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Restoration of amphetamine-induced locomotor sensitization in dopamine D1 receptor-deficient mice

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Abstract

Rationale and objectives

Amphetamine-induced sensitization is thought to involve dopamine D1 receptors. Using mice lacking dopamine D1 receptors (D −/−1 ), we found that they exhibited blunted sensitization to low doses of amphetamine, while others using different treatment and testing regimens reported inconsistent results. We investigated whether experimental variables, alteration in gene expression or cholinergic input played a role in amphetamine-induced responses.

Methods

D −/−1 and wild-type (D +/+1 ) mice pretreated with amphetamine (1 mg/kg, 3–7 days) or various doses of nicotine (chronically but intermittently) were challenged with amphetamine (0.7 and/or 1 mg/kg) after short and long abstinence periods. Expression of brain-derived neurotrophic factor (BDNF) and phosphorylated c-AMP response element binding protein (p-CREB) genes were measured under basal conditions and after acute or repeated amphetamine treatments.

Results

D −/−1 mice failed to exhibit amphetamine-induced sensitization following short-term treatments and long abstinence periods, but expressed sensitization following prolonged amphetamine treatment or a shorter abstinence period. Basal expression of p-CREB (but not BDNF) was higher in D −/−1 than D +/+1 mice and was reduced after amphetamine treatment. Prolonged nicotine pretreatment augmented locomotor responses to amphetamine in both genotypes and restored sensitization in D −/−1 mice.

Conclusions

D1 receptors were necessary for induction, but may not be necessary for expression of amphetamine-induced sensitization at low doses. The manifestation of amphetamine sensitization depended on the duration of treatment and length of the withdrawal period. Cholinergic–nicotinic stimulation restored amphetamine-induced sensitization in D −/−1 mice. Enhanced basal expression of p-CREB in D −/−1 mice may represent an adaptive mechanism related to lack of D1 receptors.

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Acknowledgments

The authors wish to thank Dr. John Drago, Dr. David Sibley, and Dr. Heiner Westphal for generously providing the D1 receptor knockout mice. This work was supported by the Canadian Institutes of Health Research and the National Institute on Drug Abuse. SRG is the recipient of a Canada Research Chair in Molecular Neuroscience from the CIHR.

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Author notes

  1. Joanna M. Karasinska

    Present address: Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada

Authors and Affiliations

  1. Department of Pharmacology, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, ON, Canada, M5S 1A8

    Mufida B. El-Ghundi, Theresa Fan, Joanna M. Karasinska, John Yeung, Millee Zhou, Brian F. O’Dowd & Susan R. George

  2. Department of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, ON, Canada, M5S 1A8

    Susan R. George

  3. Centre for Addiction and Mental Health, Toronto, ON, Canada, M5T 1R8

    Brian F. O’Dowd & Susan R. George

  4. Department of Pharmacology and Medicine, University of Toronto, Medical Sciences Building, Room 4358, 1 Kings College Circle, Toronto, ON, Canada, M5S 1A8

    Susan R. George

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  1. Mufida B. El-Ghundi
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Correspondence to Susan R. George.

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El-Ghundi, M.B., Fan, T., Karasinska, J.M. et al. Restoration of amphetamine-induced locomotor sensitization in dopamine D1 receptor-deficient mice. Psychopharmacology 207, 599–618 (2010). https://doi.org/10.1007/s00213-009-1690-5

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