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


OBJECTIVE
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.


CONCLUSIONS
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.
Jacobson
Laura H
LH
Novartis Institutes for BioMedical Research, Neuroscience Research, WSJ-386.344, 4002, Basel, Switzerland.
Cryan
John F
JF
D000818:Animals; D001418:Baclofen / Q000494:pharmacology* / Q000633:toxicity; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D018755:GABA Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D007035:Hypothermia / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009048:Motor Skills / Q000187:drug effects* / Q000502:physiology; D018080:Receptors, GABA-B / Q000235:genetics*; D045442:Rotarod Performance Test / Q000379:methods; D013045:Species Specificity
D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D001418:Baclofen