Effects of the GABAB antagonist CGP 35348 on sleep-wake states, behaviour, and spike-wave discharges in old rats

Abstract

The GABA, antagonist CGP 35348 was intraperitoneally given in doses of 100, 300, and 900 mglkg to old rats. These rats were earlier chronically provided with EEG and EMG electrodes. Sleep recordings based on visual inspection of EEG and EMG recordings were made for 3 h post injection, and spontaneous behaviour in the recording cage was additionally observed. With 100 and 300 mglkg, the drug produced an increase in the duration of REM sleep compared to the saline-injected control group. The REM sleep latency was correspondingly reduced. Non-REM sleep and total sleep duration increased and an s-shaped dose-response relationship was found. Explorative behaviour was diminished after injections with 100 and 300 mgl kg CGP 35348. The number and duration of spike-wave discharges were reduced after all doses of CGP 35348 and during all 3 recording hours. The latter outcomes confirm the strong suppressive action of this drug on spike-wave discharges; these effects have also been reported in models of absence epilepsy. The hypnotic properties and especially the increase in REM sleep after the administration of CGP 35348 deserve attention considering the paucity of drugs which facilitate REM sleep. The discovery of drugs promoting REM sleep might have theoretical as well as clinical consequences.

Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures

“…Interestingly, early studies performed in both GAERS and WAG/Rij rats found that injecting GABA B receptor antagonists either into the thalamus or systemically, blocked absence seizures (Liu et al, 1992;Snead, 1996;Puigcerver et al, 1996). These data have been interpreted as reflecting the ability of GABA B receptor antagonists to reduce slow hyperpolarizing IPSPs (and thus their ability to de-inactivate low-threshold Ca 2+ conductances) in thalamocortical relay cells (Steriade et al, 1993).…”

Spike-and-Wave Oscillations Based on the Properties of GABABReceptors

“…A series of pharmacological results suggests that GABA B receptors play a critical role in the genesis of SW discharges in rats, because GABA B agonists exacerbate seizures whereas GABA B antagonists suppress them (Hosford et al, 1992;Snead, 1992;Puigcerver et al, 1996;Smith and Fisher, 1996). The anti-absence drug clonazepam seems to act by diminishing GABA B -mediated IPSPs in thalamocortical (TC) cells, reducing their tendency to burst in synchrony (Huguenard and Prince, 1994a;Gibbs et al, 1996).…”

Diminished Presynaptic GABA_B Receptor Function in the Neocortex of a Genetic Model of Absence Epilepsy

“…In addition, as proposed for thalamocortical relay cells [37] , an increased release of GABA should activate postsynaptic GABA B receptors, thus producing robust hyperpolarizing IPSPs that contribute to de-inactivate low-threshold Ca 2+ conductances, which in turn facilitate rhythmic bursting. In line with this view, injecting GABA B receptor antagonists, either into the thalamus or systemically, blocks absence seizures in both GAERS and WAG/Rij rats [38][39][40] .…”