Chronic NT69L potently prevents drug-induced disruption of prepulse inhibition without causing tolerance

Abstract

NT69L is a neurotensin receptor agonist with antipsychotic-like activity. NT69L blocks apomorphine-induced climbing in rats with no effect on stereotypic behavior, attenuates d -amphetamine-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 1 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 (NT) 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.