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Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

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Abstract

Rationale

Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone.

Objective

The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists.

Methods

Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates.

Results

Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses.

Conclusions

These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.

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Acknowledgements

This work was supported by a grant to J.S. from the National Institute of Mental Health (MH078023) and to M.C. from Conselleria de Empresa, Universitat i Ciència, Generalitat Valenciana (BEST/2009/157). Y.B. and C.E.M. were supported by the BMBF and the European Commission by an ERANET-NEURON grant.

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  1. Andrew M. Farrar

    Present address: Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, 07102, USA

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  1. Department of Psychology, University of Connecticut, Storrs, CT, 06269-1020, USA

    Patrick A. Randall, Eric J. Nunes, Simone L. Janniere, Colin M. Stopper, Andrew M. Farrar & John D. Salamone

  2. Pharmacology Target Research, H. Lundbeck A/S, 9 Ottiliavej, Valby, Copenhagen, 2500, Denmark

    Thomas N. Sager

  3. Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Universität Bonn, Bonn, Germany

    Younis Baqi, Jörg Hockemeyer & Christa E. Müller

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Randall, P.A., Nunes, E.J., Janniere, S.L. et al. Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists. Psychopharmacology 216, 173–186 (2011). https://doi.org/10.1007/s00213-011-2198-3

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