CGP 46381

Repeated administration of CGP 46381, a gamma-aminobutyric acidB antagonist, and ethosuximide suppresses seizure-associated cyclic adenosine 3'5' monophosphate response element- and activator protein-1 DNA-binding activities in lethargic (lh/lh) mice.[Pubmed:11137764]

Neurosci Lett. 2001 Jan 19;297(3):207-10.

To characterize seizure-associated increases in cerebral cortical and thalamic cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in lethargic (lh/lh) mice, a genetic model of absence seizures, we examined the effects of ethosuximide and CGP 46381 on these DNA-binding activities. Repeated administration (twice a day for 5 days) of ethosuximide (200 mg/kg) or CGP 46381 (60 mg/kg) attenuated both seizure behavior and the increased DNA-binding activities, and was more effective than a single administration of these drugs. These treatments did not affect either normal behavior or basal DNA-binding activities in non-epileptic control (+/+) mice. Gel supershift assays revealed that the increased CRE-binding activity was attributable to activation of the binding activity of CREB, and that the c-Fos-c-Jun complex was a component of the increased AP-1 DNA-binding activity.

GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP induced by TBS but not HFS.[Pubmed:10341258]

J Neurosci. 1999 Jun 1;19(11):4609-15.

The present experiments used CGP 35348, a selective GABAB receptor antagonist with a significantly higher affinity for post- versus presynaptic receptors, to dissociate the role of antagonist concentration versus stimulation mode in determining whether GABAB receptor blockade facilitates or suppresses long-term potentiation (LTP). The antagonist was applied by pressure ejection to one of two recording sites in area CA1 of hippocampal slices before LTP was induced at both sites with either theta burst or high-frequency stimulation (TBS or HFS). TBS produced a dose-dependent facilitation of potentiation that turned into depression at the highest concentration tested, a result reflecting the dose-dependent balance between the drug's postsynaptic disinhibitory effect and its action on presynaptic autoreceptors regulating the release of GABA. In contrast, HFS-induced LTP increased monotonically with drug concentration, suggesting that blockade of postsynaptic GABAB receptors is the only factor contributing to HFS-induced LTP. To test the relevance of the two sets of LTP results, we performed behavioral studies examining the effect of different dosages of antagonist on spatial retention and found that memory was enhanced at intermediate dosages but not at very low and high concentrations, reminiscent of the bell-shaped dose-response curve obtained for TBS-induced LTP. These findings are consistent with the notion that LTP induced by electrical stimulation modeled after endogenous theta-modulated activity patterns bears more relevance to behavior than does potentiation induced by arbitrary tetanic trains.

Prolonged GABA(B) receptor-mediated synaptic inhibition in the cat spinal cord: an in vivo study.[Pubmed:9746138]

Exp Brain Res. 1998 Aug;121(3):319-33.

In pentobarbitone-anaesthetised spinal cats, a comparison was made of the effects of intravenous bicuculline hydrochloride, a GABA(A)-receptor antagonist, and several (-)-baclofen (GABA(B)-receptor) antagonists (CGP 35348, 4638 , 56999A) on the prolonged inhibition of extensor-muscle monosynaptic reflexes, recorded from lumbar ventral roots, by brief or continuous tetanic stimulation of low-threshold afferent fibres of hindlimb flexor muscles. Two components of brief tetanus inhibition were detected. Whilst possibly of similar central latency, the inhibition associated with GABA(B) receptors had a longer time course than that reduced by bicuculline. Furthermore, whereas bicuculline reduced primary afferent depolarization, generated by the inhibitory volleys, and detected as dorsal-root potentials, such potentials were generally enhanced by intravenous baclofen antagonists. The inhibition of reflexes during and after continuous (333 Hz) tetanic flexor-nerve stimulation appeared to be predominantly associated with the activation of GABA(B) receptors. In the period following continuous tetanic flexor-nerve stimulation, during which monosynaptic extensor reflexes were reduced in amplitude, the action potentials of the intraspinal terminations of extensor-muscle group-Ia afferent fibres were reduced in duration, as detected by the time course of the recovery of the threshold to extracellular microstimulation following the arrival of an orthodromic impulse. A reduction in termination action-potential duration also accompanied the reduction by microelectrophoretic (-)-baclofen of the release of excitatory transmitter from group-Ia terminations, both presynaptic effects being blocked by microelectrophoretic baclofen antagonists. However, the reduction of the duration of the action potential of individual group-Ia terminations, which followed continuous flexor-nerve stimulation, was not sensitive to the baclofen antagonist CGP 55845A, but was diminished by bicuculline methochloride. Intravenously administered bicuculline hydrochloride, however, had little or no effect on the inhibition of reflexes following continuous flexor-nerve stimulation. These observations are discussed in the context of possible intraspinal pathways and pre- and postsynaptic mechanisms for GABA(A) and GABA(B) receptor-mediated inhibition of the monosynaptic excitation of spinal motoneurones and of the functional significance of central GABA(B) receptor-associated inhibitory processes, given the relatively minimal effects on motor activity and behaviour produced by baclofen antagonists that penetrate the mammalian blood-brain barrier.