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 objectives: Many studies indicated that adenosine via its A_2A receptors influences the behavioral effects of cocaine by modulating dopamine neurotransmission. The hypothesis was tested that A_2A receptors in the nucleus accumbens (NAc) or the prefrontral cortex (PFc) may modulate cocaine reward and/or cocaine seeking behavior in rats.

Methods: The effects of local bilateral microinjections of the selective A_2A receptor agonist CGS 21680 or the A_2A receptor antagonists KW 6002 and SCH 58261 were investigated on cocaine self-administration on reinstatement of cocaine seeking.

Results: The 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 A_2A 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.

Conclusion: The results strongly support the involvement of accumbal shell A_2A receptors as a target, the activation of which exerts an inhibitory control over cocaine reward and cocaine seeking.

Keywords: Adenosine A2A receptor ligands; Cocaine seeking; Cocaine self-administration; Local microinjection; Nucleus accumbens; Prefrontal cortex; Rats.

Fig. 1

Experimental design of the study. Schematic diagrams show cocaine (0.5 mg/kg/infusion) self-administration (a), cocaine (0.25 mg/kg/infusion) self-administration (b), and extinction training/reinstatement (c) procedures with intracranial microinjections of A_2A receptor ligands

Fig. 2

Histological verification of microinjection representative probe placements in the NAc (left panels) and the PFc (right panels) of rats that underwent cocaine self-administration (a), extinction/ reinstatement tests (b), and locomotor activity (c). Plates are taken from rat brain atlas Paxinos and Watson (1998) and the black line represent right placement of probes. Due to the large number of animals utilized for studies, bilateral placements are shown for only a subset of the experimental pool

Fig. 3

Intra-NAc effects of A_2A receptor antagonists KW 6002 (KW; 1–2.5 μg/side), SCH 58261 (SCH; 1–2.5 μg/side), and CGS 21680 (CGS; 1–2.5 ng/side) on cocaine (COC; 0.25 mg/kg/infusion) self-administration in rats. The number of active and inactive lever presses (upper panels) and the number of cocaine infusions (lower panels) are shown as the mean (±SEM). **p < 0.01, ****p < 0.0001 vs vehicle (VEH) (Newman-Keuls test); ^{^^}p < 0.01, ^{^^^^}p < 0.0001 vs (VEH) (Dunnett’s test). N = 6–8 rats/group

Fig. 4

Intra-NAc effects of A_2A receptor antagonists KW 6002 (KW; 1–2.5 μg/side), SCH 58261 (SCH; 1–2.5 μg/side), and CGS 21680 (CGS; 1–2.5 ng/side) on cocaine (COC; 0.5 mg/kg/infusion) self-administration in rats. The number of active and inactive lever presses (upper panels) and the number of cocaine infusions (lower panels) are shown as the mean (±SEM). VEH—vehicle. N = 6–8 rats/group

Fig. 5

Intra-NAc effects of the A_2A receptor antagonists KW 6002 (KW; 2.5–5 μg/side) and SCH 58261 (SCH; 2.5–5 μg/side) alone (left panels) or in combination with cocaine (COC; 2.5 mg/kg, i.p; right panels) on the reinstatement of cocaine seeking in rats. The number of active and inactive lever presses is shown as mean (± SEM). VEH—vehicle, EXT—extinction training last session. N = 6 rats/group

Fig. 6

Intra-NAc effects of the A_2A receptor agonist CGS 21680 (CGS; 1–2.5 ng/side) on cocaine (COC; 10 mg/kg; left panel) or on the cue (CUE; light and tone previously associated with cocaine self-administration) plus the subthreshold dose of cocaine (COC; 2.5 mg/kg; right panel) on the reinstatement of cocaine seeking behaviors in rats. The number of active and inactive lever presses is shown as mean (± SEM). VEH—vehicle, EXT—extinction training last session.**p < 0.01 vs VEH + VEH; ^{^^^}p < 0.001 vs VEH + COC 2.5 + CUE (Newman-Keuls test). N = 7 rats/group

Fig. 7

Intra-PFc effects of the A_2A receptor agonist CGS 21680 (CGS; 1-2.5 ng/side) on cocaine (COC; 10 mg/kg; left panel) or on the cue (CUE; light and tone previously associated with cocaine self-administration) plus the subthreshold dose of cocaine (2.5 mg/kg; right panel) on the reinstatement of cocaine seeking behaviors in rats. The number of active and inactive lever presses is shown as the mean (± SEM). VEH—vehicle, EXT—extinction training last session.**p < 0.01, ***p < 0.001 vs VEH + VEH (Newman-Keuls test). N = 7 rats/group

Fig. 8

Intra-NAc and intra-PFc effects of the A_2A receptor antagonists KW 6002 (KW; 1–5 μg/side), SCH 58261 (SCH; 1–5 μg/side), and the A_2A receptor agonist CGS 21680 (CGS; 1–10 ng/side) on the locomotor activity (cm) in rats. **p < 0.01 vs vehicle (VEH) (Dunnett’s test). N = 7–8 rats/group