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The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists

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Abstract

Rationale

Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A2A receptors.

Objective

Adenosine A2A receptor antagonism has been shown to reverse the effects of DA antagonism. The present experiments were conducted to determine if this effect was dependent upon the subtype of DA receptor that was antagonized to produce the changes in effort-related choice.

Materials and methods

The adenosine A2A receptor antagonist MSX-3 (0.5–2.0 mg/kg IP) was assessed for its ability to reverse the effects of the D1 family antagonist SCH39166 (ecopipam; 0.2 mg/kg IP) and the D2 family antagonist eticlopride (0.08 mg/kg IP), using a concurrent lever pressing/chow feeding procedure.

Results

MSX-3 produced a substantial dose-related reversal of the effects of eticlopride on lever pressing and chow intake. At the highest dose of MSX-3, there was a complete reversal of the effects of eticlopride on lever pressing. In contrast, MSX-3 produced only a minimal attenuation of the effects of SCH39166, as measured by regression and effect size analyses.

Conclusions

The greater ability of MSX-3 to reverse the effects of D2 vs. D1 blockade may be related to the colocalization of D2 and adenosine A2A receptors on the same population of striatal neurons.

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Acknowledgment

This work was supported by a grant to J.S. from the National Institute of Mental Health (MH078023).

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  1. Lila T. Worden

    Present address: National Institute of Drug Abuse, National Institutes of Health, Bethesda, MD, USA

  2. Mona Shahriari

    Present address: University of Connecticut Health Center, Farmington, CT, USA

Authors and Affiliations

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

    Lila T. Worden, Mona Shahriari, Andrew M. Farrar, Kelly S. Sink & John D. Salamone

  2. Pharmazeutisches Institut, Pharmazeutische Chemie I, Universität Bonn, Bonn, Germany

    Jörg Hockemeyer & Christa E. Müller

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  1. Lila T. Worden
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Worden, L.T., Shahriari, M., Farrar, A.M. et al. The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists. Psychopharmacology 203, 489–499 (2009). https://doi.org/10.1007/s00213-008-1396-0

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