Effects of neurotensin receptor antagonism on latent inhibition in Sprague-Dawley rats

Rationale: It has been postulated that the tridecapeptide neurotensin (NT) functions as an endogenous antipsychotic peptide. A critical test of this hypothesis would be to determine if NT is involved in the expression of latent inhibition (LI), a psychophysiological and pharmacological model of schizophrenia. Objective: This report describes the effects of disrupting NT neurotransmission by systemic administration of the NT receptor antagonists SR48692 and SR142948A on the acquisition of LI in rats. Methods: The effects of 30-300 mug/kg SR48692 or 0.1-100 mug/kg SR142948A on the expression of LI following 0, 20 or 30 pre-exposures were first investigated. This was followed by the assessment of the effects of 10 mug/kg SR142948 A on the LI effect of increasing stimulus pre-exposures (10-40). Finally, the role of dopamine transmission in the effects of SR142948A on the acquisition of LI (30 pre-exposures) was tested by coadministering 10 mug/kg SR142948A and 100 mg/kg of the dopamine D-2 antagonist sulpiride. Results: The higher tested doses of SR48692 (100-300 mug/kg) and SR142948A (10100 mug/kg) decreased acquisition of LI following 20, 30 and even 40 pre-exposures to the to-be- conditioned stimulus. Cotreatment with the dopamine D, antagonist sulpiride prevented the LI-disrupting effects of SR142948A. Conclusions: NT neurotransmission appears to be necessary for the acquisition of LI. The main effect of NT receptor antagonism is a disruption of LI, most likely via enhancement of dopamine transmission. This effect is opposite that of antipsychotic drugs, which have been shown to enhance NT release, supporting the hypothesis of NT as an endogenous antipsychotic peptid