Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats

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.

Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine

“…The latter authors found also that none of the CGS 21680 effective doses changed the inactive lever responses, which indicated the drug specificity. Wydra and colleagues [ 92 ] also pointed to the important role of the localization of A 2A Rs in controlling the rewarding effects of cocaine. Namely, in the intra-accumbal shell, but not the intra-infralimbic prefrontal cortex, microinjections of CGS 21680 (1.0–2.5 ng/side) dose-dependently decreased cocaine (0.25 mg/kg/infusion) self-administration.…”

“…If pharmacological stimulation of A 2A Rs attenuated the drug reward, the tonic activation of these receptors with selective antagonists seemednot to be linked to drug motivational or reinforcing effects. Thus, neither systemic administration of MSX-3 (3.0 mg/kg) nor systemic or local (into the nucleus accumbens or prefrontal cortex) microinjections of KW 6002 (1.0–2.5 μg/side) or SCH 58261 (1.0–2.5 µg/side) altered cocaine self-administration in squirrel monkeys [ 96 ] or rats [ 92 ].…”

“…), quinpirole- and cue-induced reinstatement of cocaine-seeking behavior [ 111 ]. This effect may be associated with adenosine signaling in the rat nucleus accumbens, as reduced cocaine-induced (15 mg/kg), quinpirole-induced [ 112 ], or the cue plus the subthreshold dose of cocaine-induced (2.5 mg/kg) [ 92 ] reinstatement of cocaine seeking was reported following the intra-accumbal microinjection of CGS 21680 (2.5 ng/side), but not after pharmacological stimulation of the A 2A Rs within the prefrontal cortex [ 92 ]. The effects of the A 2A R stimulation with CGS 21680 (0.3 mg/kg) in methamphetamine-seeking behavior were partially consistent with the above observations for cocaine.…”

“…Contrary to the stimulation of A 2A Rs, their accumbal and systemic blockade with MSX-3 (10 µg/side and 6 mg/kg, respectively) or SCH 58261 (5 µg/side) produced cocaine-seeking behavior [ 92 , 112 ]. In addition, intra-accumbal microinjection with MSX-3 (10 µg/side) [ 112 ], but not KW 6002 (2.5–5.0 µg/side) and SCH 58261 (2.5 µg/side) [ 92 ], potentiated the reinstatement of cocaine-seeking behavior induced only by sub-threshold doses of cocaine and quinpirole, suggesting that removing the tonic activity of A 2A R enabled behaviors mediated by DA receptors [ 112 ].…”

“…Contrary to the stimulation of A 2A Rs, their accumbal and systemic blockade with MSX-3 (10 µg/side and 6 mg/kg, respectively) or SCH 58261 (5 µg/side) produced cocaine-seeking behavior [ 92 , 112 ]. In addition, intra-accumbal microinjection with MSX-3 (10 µg/side) [ 112 ], but not KW 6002 (2.5–5.0 µg/side) and SCH 58261 (2.5 µg/side) [ 92 ], potentiated the reinstatement of cocaine-seeking behavior induced only by sub-threshold doses of cocaine and quinpirole, suggesting that removing the tonic activity of A 2A R enabled behaviors mediated by DA receptors [ 112 ]. Similarly, a systemic blockade of A 2A Rs by KW 6002 (0.25–0.5 mg/kg) or SCH 58261 (2 mg/kg) [ 91 ], or KW 6002 (1–3 mg/kg) [ 71 ] in rats extinguished from cocaine self-administration or 9-chloro-2-(2-furanyl)-[ 1 , 2 , 4 ]triazolo[1,5-c]quinazolin-5-amine (CGS 15943; 0.032–0.32 mg/kg) in baboons [ 114 ] reinstated cocaine-seeking, and this effect was eliminated by the D 2 -like receptor antagonist raclopride (0.1–0.4 mg/kg) [ 111 ].…”