The results show that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors. Therefore, the present study provides a rationale for the use of cannabinoid antagonists in the treatment of opiate addiction.

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...

Rationale While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. Objectives To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT −/− ) rat and the involvement of compensatory changes in 5-HT 1A receptor function are the objectives of the study. Materials and methodsThe SERT −/− rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine selfadministration. In addition, the function and expression of 5-HT 1A receptors was assessed using telemetry and autoradiography, respectively, and the effect of 5-HT 1A receptor ligands on cocaine's psychomotor effects were studied.Results Cocaine-induced hyperactivity and conditioned place preference, as well as intravenous cocaine selfadministration were enhanced in SERT −/− rats. Furthermore,

Rats, like humans, show strong individual differences in their response to anxiogenic and stressful stimuli. In the present study we evaluated whether differences in stress-induced self-grooming behaviour may predict an individual's vulnerability to engage in drug self-administration behaviour. From a population of Wistar rats, the lower and upper quartile with respect to time spent self-grooming on an elevated plus maze (EPM) were selected and trained to intravenously self-administer cocaine under fixed and progressive ratio schedules of reinforcement. High grooming (HG) rats reached considerably higher breakpoints than low grooming (LG) rats but showed no differences in acquisition rate and dose-response relationships. Further, EPM exposure elicited higher anxiety levels and enhanced plasma corticosterone secretion in HG rats. In addition, HG rats did not display enhanced novelty-seeking and still spent more time self-grooming during an EPM re-test following the cocaine self-administration procedure, indicating that stress-induced self-grooming is a stable behavioural trait marker. Neurochemically, electrically evoked [(3)H]dopamine release in vitro was profoundly lower in brain slices from the substantia nigra, medial prefrontal cortex and amygdala of naive HG rats as compared to LG rats, whereas no differences were found in the nucleus accumbens shell and core, the ventral tegmental area and caudate putamen. In conclusion, stress-induced self-grooming specifically predicts enhanced motivation to self-administer cocaine rather than sensitivity to its reinforcing effects. Responsiveness of dopaminergic nerve terminals in the medial prefrontal cortex and amygdala may represent pre-existing underlying factors.

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