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On the role of adenosine (A)2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats

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Abstract

Rationale

Several studies have suggested the inhibitory control of adenosine (A)2A receptor stimulation in cocaine-induced behavioral actions.

Objectives

A combination of systemic or local drug injections and in  vivo neurochemical analysis investigated A2A receptors in cocaine and food reward.

Methods

Rats, trained to self-administer cocaine or food, were tested with the selective A2A receptor antagonists KW 6002 and SCH 58261 or the selective A2A receptor agonist CGS 21680. Extracellular dopamine, glutamate, and GABA levels in the nucleus accumbens and ventral pallidum were determined following intra-accumbal CGS 21680 administration during cocaine self-administration.

Results

Neither KW 6002 nor SCH 58261 (0.25–1 mg/kg) altered cocaine self-administration (0.125–0.5 mg/kg/infusion), while CGS 21680 (0.2–0.4 mg/kg) produced a downward shift in the cocaine dose–response curve under a fixed ratio schedule of reinforcement and decreased the cocaine breaking point. CGS 21680 blocked also operant responding for food, while the A2A receptor antagonists were inactive. Local steady-state infusion of CGS 21680 (10 μM) during cocaine self-administration increased the active level pressing that was accompanied with reduced dopamine and increased GABA in the nucleus accumbens in the absence of changes in GABA and glutamate levels in the ventral pallidum. Pretreatment with systemic KW 6002 counteracted the increases in number of cocaine infusions seen after intra-accumbal administration of CGS 21680.

Conclusion

The findings support a role of A2A receptors in modulating goal-maintained behaviors. They also indicate that increased accumbal GABA release involving an antagonistic A2A-D2 receptor interaction can participate in mediating the inhibitory effects of the A2A agonist on cocaine reward.

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Acknowledgments

This research was supported by the grants no. N N401 019635 and 2011/03/N/NZ7/06294 (Poland), from the Brain Fund (Uppsala, Sweden) and the Swedish Research Council (04X-715).

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Correspondence to Małgorzata Filip.

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Fig. S1

Histological verification of microdialysis probe placements in the nucleus accumbens (left panels) and the ventral pallidum (right panels) of rats that underwent VEH and/or CGS 21680 local infusions during the cocaine self-administration session. Plates are taken from Paxinos and Watson (1998) and the straight lines represent the 2-mm dialyzing lengths of the probes. The figure shows bilateral placements for only a subset of the experimental pool of cocaine or CGS 21680 group (PDF 106 kb)

Fig. S2

Representative records of cocaine self-administration following A2A receptor agonist or vehicle systemic or local administration. Each vertical line represents separate cocaine infusion earned in a 2-h session. (a) Effects of CGS 21680 (ip) pretreatment on cocaine (0.5 mg/kg/infusion) self-administration, (b) Effects of CGS 21680 (ip) pretreatment on cocaine (0.25 mg/kg/infusion) self-administration, (c) Effects of CGS 21680 (intra-nucleus accumbens; NAC) pretreatment on cocaine (0.5 mg/kg/infusion) self-administration. (PDF 51 kb)

Fig. S3

Effects of the A2A receptor ligands on horizontal locomotor activity in drug-naive rats. Horizontal locomotor activity was expressed as distance in cm (±SEM) and recorded during 15-min bins (panels a,c,e) and a 2-h period (panels b,d,f). Data are presented as ± SEM. *p<0.05, **p<0.01, ***p<0.001 vs. vehicle (VEH) (Dunnett’s test). N= 6-8 rats/group (PDF 127 kb)

Fig. S4

Effects of the A2A receptor ligands on horizontal locomotor activity in cocaine-experienced rats. Horizontal locomotor activity was expressed as distance in cm (±SEM) and recorded during 15-min bins (panels a,c,e) and a 2-h period (panel b,d,f). Data are presented as ± SEM. **p<0.01, ***p<0.001 vs. vehicle (VEH) (Newman-Keuls’ test); ^p< 0.05, ^^^p< 0.001 vs. VEH (Dunnett’s test). N= 6-8 rats/group. (PDF 57 kb)

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Wydra, K., Gołembiowska, K., Suder, A. et al. On the role of adenosine (A)2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats. Psychopharmacology 232, 421–435 (2015). https://doi.org/10.1007/s00213-014-3675-2

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