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Caffeine and a selective adenosine A2A receptor antagonist induce reward and sensitization behavior associated with increased phospho-Thr75-DARPP-32 in mice

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Abstract

Rationale

Caffeine, an antagonist of adenosine A1 and A2A receptor, is the most widely used psychoactive substance in the world. Evidence indicates that caffeine interacts with the neuronal systems involved in drug reinforcing. Although adenosine A1 and/or A2A receptor have been found to play important roles in the locomotor stimulation and probably reinforcing effect of caffeine, the relative contribution of the A1 and/or A2A receptors to the acute and chronic motor activation and reinforcing effects of caffeine has not been completely investigated.

Objective

The roles of adenosine A1 and/or A2A receptor and the association of phospho-Thr75-dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) in the motor activation and reinforcing effects of caffeine, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A1 antagonist, and 5-amino-7-(β-phenylethyl)-2-(8-furyl) pyrazolol [4,3-e]-1,2,4-triazolol [1,5-c] pyrimidine (SCH58261), a selective A2A receptor antagonist were examined.

Methods

Locomotor stimulation and behavioral sensitization of caffeine, DPCPX, and SCH58261 were studied in C57BL/6 male mice following acute and chronic administration. Conditioned place preference (CPP) paradigm was used to evaluate the drug-seeking potential of these compounds. Furthermore, the expression of phospho-Thr75-DARPP-32 in striatal membrane from behaviorally sensitized mice was analyzed by Western blot.

Results

Caffeine and SCH58261 but not DPCPX induced CPP and locomotor sensitization in C57BL/6 mice. The locomotor sensitization after chronic treatment was associated with increased DARPP-32 phosphorylation at Thr75 in the striatum.

Conclusion

Caffeine-induced reinforcing effect and behavioral sensitization are mediated by antagonism at adenosine A2A receptor. These effects are associated with phosphorylation of DARPP-32 at Thr75 in the striatum.

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Acknowledgment

This study was supported partly by grants from National Science Council, Taiwan (NSC952745B-320-002-URD-02) and Tzu Chi University. The authors would like to thank the technical assistance of Ms. K. J. Chen.

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Authors and Affiliations

  1. Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, 970, Taiwan

    Chih W. Hsu

  2. Institute of Medical Sciences, Tzu Chi University, 701 Sec. 3, Chung Yang Rd, Hualien, 970, Taiwan

    Chih W. Hsu

  3. Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, 970, Taiwan

    C. Y. Chen & Ted H. Chiu

  4. School of Medicine, Tzu Chi University, Hualien, 970, Taiwan

    Chin-Shine Wang

  5. Department of Pharmacology, Tzu Chi University, 701 Sec. 3, Chung Yang Rd, Hualien, 970, Taiwan

    Ted H. Chiu

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  1. Chih W. Hsu
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  2. C. Y. Chen
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  3. Chin-Shine Wang
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Correspondence to Chih W. Hsu or Ted H. Chiu.

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Hsu, C.W., Chen, C.Y., Wang, CS. et al. Caffeine and a selective adenosine A2A receptor antagonist induce reward and sensitization behavior associated with increased phospho-Thr75-DARPP-32 in mice. Psychopharmacology 204, 313–325 (2009). https://doi.org/10.1007/s00213-009-1461-3

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