Effects of GABA agonists on body temperature regulation in GABA_B(1)^−/− mice

Abstract

Activation of GABAB receptors evokes hypothermia in wildtype (GABAB(1)+/+) but not in GABAB receptor knockout (GABAB(1)−/−) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABAB receptor agonist γ‐hydroxybutyrate (GHB), and of the GABAA receptor agonist muscimol. In addition, basal body temperature was determined in GABAB(1)+/+, GABAB(1)+/− and GABAB(1)−/− mice. GABAB(1)−/− mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting, PCR and Western blotting. GABAB 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. GABAB(1)−/− mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABAB(2) receptor protein was below the detection limit in brains from GABAB(1)−/− mice, in the absence of changes in mRNA levels. GABAB receptor‐binding sites were absent in brain membranes from GABAB(1)−/− mice. GABAB(1)−/− mice were hypothermic by approximately 1°C compared to GABAB(1)+/+ and GABAB(1)+/− mice. Injection of baclofen (9.6 mg kg−1) produced a large reduction in body temperature and behavioural effects in GABAB(1)+/+ and in GABAB(1)+/− mice, but GABAB(1)−/− mice were unaffected. The same pattern was seen after administration of GHB (400 mg kg−1). The GABAA receptor agonist muscimol (2 mg kg−1), on the other hand, produced a more pronounced hypothermia in GABAB(1)−/−mice. In GABAB(1)+/+ and GABAB(1)+/− mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABAB(1)−/− mice, muscimol triggered periods of intense jumping and wild running. It is concluded that hypothermia should be added to the characteristics of the GABAB(1)−/−phenotype. Using this model, GHB was shown to be a selective GABAB receptor agonist. In addition, GABAB(1)−/− mice are hypersensitive to GABAA receptor stimulation, indicating that GABAB tone normally balances GABAA‐mediated effects. British Journal of Pharmacology (2003) 140, 315–322. doi:

Assessment of luteolin (3′,4′,5,7-tetrahydroxyflavone) neuropharmacological activity

“…There are reports of other flavonoidtype molecules like quercetin [55] or flavonoid-enriched extracts [56] interfering with haloperidol-induced catalepsy with different outcomes but the present results suggest that luteolin has a baclofen-like effect in this test. However, it must be noted that unlike baclofen [57], luteolin did not produce any significant reduction in the animals' body temperature (results not shown).…”

Genetic and Pharmacological Evidence of a Role for GABAB Receptors in the Modulation of Anxiety- and Antidepressant-Like Behavior

“…In a variety of paradigms, it has been shown that BALB/c mice exhibit increased anxiety-related behaviors compared to other inbred strains of mice (Belzung and Griebel, 2001). The use of mice on this background strain was essential for the generation of GABA B -related knockout animals, as mice on other background strains died very prematurely (Prosser et al, 2001;Queva et al, 2003). Interestingly, unlike genetic deletion, chronic pharmacological antagonism of GABA B receptors with CGP56433A failed to alter anxiety-related behavior in the light-dark box ( Figure 5).…”

“…Firstly, mice that lack the GABA B(1) subunit (Prosser et al, 2001;Queva et al, 2003;Schuler et al, 2001) have been generated. Secondly, with positive allosteric modulators, novel pharmacological tools for GABA B receptors have been characterized (Urwyler et al, 2001;Urwyler et al, 2003).…”

Survey and critical appraisal of pharmacological agents with potential thermo-modulatory properties in the context of artificially induced hypometabolism

“…An in vitro study using hypothalamic medial preoptic slices revealed that both GABAA and GABAB receptor agonists inhibit neuronal tonic activity, implying a potential of GABA receptor agonists to modulate the Ztn [78]. In murine GABAB knockout and partial knockdown models, hypothermic responses were observed in GABAB +/-and wild type (GABAB +/+ ) mice but remained absent in GABAB -/-mice, supporting the notion that GABA receptors regulate temperature homeostasis via the Ztn [77]. Despite the established pentobarbital-GABA signaling link and the apparent relationship between GABA receptor agonism and Tb control, the evidence is presently too scant to classify pentobarbital as an anapyrexic agent.…”

“…Despite the widespread view that pentobarbital has no anapyrexic effects, more recent studies suggest that γ-aminobutyric acid (GABA) receptors, the main target of pentobarbital, may play a role in thermal homeostasis [77]. An in vitro study using hypothalamic medial preoptic slices revealed that both GABAA and GABAB receptor agonists inhibit neuronal tonic activity, implying a potential of GABA receptor agonists to modulate the Ztn [78].…”