Relapse to Cocaine- and Heroin-Seeking Behavior Mediated by Dopamine D2 Receptors Is Time-Dependent and Associated with Behavioral Sensitization

Abstract

The sensitizing properties of drugs of abuse have been proposed to play an important role in the persistence of drug seeking behavior. We decided to evaluate the temporal relationship of dopamine D2 receptor-mediated drug seeking behavior and behavioral sensitization in animals with a history of cocaine and heroin self-administration. During early phases of withdrawal ( Ͻ 1 week), activation of dopamine D2 receptors with quinpirole resulted in robust, dose-dependent, reinstatement of (non-reinforced) responding in both cocaine-and heroin-trained rats. Cocaine and heroin seeking induced by quinpirole was associated with a dramatic enhancement of the psychomotor stimulant effects of the D2 agonist, indicating that sensitization to D2-mediated events had developed. During the late phase of withdrawal ( Ͼ 3 weeks), reinstatement of cocaine seeking by quinpirole was still apparent, but less robust. In heroin-trained rats, increases of respondingStudying the neurobiology of drug addiction in laboratory animals, recent advances indicate that drug seeking behavior can be triggered by drug-associated (conditioned) cues, by stressful stimuli and by reexposure to the previously experienced drug (McFarland and Ettenberg 1997;Self et al. 1996;De Vries et al. 1998b;Shaham et al. 2000); events also known to trigger drug craving and relapse in human addicts (Meyer and Mirin 1979;Kosten et al. 1986;O'Doherty and Davies 1987;Jaffe et al. 1989;McFall et al. 1992; Ludwig et al. 1994;De Wit 1996). Moreover, in laboratory animals drug-seeking behavior can be evoked and observed even after prolonged periods of drug abstinence (weeks to at least one month) (Shaham et al. 1994;De Vries et al. 1998b;Katner et al. 1999). Therefore, stimulus-induced reinstatement of extinguished self-administration behavior is widely accepted as an animal model representing defining characteristics of relapse behavior in humans. The identification of the neurobiological factors that maintain drug seeking may provide tools that interfere in the complex process of relapse behavior in human addicts. In this respect, it is generally believed that long-lasting neuroadaptive changes in the mesolimbic dopamine circuitry are crucial for ongoing addiction behavior (Robinson and Berridge 1993;Self and Nestler 1998). Indeed, there is ample evidence for a central role of the dopaminergic ventral tegmental area (VTA) and its main projection target, the nucleus accumbens, in the motivational effects of addictive drugs (for reviews: Wise and Bozarth 1987;Koob 1992;Robinson and Berridge 1993). In general, repeated exposure to drugs of abuse induce time-dependent neuroadaptations within the mesolimbic dopamine circuitry, thought to underlie an enhanced behavioral responsiveness (sensitization) upon renewed exposure to the drug. Although it has been proposed that the sensitizing effects of drugs of abuse may enhance their incentivemotivational properties and, as such, play an important role in the persistence of drug seeking behavior (Robinson and Berridge 1993), compelling...

Addiction-Related Alterations in D1 and D2 Dopamine Receptor Behavioral Responses Following Chronic Cocaine Self-Administration

“…Given that prominent D 2 receptor sensitization develops in both low and high intake groups, and this overall effect was found in a previous study comparing cocaine to saline self-administration (De Vries et al, 2002), it is possible that D 2 receptor sensitization reflects intracellular alterations in D 2 receptor coupling, or an indirect enhancement via perturbations in neural input to D 2 -containing neurons, rather than an increase in D 2 receptor surface expression. Further investigation is needed to determine whether these changes are reflected in differential sensitivity to dopamine receptor-regulated biochemical or electrophysiological responses.…”

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

“…It is not clear, therefore, which of the many behavioral and psychological consequences of cocaine self-administration are due to changes in dorsal striatal D2 High receptors. Seeman and his colleagues (2002,2007) have reported that sensitization to amphetamine is associated with an increase in D2 High receptors, and both experimenter-administered cocaine and cocaine self-administration experience have been reported to produce behavioral supersensitivity to a challenge injection with a direct D2 receptor agonist (De Vries, et al, 2002, Edwards, et al, 2007. It has also been reported that both the limited and extended access cocaine self-administration procedures used in the current study produce psychomotor sensitization (Ferrario, et al, 2005, Knackstedt andKalivas, 2007).…”

“…However, a long-standing puzzle in this area is that preclinical studies have consistently found that rats treated with amphetamine or cocaine, and then withdrawn, are hypersensitive to the psychomotor activating and incentive motivational effects of these "indirect agonists" (Robinson and Berridge, 1993), and even more importantly, to the psychomotor effects of direct-acting D2 agonists (Ujike, et al, 1990, De Vries, et al, 2002, Edwards, et al, 2007. Studies examining the effects of cocaine treatment on D2 receptor binding in rodents are mixed, with reports of increases (Trulson andUlissey, 1987, Peris, et al, 1990), decreases (Kleven, et al, 1990, Maggos, et al, 1998 or no change (Dwoskin, et al, 1988, Claye, et al, 1995.…”

Gamma-vinyl GABA inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a non-dopaminergic mechanism

“…For example, cocaine priming significantly elevates extracellular NAc DA (Neisewander et al, 1996;McFarland et al, 2003;Xi et al, 2006). Also, systemic or intra-NAc administration of direct or indirect DA receptor agonists elicit, while DA receptor antagonists block, cocaine-induced reinstatement of drug-seeking behavior (Self et al, 1996;De Vries et al, 2002;Vorel et al, 2002). In addition, repeated cocaine administration produces enduring alterations in basal DA transmission, DA response to cocaine priming and/or expression of DA receptors in reward-related brain regions (Kuhar and Pilotte, 1996;Lu et al, 2003;Staley and Mash, 1996).…”