Boules, Mona

Bipolar disorder is treated with mood stabilizers. mRNA data show that these drugs regulate synaptic protein expression. To determine protein levels and post‐translational processing of proteins and to determine if paliperidone (PALI), risperidone active metabolite, regulates synaptic proteins similar to mood stabilizers, we determined protein expression profiles in the PFC with chronic drug treatments. LiCl, valproate (VAL), or PALI was given daily by i.p. injections to 4 male Sprague‐Dawley rats/group for 28 d. Controls = 0.9% saline and 0.3% tartaric acid. Brains were dissected 24 h after final injections. Synaptoneurosomal proteins were extracted and separated by DIGE. Simultaneously, phosphorylation changes were determined (ProQ diamond staining). Reproducibly present data in all biological replicates were analyzed and compared with their respective controls using Interpreter (Ludesi). Proteins with differential expression and phosphorylation were identified by nano‐LC MS. PALI, LiCl, and VAL treatment resulted in similar protein expression profiles and phosphorylation patterns at the synaptoneurosomal level, suggesting that the mode of action for this drug is similar to that of mood stabilizers and supporting its use for this purpose. Interestingly, the expression profile for PALI was more similar to that of LiCl than that of VAL. Supported by a grant from Janssen Pharmaceutica, Inc.

Neurotensin (NT) is a neuropeptide that is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various mental disorders. This review outlines data implicating NT in the pathophysiology and management of major mental disorders such as schizophrenia, drug addiction, and autism. The data suggest that NT receptor analogs have the potential to be used as novel therapeutic agents acting through modulation of neurotransmitter systems dys-regulated in these disorders.

Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

SUMMARYPre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) receptors. We hypothesized that the NT receptor agonist (NT69L) would prevent PPI disruption in mice challenged with d-amphetamine (10 mg kg–1) and dizocilpine (1 mg kg–1). We investigated the role of NTS1 and NTS2 in PPI using wild-type (WT), NTS1 (NTS1–/–) and NTS2 (NTS2–/–) knockout mice, via its disruption by psychotomimetic drugs, as well as the ability of clozapine and NT69L to block these PPI disruptions. There were no differences in baseline PPI across the three genotypes. d-Amphetamine and dizocilpine disrupted PPI in WT and NTS2–/– mice but not in NTS1–/– mice. In WT mice, clozapine (1 mg kg–1) and NT69L (1 mg kg–1) significantly blocked d-amphetamine-induced disruption of PPI. Similarly, in WT mice, clozapine significantly blocked dizocilpine-induced PPI disruption, but NT69L did not. In NTS2–/– mice clozapine blocked d-amphetamine-but not dizocilpine-induced PPI disruption, while NT69L blocked both d-amphetamine- and dizocilpine-induced PPI disruption. Our results indicate that NTS1 seems essential for d-amphetamine and dizocilpine disruption of PPI. Additionally, this report provides support to the hypothesis that NT analogs could be used as novel antipsychotic drugs.