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

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 GABA B receptors in anxiety and depression. Investigation of the phamacogenetics of GABA B receptor activation may aid in the understanding of mechanisms underlying the role of GABA B in affect.

Objectives: The aim of current study was to determine the relative sensitivity of different mouse strains to GABA B receptor agonism in two models of GABA B 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 GABA B receptor populations that mediate hypothermia and ataxia. Further, these studies demonstrate that background strain is an important determinant of GABA B receptor mediated responses, and that hypothermic and ataxic responses may be influenced by independent genetic loci.