Neurotensin, a tridecapeptide, is widely distributed in the brain and gastrointestinal tract. It possesses analgesic, hypothermic, and antipsychotic-like properties. Neurotensin's effects are mediated mainly through two receptor subtypes, NTS1 and NTS2. Activation of NTS1 has been implicated in most of the pharmacological effects of neurotensin, but is associated with hypothermia and hypotension. We report on a novel neurotensin analog with higher selectivity to NTS2, namely, NT79 which exhibits selective behavioral effects.NT79 was tested in animal models for pain (thermal -hot plate test; visceral -acetic acid-induced writhing test), and in animal models that are predictive of antipsychotic-like effects (apomorphineinduced climbing; d-amphetamine-induced hyperactivity; disruption of prepulse inhibition). Its effects on body temperature and on blood pressure were also determined. Neurochemical changes in extracellular neurotransmitters were measured using in vivo microdialysis while the rats were simultaneously evaluated for acetic acid-induced writhing with and without pretreatment with NT79.Binding data at molecularly-cloned hNTS1 and hNTS2 suggest selectivity for hNTS2. NT79 blocked the acetic acid-induced writhing with an ED 50 of 0.14μg/kg, while having no effect on thermal nociception. The writhing was paralleled by an increase in 5-HT which was attenuated by NT79. NT79 demonstrated antipsychotic-like effects by blocking apomorphine-induced climbing, damphetamine-induced hyperactivity, and reducing d-amphetamine-and DOI-induced disruption of prepulse inhibition. Uniquely, it caused no significant hypothermia and was without effect on blood pressure. NT79, with its higher selectivity to NTS2, may be potentially useful to treat visceral pain, and psychosis without concomitant side effects of hypothermia or hypotension.

Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepres-

NT69L is a neurotensin receptor agonist with antipsychotic-like activity. NT69L blocks apomorphine-induced climbing in rats with no effect on stereotypic behavior, attenuates damphetamine-induced hyperactivity, and blocks pharmacologically-induced disruption of prepulse inhibition (PPI) of the startle response. Repeated administration of NT69L results in tolerance to some, but not to all of its effects. Because schizophrenic patients require long term treatment, chronic (21-day) administration of NT69L was tested in PPI with comparisons to chronic haloperidol and clozapine treatment.Sprague-Dawley rats received acute or 21 daily, subcutaneous injections of NT69L (1.0 mg/kg). On days one and 21 the NT69L injection was followed 30 min later by treatment with either saline; the dopamine agonist, d-amphetamine (5.0 mg/kg); or the serotonin 5-HT 2A psychotomimetic receptor agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] DOI (0.5 mg/kg). Experiments were repeated with either haloperidol (1 mg/kg) or clozapine (20 mg/kg) in place of NT69L. Acute injection of NT69L significantly blocked d-amphetamine and DOI disruption of PPI. As with the acute injection, 21 daily administrations of NT69L also blocked d-amphetamine-and DOI-induced disruption of PPI. The data show that animals do not develop tolerance to the antipsychotic-like effects of NT69L when tested in the PPI of the startle response. The persistent efficacy of NT69L with chronic treatment provides further support for the therapeutic use of neurotensin agonists to treat schizophrenia and possibly other disorders that are characterized by PPI deficits. The modulatory role of NT69L on the dopaminergic and serotonergic neurotransmission systems both of which are implicated in the pathophysiology of schizophrenia is discussed.