Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: Evidence from animal models of sensorimotor gating

To date, none of the available antipsychotic drugs are curative, all have s ignificant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become inc reasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between seve ral interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a prom ising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least i n part, by increasing the synthesis and release of the neuropeptide neurote nsin (NT). In this report, we demonstrate that NT neurotransmission is crit ically involved in the behavioral effects of antipsychotic drugs in two mod els of antipsychotic drug activity: disrupted prepulse inhibition of the ac oustic startle response (PPI) and the latent inhibition (LI) paradigm. Bloc kade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-di methoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)- N-methylcarbamoyl)-2-isopro pylphenyl)-1H-pyrazole-3- carbonyl]-amino]-adamantane-2-carboxylic acid, hy drochloride (SR 142948A) prevented the normal acquisition of LI and haloper idol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-res toring effects of haloperidol and the atypical antipsychotic drug quetiapin e in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic dru g dose-response curve in isolation-reared rats. These novel findings, toget her with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.