摘要：

Activation of GABA[subB] receptors evokes hypothermia in wildtype (GABA[sup+/+][subB(1)]) but not in GABA[subB] receptor knockout (GABA[sup-/-][subB(1)]) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABA[subB] receptor agonist γ-hydroxybutyrate (GHB), and of the GABA[subA] receptor agonist muscimol. In addition, basal body temperature was determined in GABA[sup+/+][subB(1)], GABA[sup+/-][subB(1)] and GABA[sup+/+][subB(1)] mice. 2 GABA[sup-/-] [subB(1)] mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting. PCR and Western blotting. GABA[subB] receptor-binding sites were quantified with radioligand binding. Measurement of body temperature was done using subcutaneous temperature-sensitive chips, and behavioural changes after drug administration were scored according to a semiquantitative scale. 3 GABA[sup-/-][subB(1)] mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABA[subB(2)] receptor protein was below the detection limit in brains from GABA[sup-/-][subB(1)] mice, in the absence of changes in mRNA levels. 4 GABA[subB] receptor-binding sites were absent in brain membranes from GABA[sup-/-][subB(1)] mice. 5 GABA[sup-/-][subB(1)] mice were hypothermic by approximately 1&deg,C compared to GABA[sup+/+][subB(1)] and GABA[sup+/-][subB(1)] mice. 6 Injection of baclofen (9.6 mgkg[sup-1]) produced a large reduction in body temperature and behavioural effects in GABA[sup+/+][subB(1)] and in GABA[sup+/-][subB(1)] mice. but GABA[sup-/-][subB(1)] mice were unaffected. The same pattern was seen after administration of GHB (400mg kg[sup-1]). The GABA[subA] receptor agonist muscimol (2 mg kg[sup-1]), on the other hand. produced a more pronounced hypothermia in GABA[sup-/-][subB(1)] mice. In GABA[sup+/+][subB(1)] and GABA[sup+/-][subB(1)] mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABA[sup-/-][subB(1)] mice, muscimol triggered periods of intense jumping and wild running. 7 It is concluded that hypothermia should be added to the characteristics of the GABA[sup-/-][subB(1)] phenotype. Using this model, GHB was shown to he a selective GABA[subB] receptor agonist. In addition, GABA[sup-/-][subB(1)] mice are hypersensitive to GABA[subA] receptor stimulation, indicating that GABA[subB] tone normally balances GABA[subA]-mediated effects.

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