| Numerous lines of evidence suggest an critical role of neurotensin (NT) in the mechanism of action of antipsychotic drugs (APDs) and the pathogenesis of schizophrenia. Dopamine receptor agonist and NMDA receptor antagonist activation of the mesolimbic dopamine system increases locomotion and disrupts prepulse inhibition of acoustic startle (PPI), paradigms frequently used to model the psychophysiological constructs of schizophrenia and the pharmacology of APDs. The NT1 receptor in the nucleus accumbens (NAcc) appears to mediate the antipsychotic-like properties of NT. In order to further test this hypothesis, an NT1 receptor expressing lentiviral vector was constructed. In vitro expression and functionality of the NT1 receptor was assessed using [125I]-NT binding, cAMP and IP3 assays. Next, the effect of NT1 receptor overexpression in the NAcc on d-amphetamine and dizocilpine-induced disruption of PPI and locomotion was examined in rats. Viral-mediated NAcc overexpression of the NT1 receptor antagonized d-amphetamine- and dizocilpine-induced PPI disruption, and hyperlocomotion. The protective effect against dizocilpine was blocked by the NT receptor antagonist SR142948A. These results taken together, suggest that increasing NAcc NT neurotransmission via NT1 receptor overexpression decreases the effects of dopamine agonists and NMDA antagonists on the functional output of the NAcc maintaining its inhibitory tone over the ventral pallidum and other brain regions, producing behavioral effects similar to those of atypical APDs. Based on evidence that not all effects of dizocilpine on PPI in the NAcc are mediated by dopamine, it is possible that the antipsychotic-like properties of NT in the NAcc could be related to modulation of other neurotransmitter systems in addition to dopamine (serotonin, glutamate). Furthermore, these results provide a rationale for the development of NT1 receptor agonists as novel APDs. In addition, the NT1 receptor vector might be a valuable tool for understanding the mechanism of action of APDs and may have potential therapeutic applications. |
