Behavioural Brain Research 202 (2009) 192–197 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report The neurotensin agonist NT69L improves sensorimotor gating deficits in rats induced by a glutamatergic antagonist, but not by dopaminergic agonists R.L. Secchi a , E. Sung a , L.R. Hedley a , D. Button b , R. Schreiber a,∗ a CNS Therapy Area, Department of Neurobehavior, Roche Pharmaceuticals, Palo Alto, CA 94304, USA b CNS Therapy Area, Department of Neuropharmacology, Roche Pharmaceuticals, Palo Alto, CA 94304, USA article info Article history: Received 5 February 2009 Received in revised form 23 March 2009 Accepted 24 March 2009 Available online 1 April 2009 Keywords: Acoustic startle response Amphetamine Apomorphine Pre-pulse inhibition Schizophrenia abstract An imbalance between different neurotransmitter systems is involved in the pathophysiological processes underlying schizophrenia. Since the neurotensin (NT) system modulates the activity of several of these neurotransmitters, drugs acting upon the NT system may act as novel antipsychotic drugs. This hypothesis is supported by studies with NT in animal models. For example, intracranial injection of NT improves sensorimotor gating in rats [Feifel D, Minor KL, Dulawa S, Swerdlow NR. The effects of intra-accumbens neurotensin on sensorimotor gating. Brain Research 1997;760:80–4]. NT-mimetics, such as NT69L, have been developed which are more resistant to enzymatic degradation than the native NT peptide. In the present study, the potential antipsychotic properties of NT69L were evaluated in a rat pre-pulse inhibition (PPI) paradigm. PPI is a measure of sensorimotor gating where a weak auditory stimulus, or pre-pulse, inhibits the startle response to a strong stimulus, or pulse. Schizophrenic patients exhibit deficits in their PPI response. This condition can be mimicked in rats with psychotomimetic drugs and the resulting PPI deficit is reversed by antipsychotic drugs. NT69L (0.1–10mg/kg i.p.) reversed disruptions of the PPI response induced by the NMDA antagonist dizocilpine (0.1mg/kg s.c.) for at least 1-h post-injection, but did not reverse disruptions induced by the dopaminergic agonists apomorphine and d-amphetamine (0.5 and 5 mg/kg s.c., respectively). These results confirm that NT69L possesses antipsychotic-like activity and therefore could be beneficial in the treatment of schizophrenia. © 2009 Elsevier B.V. All rights reserved. 1. Introduction While dopamine hyperactivity contributes to the pathophysiol- ogy of schizophrenia, this disease does not result from dysfunction of a single neurotransmitter system alone, but rather from an imbalance between several interacting neurotransmitters, includ- ing dopaminergic, serotoninergic, glutamatergic, cholinergic and GABA-ergic systems [2]. Therefore, it is expected that drug treat- ments affecting several of these neurotransmitters may yield a superior antipsychotic profile as compared to drugs predomi- nantly affecting a single system. Hence, a promising drug discovery approach consists of targeting neuropeptide neuromodulator sys- tems that regulate several of the neurotransmitter systems affected in schizophrenia [3,15]. Several lines of evidence support a potential role for the neuropeptide neuromodulator neurotensin (NT) in the pathophys- iology of schizophrenia. NT-containing neurons are mainly found in dopaminergic brain regions involved in the effects of antipsy- ∗ Corresponding author. Present address: Sepracor Inc., 84 Waterford Drive, Marl- borough, MA 01752-7010, USA. Tel.: +1 508 787 4169; fax: +1 508 490 5454. E-mail address: rudy.schreiber@sepracor.com (R. Schreiber). chotic drugs [22]. NT receptors are co-localized with mesocortical, mesolimbic and nigrostriatal dopamine projections and these two systems exert numerous effects on each other [2]. Biochemical studies have shown that antipsychotic drug treatment increase NT neurotransmission, and centrally administrated NT produces bio- chemical and behavioral effects similar to those observed following antipsychotic drugs [1]. Intracisternal administration of NT attenu- ates locomotor hyperactivity induced by d-amphetamine and other stimulants known to produce excess dopamine release [15]. In a model of sensorimotor gating, central and systemic administration of NT in rats dose-dependently blocked d-amphetamine-induced disruption of the pre-pulse inhibition (PPI) of the acoustic startle response, suggesting antipsychotic activity [7,16]. Finally, within a sub-population of schizophrenic patients, levels of NT in cere- brospinal fluid were lower compared to controls, and those levels returned to normal following neuroleptic treatment [23]. While centrally administered NT is biologically active [4,7,8], it produces no observable effects in the CNS following systemic administration. This has led to the development of a new class of analogs that, when administered systemically, are more resistant than NT to enzymatic degradation and can pass the blood brain barrier. These analogs share the same characteristics as NT such as their ability to induce antinociception and hypothermia [4,21]. 0166-4328/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2009.03.034