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Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine

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Abstract

Rationale

Enhanced sensitivity to the euphoric and locomotor-activating effects of psychostimulants may influence an individual's predisposition to drug abuse and addiction. While drug-induced behaviors are mediated by the actions of several neurotransmitter systems, past research revealed that the corticotropin-releasing factor (CRF) system is important in driving the acute locomotor response to psychostimulants.

Objectives

We previously reported that genetic deletion of the CRF type-2 receptor (CRF-R2), but not the CRF type-1 receptor (CRF-R1) dampened the acute locomotor stimulant response to methamphetamine (1 mg/kg). These results contrasted with previous studies implicating CRF-R1 in the locomotor effects of psychostimulants. Since the majority of previous studies focused on cocaine, rather than methamphetamine, we set out to test the hypothesis that these drugs differentially engage CRF-R1 and CRF-R2.

Methods

We expanded our earlier findings by first replicating our previous experiments at a higher dose of methamphetamine (2 mg/kg), and by assessing the effects of the CRF-R1-selective antagonist CP-376,395 (10 mg/kg) on methamphetamine-induced locomotor activity. Next, we used both genetic and pharmacological tools to examine the specific components of the CRF system underlying the acute locomotor response to cocaine (5–10 mg/kg).

Results

While genetic deletion of CRF-R2 dampened the locomotor response to methamphetamine (but not cocaine), genetic deletion and pharmacological blockade of CRF-R1 dampened the locomotor response to cocaine (but not methamphetamine).

Conclusions

These findings highlight the differential involvement of CRF receptors in acute sensitivity to two different stimulant drugs of abuse, providing an intriguing basis for the development of more targeted therapeutics for psychostimulant addiction.

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Acknowledgments

This research was supported by the National Institutes of Health [Grants P50DA018165 (AER, GPM), RO3DA02854 (AER, GPM) and T32DA007262 (WJG, via Kim A. Neve)]. We thank Ju Li and Dawn M. Cote for their excellent technical assistance. These experiments were performed in compliance with current laws designated by the USA. The authors have no conflicts of interest to report.

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Authors and Affiliations

  1. Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    William J. Giardino, Gregory P. Mark & Andrey E. Ryabinin

  2. Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Mary P. Stenzel-Poore

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  1. William J. Giardino
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  2. Gregory P. Mark
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  3. Mary P. Stenzel-Poore
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  4. Andrey E. Ryabinin
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Correspondence to Andrey E. Ryabinin.

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Giardino, W.J., Mark, G.P., Stenzel-Poore, M.P. et al. Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine. Psychopharmacology 219, 1055–1063 (2012). https://doi.org/10.1007/s00213-011-2433-y

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  • DOI: https://doi.org/10.1007/s00213-011-2433-y

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