Dissociating scopolamine-induced disrupted and persistent latent inhibition: stage-dependent effects of glycine and physostigmine

Latent inhibition (LI) is the poorer conditioning to a stimulus seen when conditioning is preceded by repeated non-reinforced pre-exposure to the stimulus. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia. We showed that the pro-psychotic muscarinic antagonist scopolamine can produce LI disruption or LI persistence depending on dose and stage of administration: low doses disrupt LI acting in the pre-exposure stage of the LI procedure, whereas higher dose produces abnormally persistent LI via action in the conditioning stage. The two LI abnormalities show distinct response to antipsychotic drugs (APDs), with LI disruption, but not LI persistence, reversed by APDs. The objective of this study is to show that both LI abnormalities will be reversed by the cognitive enhancers, glycine and physostigmine, in a stage-specific manner, reversing each abnormality via the stage at which it is induced by scopolamine. LI was measured in a conditioned emotional response procedure. Scopolamine, physostigmine, and glycine were administered in pre-exposure and/or in conditioning. Scopolamine (0.15 mg/kg)-induced disrupted LI was reversed by glycine (800 mg/kg) and physostigmine (0.15 mg/kg) via action in pre-exposure, whereas scopolamine (1.5 mg/kg)-induced persistent LI was reversed by these compounds via action in conditioning. In addition, glycine reversed scopolamine-induced disrupted LI via action in conditioning. Finally, glycine failed to reverse amphetamine-induced disrupted LI. These results extend the pharmacological differentiation between scopolamine-induced disrupted and persistent LI and indicate that the scopolamine LI model may have a unique capacity to discriminate between typical APDs, atypical APDs, and cognitive enhancers.