Evidence for an involvement of GABA in the mediation of the cerebellar cGMP decrease and the anticonvulsant action of diazepam

Abstract

Subcutaneous injections of isoniazid or picrotoxin increase the cerebellar content of 3′,5′-cyclic guanosine monophosphate (cGMP) without changing the 3′,5′-cyclic adenosine monophosphate cAMP. This increase was dose dependent and the threshold for the cGMP increase was lower than that for convulsions. In cerebellum the increase of cGMP content elicited by isoniazid but not that caused by picrotoxin was paralleled by a decrease of GABA content. Diazepam doses starting from 1.74 μmol/kg intraperitoneally produced a dose dependent decrease of cerebellar cGMP concentration without changing cAMP or GABA content. Smaller doses of diazepam (0.5 μmol/kg i.p.) failed to decrease the basal cerebellar content of cGMP. However, this dose of diazepam antagonized the increase of cGMP produced by isoniazid but not that produced by picrotoxin. Higher doses of diazepam were necessary to block the increase of cerebellar cGMP elicited by picrotoxin. Low doses of diazepam (0.14 μmol/kg) antagonized the convulsions in 50% of the rats injected with 3.3 mmol/kg of isoniazid. The doses of diazepam required to block picrotoxin, pentylenetetrazol or strychnine convulsions were 7, 25 and 40 times higher than those required to block isoniazid convulsions, respectively. Desmethyldiazepam, chloridiazepoxide, oxazepam were also several times more potent in antagonizing isoniazid than picrotoxin, pentylenetetrazol, or strychnine convulsions. In contrast, barbiturates were equipotent against all the convulsants studied. These experiments suggest that diazepam may act in the CNS either by altering the disposition of endogenous GABA or by mimicking the action of GABA at specific synaptic receptors.