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Differential sensitivity to the motor and hypothermic effects of the GABAB receptor agonist baclofen in various mouse strains

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Abstract

Rationale

Comparison of different mouse strains can provide valuable information about the genetic control of behavioural and molecular phenotypes. Recent evidence has demonstrated the importance of GABAB receptors in anxiety and depression. Investigation of the phamacogenetics of GABAB receptor activation may aid in the understanding of mechanisms underlying the role of GABAB in affect.

Objectives

The aim of current study was to determine the relative sensitivity of different mouse strains to GABAB receptor agonism in two models of GABAB receptor function, namely hypothermia and motor incoordination.

Methods

Mice each from 11 strains (BALB/cByJIco, DBA/2JIco, OF1, FVB/NIco, CD1, C3H/HeOuJIco, 129/SvPasIco, NMRI, C57BL/6JIco, A/JOlaHsd and Swiss) were trained to walk on a rotarod for 300 s. On the following day, mice received 0, 3, 6 or 12 mg/kg of l-baclofen PO. Rectal temperature and rotarod performance were measured at 0, 1, 2 and 4 h after drug application.

Results

l-Baclofen produced a significant dose-dependent hypothermia and ataxia in most, but not all, mouse strains examined. The magnitude and duration of response was influenced by strain, with mice of the 129/SvPasIco strain showing largest hypothermic response to 12 mg/kg l-baclofen and C3H/HeOuJIco the lowest, whereas the BALB/cByJIco strain demonstrated greatest ataxic response on the rotarod, and NMRI the least. Interestingly, some strains (notably C3H/HeOuJIco) had marked differential hypothermic and ataxic responses, with minimal body temperature responses to l-baclofen but significant ataxia on the rotarod observed.

Conclusion

There is differential genetic control on specific GABAB receptor populations that mediate hypothermia and ataxia. Further, these studies demonstrate that background strain is an important determinant of GABAB receptor mediated responses, and that hypothermic and ataxic responses may be influenced by independent genetic loci.

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Acknowledgements

The authors would like to thank Cedric Mombereau for initiating inter-strain temperature studies and Christine Hunn and Hugo Buerki for excellent technical support. The authors would like to thank Dr. David Slattery for critical reading of the manuscript. This work is supported by National Institutes of Mental Health/National Institute on Drug Abuse grant U01 MH69062 to J.F.C.

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  1. Novartis Institutes for BioMedical Research, Neuroscience Research, WSJ-386.344, 4002, Basel, Switzerland

    Laura H. Jacobson & John F. Cryan

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Jacobson, L.H., Cryan, J.F. Differential sensitivity to the motor and hypothermic effects of the GABAB receptor agonist baclofen in various mouse strains. Psychopharmacology 179, 688–699 (2005). https://doi.org/10.1007/s00213-004-2086-1

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