Abstract
Rationale and objectivesMany studies indicated that adenosine via its A2A receptors influences the behavioral effects of cocaine by modulating dopamine neurotransmission. The hypothesis was tested that A2A receptors in the nucleus accumbens (NAc) or the prefrontral cortex (PFc) may modulate cocaine reward and/or cocaine seeking behavior in rats.MethodsThe effects of local bilateral microinjections of the selective A2A receptor agonist CGS 21680 or the A2A receptor antagonists KW 6002 and SCH 58261 were investigated on cocaine self-administration on reinstatement of cocaine seeking.ResultsThe intra-NAc shell, but not intra-infralimbic PFc, administration of CGS 21680 significantly reduced the number of active lever presses and the number of cocaine (0.25 mg/kg) infusions. However, tonic activation of A2A receptors located in the NAc or PFc did not play a role in modulating the rewarding actions of cocaine since neither KW 6002 nor SCH 58261 microinjections altered the cocaine (0.5 mg/kg) infusions. The intra-NAc but not intra-PFc microinjections of CGS 21680 dose- dependently attenuated the reinstatement of active lever presses induced by cocaine (10 mg/kg, i.p.) and the drug-associated combined conditioned stimuli using the subthreshold dose of cocaine (2.5 mg/kg, i.p.). On the other hand, the intra-NAc pretreatment with SCH 58261, but not with KW 6002, given alone evoked reinstatement of cocaine seeking behavior.ConclusionThe results strongly support the involvement of accumbal shell A2A receptors as a target, the activation of which exerts an inhibitory control over cocaine reward and cocaine seeking.
Highlights
Substance-use disorder is a chronic relapsing disorder characterized by compulsive drug intake and drug seeking, loss of control over drug intake, and a persistent craving for the drug
The animals used for the intra-nucleus accumbens (NAc) and intra-prefrontal cortex (PFc) microinjection studies had 26–30 or 22–30 self-administrated infusions of cocaine with the daily mean cocaine intake amounting to 12–15 mg/kg or 11–15 mg/kg, respectively
When the dose of cocaine was reduced to 0.25 mg/kg/infusion the animals had 39–50 or 33–53 self-administrated infusions of cocaine with the daily mean cocaine intake amounting to 9.75–12.5 mg/kg or 8.25–13.25 mg/kg for the intra-NAc or the intra-PFc microinjection studies, respectively
Summary
Substance-use disorder (drug addiction) is a chronic relapsing disorder characterized by compulsive drug intake and drug seeking, loss of control over drug intake, and a persistent craving for the drug. The neuronal basis of cocaine addiction includes activation of the mesocorticolimbic circuitry with changes in dopamine (DA) and glutamate neurotransmissions (Arbuthnott et al 1970; Kalivas 2009; Koob 2009). The meso-limbic DA system (Fuxe 1965) was linked mainly to compulsive drug use. The glutamate system was linked mainly to relapse after drug seeking and the circuitry included a glutamate pathway from the prefrontal cortex (PFc) to the NAc (McFarland and Kalivas 2001). Administration of cocaine into the PFc restored seeking behavior (Park et al 2002)
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