RT Journal Article
SR Electronic
T1 Enhanced Neurotensin Neurotransmission Is Involved in the Clinically Relevant Behavioral Effects of Antipsychotic Drugs: Evidence from Animal Models of Sensorimotor Gating
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 601
OP 608
DO 10.1523/JNEUROSCI.21-02-00601.2001
VO 21
IS 2
A1 Elisabeth B. Binder
A1 Becky Kinkead
A1 Michael J. Owens
A1 Clinton D. Kilts
A1 Charles B. Nemeroff
YR 2001
UL http://www.jneurosci.org/content/21/2/601.abstract
AB To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose–response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.