Blockade of latent inhibition following pharmacological increase or decrease of GABA(A) transmission.

The latent inhibition (LI) phenomenon refers to the retardation in learning of an association between a stimulus and a consequence if that stimulus had been previously experienced without consequence. An earlier study demonstrated that the benzodiazepine receptor agonist chlordiazepoxide (CDP), when administered before the phase of preexposure to the to-be-conditioned stimulus, impaired animals' ability to develop LI. The present study was designed to investigate the effect of the anxiogenic drugs pentylenetetrazole (PTZ) and the benzodiazepine partial inverse agonist Ro15-4513 on LI. Both anxiogenics, in contrast to CDP, are known for their GABA inhibitory action. The effects produced by the combined administration of a GABAergic function facilitator and inhibitor (CDP/PTZ and CDP/Ro15-4513) were also investigated. Both anxiogenic drugs led to an attenuation of LI, and, similarly to CDP, this attenuation was exclusively due to their administration prior to the preexposure stage of the experiment. However, this effect was abolished when anxiolytic and anxiogenic drugs were administered together, suggesting a pharmacological rather than behavioral summation of effects. These data also demonstrate the bidirectional GABAergic modulation of the LI phenomenon: both increased and decreased GABA(A) receptor activation led to reduced LI, thereby suggesting that an optimal receptor activation level is necessary for the normal establishment of LI.