Proconflict and electrocorticographic effects of drugs modulating GABAergic neurotransmission

Proconflict and electrocorticographic effects of drugs acting on the benzodiazepine (BDZ)/GABA/chloride-ionophore receptor complex were studied in rats in an attempt to correlate their anxiogenic and epileptogenic activities. Evidence for proconflict activity was assessed by means of an operant conflict procedure based on the simultaneous reward and punishment of a conditioned task, while epileptogenic properties were assessed by monitoring the electrocorticogram (ECoG) of free-moving rats. Pentylenetetrazole and picrotoxin, which act through a site on the chloride channel, and the benzodiazepine (BDZ) inverse agonist FG 7142 showed epileptogenic alterations in the ECoG at doses, respectively, 8, 2 and 3 times higher than those eliciting a significant proconflict effect. For the partial inverse agonist CGS 8216, a ratio of about 60 was found while the BDZ antagonist Ro 15-1788 showed neither epileptogenic nor proconflict activity, except at the highest tested dose for the latter effect (40 mg X kg-1 PO). Inhibition of GABA transmission may mediate both anxiogenic and epileptogenic actions, and a link between these properties may exist as a continuous spectrum of negative intrinsic efficacy at the central BDZ/GABA/chloride-ionophore receptor complex.