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 (1.0mg/kg). On days 1 and 21 the
NT69L injection was followed 30 min later by treatment with either saline; the
dopamine agonist,
d-amphetamine (5.0mg/kg); or the
serotonin 5-HT(2A) psychotomimetic receptor agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] DOI (0.5mg/kg). Experiments were repeated with either
haloperidol (1mg/kg) or
clozapine (20mg/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.