Using Pharmacology of Disrupted and Persistent LI to Model Domains of Pathology in Schizophrenia

Disrupted and persistent LI can be seen as two poles of dysfunctional attentional control, namely, a failure to inhibit attention to irrelevant stimuli and a failure to re-deploy attention when previously irrelevant stimuli become relevant. The former would likely give rise to the aberrantly increased salience perception and distracti-bility that are associated with psychotic symptoms, whereas the latter would result in the cognitive inflexibility and impaired attentional shifting that are associated with negative/cognitive symptoms. Indeed, both disrupted and excessively strong LI are found in schizophrenia patients, the former associated with acute psychosis and the latter associated with predominance of negative symptoms.

Based on their distinct pharmacological profiles, LI abnormalities produced by amphetamine, haloperidol, NMDA antagonists, and scopolamine have been suggested to represent four domains of pathology in schizophrenia (Table 2). Amphetamine- and scopolamine-induced disrupted LI represents the domain of positive symptoms, the only domain responsive to both typical and atypical APDs. Notably, disrupted LI is responsive to APDs irrespective of the mechanisms underlying the disruption. NMDA antagonist-induced persistent LI represents a (hypoglutamatergia-driven) domain of negative/cognitive

Latent Inhibition. Fig. 4. Effects of clozapine, glycine, or physostigmine on haloperidol-induced persistent LI. Mean times (logarithmically transformed) to complete 25 licks in the presence of the tone of PE and NPE rats treated with vehicle or haloperidol (hal) and pre-treated with clozapine (5 mg/kg), glycine (800 mg/kg), or physostigmine (0.15 mg/kg). No LI was evident in the vehicle control but there was LI in rats treated with haloperidol. Haloperidol-induced persistent LI was antagonized only by clozapine. Clozapine and glycine but not physostigmine led to LI persistence in vehicle-treated rats.

Latent Inhibition. Table 2. Five pharmacological LI models proposed to model five domains of pathology of schizophrenia.

Model

Disrupted LI

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