Modulation of Cocaine‐induced Sensitization by κ‐Opioid Receptor Agonists: Role of the Nucleus Accumbens and Medial Prefrontal Cortex

The behavioral effects of cocaine are enhanced in individuals with a prior history of intermittent cocaine use. 1 This phenomenon, referred to as behavioral sensitization, can persist for months following the cessation of drug use and has been implicated in the reinstatement of compulsive drug-seeking behavior. 2 Abstinence from cocaine also produces long-term alterations in mesocorticolimbic dopamine (DA) neurotransmission. Basal DA levels within the nucleus accumbens (NAC) are elevated during the early phase of abstinence from cocaine and there is a progressive increase in cocaine-evoked DA levels as abstinence proceeds. 1,3 These alterations in DA neurochemistry are thought to underlie the initiation and expression of behavioral sensitization. The coadministration of κ-opioid receptor agonists with cocaine prevents the development of sensitization to cocaine. 4 Systemically administered κ-opioid agonists also prevent alterations in DA neurochemistry that occur within the NAC during abstinence from cocaine. The site of action of κ-opioid agonists in producing these effects is unknown. The present studies examined the role of κ-opioid receptors in the NAC and medial prefrontal cortex (mPFC) in mediating the interaction of κ-opioid agonists with cocaine. Male Sprague-Dawley rats were stereotaxically implanted with bilateral guide cannula aimed at the NAC or at the NAC and mPFC. 5 Drug treatments commenced one week later. Rats received once daily injections of cocaine (20.0 mg/kg, i.p.) or saline for five days. On days 3-5, they received intracranial infusions of the κ-opioid agonist, U69593 (1.0 μg/side), 5 min prior to i.p. injections. Microdialysis was conducted 3 and 21 days later. A 2.0-mm dialysis probe was perfused with artificial cerebrospinal fluid, and inserted into the NAC. Twelve hr later, 3 dialysis samples (perfusion rate: 1.1 μl/min) were collected at 25-min intervals for determination of basal DA levels. Animals were then injected with cocaine (20.0 mg/kg, i.p.) and samples were collected for 100 min. DA levels were quantified by HPLC/EC detection. Locomotor activity was rated during dialysis studies using a 9-point rating scale. 4 Data were analyzed using two factor analyses of variance and tests of contrast. Only data from animals with histologically correct cannula placements were used in statistical analyses. DA levels in the NAC were elevated 3 days after the cessation of cocaine treatment. Although sensitization to the psychomotor stimulant effects of cocaine was evident at this time point, cocaine-evoked DA overflow was significantly less than that of control (saline-treated) animals. On abstinence day 21, basal DA levels had normalized (Fig. 1) and cocaine-evoked DA overflow was significantly enhanced relative to controls. In animals that had received intra-NAC infusions of U69593 with cocaine, the elevation of basal DA levels was prevented (Fig. 1) and no enhancement of cocaine-evoked DA overflow was seen. NAC infusions also attenuated sensitization to the psychomotor stimulant effects of cocaine (Fig. 2). In contrast, mPFC infusions of U69593 attenuated, but did not prevent, the elevation of basal DA levels that occurred on abstinence day 3. At this time point, the responsiveness of DA neurons to a challenge dose of cocaine was significantly enhanced, and the behavioral response to cocaine was significantly greater than that in cocaine-treated animals (Fig. 2). Influence of intra-NAC U69593 upon abstinence-induced alterations in basal DA levels in the NAC. (A) Abstinence day 3. (B) Abstinence day 21. * denotes significant difference from control (saline-treated) group; ** denotes significant difference from cocaine-treatment group, p≤ 0.05. Influence of intra-NAC (A) and intra-mPFC (B) U69593 infusion upon sensitization to the psychomotor stimulant effects of cocaine. The data were obtained 3 days following the cessation of the cocaine- and U69593/cocaine-treatment regimens. * denotes significant difference from control (saline-treated) group; ** denotes significant difference from cocaine-treatment group, p≤ 0.05. Basal and cocaine-evoked DA levels in the NAC are increased following repeated cocaine administration. These neurochemical alterations are thought to result, in part, from cocaine-induced decreases in DA levels within the mPFC and disinhibition of pyramidal cells projecting to the ventral tegmental area and NAC. 7 Decreased DA in the mPFC and a reduction in D2-receptor-mediated stimulation of GABA release in the mPFC have been implicated in the disinhibition process. 8 Increasing evidence suggests that these alterations in mesocorticolimbic neurotransmission underlie cocaine-induced behavioral sensitization. 7 The activation of NAC κ-opioid receptors suppressed behavioral sensitization to cocaine and prevented cocaine-induced increases in basal and drug-evoked DA levels in the NAC. In contrast, the activation of mPFC κ-receptors exacerbated the development of behavioral sensitization and increased cocaine-evoked DA levels. The mechanisms mediating the opposing effects of κ-receptor activation in these two brain regions are unclear. κ-Agonists decrease DA release and downregulate D2 receptors. 9 These actions may underlie the differing effects of U69593. Inhibition of DA release and D2 receptor downregulation in the mPFC would disinhibit pyramidal cell firing and enhance the behavioral and neurochemical effects produced by the repeated administration of cocaine. In contrast, decreases in DA release within the NAC that occur following the activation of κ-opioid receptors in this brain region would oppose the increase in NAC DA levels that occur in response to the repeated administration of cocaine and attenuate behavioral sensitization. In conclusion, the activation of κ-opioid receptors in the NAC, but not the mPFC, prevents alterations in behavior and DA neurochemistry that occur during abstinence from cocaine. Similar effects are observed in response to systemically administered κ-opioid agonists. As such, an involvement of NAC κ-opioid receptors in mediating the interaction of systemically administered κ-opioid agonists with cocaine is indicated. This work was supported by the NIDA IRP and NIDA Grant DA 10084.