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A functional role for the dopamine D3 receptor in the induction and expression of behavioural sensitization to ethanol in mice

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Abstract

Rationale

We previously reported that mice lacking dopamine D3 receptors (D3R) were resistant to behavioural sensitization to ethanol (EtOH). Since knockout mice have permanent receptor inactivation, we investigated how temporary pharmacological blockade and activation of D3Rs affected the induction or expression of EtOH sensitization.

Materials and method

In induction studies, DBA/2 mice received 0, 10 or 75 mg/kg, subcutaneous (s.c.) of the D3R antagonist, U99194A ,before each of seven EtOH (2.2 g/kg, intraperitoneal) or saline injections. Locomotor activity (LMA) was assessed in activity chambers. In expression studies, mice received seven injections of EtOH or saline, followed 14 days later with U99194A or vehicle immediately before a test dose of EtOH (1.8 g/kg). In separate experiments, the effects of the D3R agonist PD128907 (0.01 mg/kg, s.c.) were similarly examined during and after EtOH sensitization.

Results

Chronic co-administration of low-dose U99194A blocked the induction of EtOH sensitization, while acute U99194A had no effect in mice that were already sensitized. Chronic co-administration of PD128907 resulted in decreased LMA but this effect was also seen in saline-treated mice, suggesting a simple subtractive effect. In previously sensitized mice, acute PD128907 significantly attenuated the expression of EtOH sensitization, indicating an enhanced response to the drug.

Conclusions

Results suggest a modulatory role for the D3R in behavioural sensitization to EtOH, where D3R blockade is associated with induction and D3R stimulation is associated with expression of EtOH sensitization. A model is suggested to account for these complementary functions of the D3R at different stages of EtOH sensitization.

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Acknowledgements

Supported by NSERC grant # RGPIN 170079-04. The authors thank Ashlie Soko and Katrina Deverell for the expert care provided to the animals used in the study. We are also grateful to Dr. A. D. Lê, Kathy Coen and Roger Raymond for their generous assistance with analyses of blood ethanol concentrations.

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  1. Psychology Department, University of Toronto, Toronto, ON, Canada

    Sarah Jane Harrison

  2. Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada

    José N. Nobrega

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  1. Sarah Jane Harrison
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Correspondence to José N. Nobrega.

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Harrison, S.J., Nobrega, J.N. A functional role for the dopamine D3 receptor in the induction and expression of behavioural sensitization to ethanol in mice. Psychopharmacology 207, 47–56 (2009). https://doi.org/10.1007/s00213-009-1629-x

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  • DOI: https://doi.org/10.1007/s00213-009-1629-x

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