstrate that exposure to drug-paired cues during a stressful state can greatly potentiate cocaine-seeking and suggest that future treatment interventions should target multiple modalities.

Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse.

BACKGROUND Aripiprazole (Abilify) is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D2 receptors and low side effects. Based on pharmacologic properties that include a stabilization of mesocorticolimbic DA activity, a pathway implicated in addiction, aripiprazole was tested for its ability to prevent relapse to cocaine seeking in rats. METHODS We assessed the dose-dependent effects of aripiprazole on conditioned cue-induced and cocaine-primed reinstatement of drug-seeking behavior following chronic intravenous cocaine self-administration in an animal model of relapse. RESULTS Aripiprazole potently and dose-dependently attenuated responding on the previously cocaine-paired lever during both reinstatement conditions, with slightly greater efficacy at reducing conditioned-cued reinstatement. Aripiprazole was effective at doses that failed to alter cocaine self-administration, food self-administration, reinstatement of food-seeking behavior, or basal locomotor activity, suggesting selective effects of aripiprazole on motivated drug-seeking behavior. CONCLUSIONS These results in a relapse model show that aripiprazole can block cocaine seeking without affecting other behaviors. The D2 partial agonist properties of aripiprazole likely account for the blockade of reinstatement of cocaine-seeking behavior. Given its established efficacy and tolerability as a treatment for psychosis, aripiprazole may be an excellent therapeutic choice for reducing craving and preventing relapse in people with cocaine dependency.

The role of the basolateral amygdala in stimulus-reward memory and extinction memory consolidation and in subsequent conditioned cued reinstatement of cocaine seeking.

The consolidation of cue–cocaine associations and extinction learning (i.e. cue–no cocaine associations) into long‐term memory probably regulates the long‐lasting control of conditioned stimuli (CS) over cocaine‐seeking behaviour, and the basolateral amygdala (BLA) may play a role in this phenomenon. To test this hypothesis, rats previously trained to self‐administer cocaine underwent a single classical conditioning (CC) session, during which they received passive pairings of cocaine infusions and a novel light + tone stimulus complex. After additional self‐administration sessions in the absence of CS presentation and subsequent extinction training sessions, the ability of the CS to reinstate cocaine‐seeking on five test days was assessed. Rats received intra‐BLA microinfusions of vehicle or the Na+‐channel blocker tetrodotoxin (TTX) immediately after CC (consolidation of CS–cocaine associations) or immediately after reinstatement testing (consolidation of extinction learning). TTX administered immediately after CC attenuated subsequent CS‐induced reinstatement. In contrast, TTX administered after the first reinstatement test impaired the extinction of cocaine‐seeking behaviour during a second reinstatement test by disrupting extinction memory. Overall, these findings suggest that Na+ channel‐mediated mechanisms within the BLA mediate the consolidation of both cocaine–stimulus association and extinction learning, two processes that have opposite effects on subsequent cue‐induced cocaine‐seeking behaviour.

Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats

BACKGROUND Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse. METHODS Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone+light), the anxiogenic drug yohimbine (2.5mg/kg, IP), a priming injection of nicotine (0.3mg/kg, SC), or combinations of drug+cues to reinstate nicotine-seeking. RESULTS Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests. CONCLUSIONS These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.

Attenuation of cocaine-seeking by progesterone treatment in female rats

Clinical research suggests that gender differences exist in cocaine dependence. Similarly, preclinical studies have shown that female rats exhibit higher response rates during cocaine self-administration, early extinction, and cocaine-primed reinstatement of drug-seeking. These effects are also estrous cycle dependent and inversely related to plasma progesterone, in that proestrus females (high progesterone) exhibit less cocaine-seeking, while estrous females (low progesterone) show the greatest cocaine-seeking. Based on these findings, we hypothesized that progesterone would attenuate cocaine-seeking behavior in intact, freely cycling animals. The role of the estrous cycle on cocaine-seeking behavior during early (first acquisition day) versus late (last maintenance day) cocaine self-administration was also examined. Female, Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/infusion, IV) along a FR1 schedule, followed by daily extinction sessions in the absence of cocaine reinforcement. Once responding was extinguished, rats received an injection of cocaine (10 mg/kg, IP) immediately prior to reinstatement testing. Progesterone (2 mg/kg, SC) or vehicle was administered 20 and 2h prior to the first day of extinction (early cocaine withdrawal) and the reinstatement trials. To determine estrous cycle phase, we assessed vaginal cytology prior to the first acquisition and last maintenance days of cocaine self-administration, the first day of extinction training, and each reinstatement test. During early and late cocaine self-administration, proestrus and estrous females exhibited the greatest levels of active lever responding, respectively. A significant increase in responding also occurred during cocaine-primed reinstatement for estrous versus nonestrous females, an effect that was selectively attenuated by progesterone. However, progesterone was not effective at reducing cocaine-primed reinstatement for females in other phases of the estrous cycle, nor was it effective at reducing cocaine-seeking during early withdrawal. Taken together, these results suggest that progesterone may be a useful therapeutic for preventing relapse in abstinent female cocaine users, especially when the likelihood of relapse is greatest.

Corticotrophin releasing factor (CRF) induced reinstatement of cocaine seeking in male and female rats

Significant sex differences have been demonstrated in clinical and preclinical studies of cocaine addiction, with some of the most consistent differences noted in regard to the role of stress and craving. The current study examined stress-induced reinstatement of cocaine seeking in male and female rats in an animal model of relapse using corticotropin-releasing factor (CRF) administration. Both male and female rats demonstrated increased cocaine seeking in response to CRF. CRF-induced reinstatement was highly variable across both male and female rats, and further analysis revealed a subpopulation that was particularly sensitive to CRF (high responders). Female high responders displayed significantly increased responding to CRF compared to males. Individual differences in stress responsivity could thus contribute to the likelihood of relapse, with females showing greater heterogeneity to stress-induced relapse.

Systems Level Neuroplasticity in Drug Addiction

Drug addiction is a chronic relapsing disorder for which research has been dedicated to understand the various factors that contribute to development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide a broad overview of various theories of addiction, drugs of abuse, and the neurobiology involved across the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the involvement of these pathways and associated circuits in mediating conditioned responses, drug craving, and loss of behavioral control thought to underlie withdrawal and relapse. With a better understanding of the neurobiological factors that underlie drug addiction, continued preclinical and clinical research will aid in the development of novel therapeutic interventions that can serve as effective long-term treatment strategies for drug-dependent individuals.