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The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat

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An Erratum to this article was published on 23 October 2008

Abstract

Rationale and objectives

Given that adenosine A2A antagonists appear to be therapeutic in several animal models of Parkinson’s disease (PD), we examined the extent to which caffeine and selective A2A and A1 antagonists could enhance contralateral forepaw stepping in the unilateral 6-OHDA-lesioned rat.

Materials and methods

Following unilateral injections of 12 μg 6-OHDA into the medial forebrain bundle (MFB), frequency of stepping with both front paws was counted separately as the paws were dragged anteriorally and laterally by a treadmill.

Results

The MFB lesions decreased contralateral stepping by 74–83%, and 8 mg/kg 3,4-dihydroxy-l-phenylalanine (L-DOPA) increased contralateral stepping by 25–26%. Caffeine given systemically (15 mg/kg) or into the dorsal striatum or external globus pallidus (GPE; 20–40 μg) increased contralateral forepaw stepping by 14%, 27%, and 26%, respectively, and enhanced the effect of 8 mg/kg L-DOPA on stepping. The selective A2A antagonist SCH-58261 (2 mg/kg) also increased stepping by 13% and enhanced the therapeutic effect of L-DOPA, whereas the selective A2A antagonist 8-cyclopentyltheophylline (3–7 mg/kg) and A1 agonist N 6-cyclopentyladenosine (0.03–0.2 mg/kg) had no effect. None of these drugs appeared to produce dyskinesic effects.

Conclusions

In this well-validated animal model of the akinesic effects of PD, caffeine and a selective A2A, but not an A1, antagonist were able to provide both monotherapeutic and adjunctive therapeutic effects. These data are consistent with the hypothesis that A2A antagonists may be therapeutic in human PD patients and indicate that the dorsal striatum and GPE are critical sites of therapeutic action.

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Acknowledgements

This study was based on research submitted by N. A. Langelier, B. S. Oriel, and C. Reedy as partial fulfillment for Bachelor of Science degrees. Portions of these data were presented at the Society for Neuroscience meetings in 2005 and 2006.

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Authors and Affiliations

  1. Program in Neuroscience, Bates College, Lewiston, ME, 04240, USA

    John E. Kelsey, Nicole A. Langelier & Brad S. Oriel

  2. Department of Psychology, Bates College, Lewiston, ME, 04240, USA

    John E. Kelsey & Catherine Reedy

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  1. John E. Kelsey
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  2. Nicole A. Langelier
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  3. Brad S. Oriel
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  4. Catherine Reedy
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Correspondence to John E. Kelsey.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-008-1361-y

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Kelsey, J.E., Langelier, N.A., Oriel, B.S. et al. The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat. Psychopharmacology 201, 529–539 (2009). https://doi.org/10.1007/s00213-008-1319-0

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