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Boules M.,Neuropsychopharmacology Laboratory | Netz R.,Neuropsychopharmacology Laboratory | Fredrickson P.A.,Mayo Medical School | Richelson E.,Neuropsychopharmacology Laboratory | Richelson E.,Mayo Medical School
Behavioural Pharmacology | Year: 2016

Neurotensin (NT) is a neuropeptide that acts as a neurotransmitter and neuromodulator in the central nervous system. Several studies suggest a therapeutic role for NT analogs in nicotine and other psychostimulant addictions. We studied the effects of the nonselective NT receptor agonist NT69L, which has equal affinity for the two major NT receptors, NTS1 and NTS2, on the expression of cocaineconditioned place preference (cocaine-CPP) and reinstatement after extinction. Robust cocaine-CPP was obtained after 5 days of conditioning. Extinction was induced using eight repeated daily injections of saline. Reinstatement was prompted by priming with one injection of cocaine (12 mg/kg intraperitoneally). On the test day, NT69L (1 mg/kg intraperitoneally) was administered 30 min before assessing cocaine-CPP. Extinction led to the loss of cocaine-CPP. One injection of cocaine (12 mg/kg intraperitoneally) for cocaine priming reinstated cocaine- CPP. NT69L blocked cocaine-CPP reinstatement in cocaineprimed animals. In addition, NT69L blocked cocaine-CPP reinstatement when administered before priming with cocaine. Thus, the NT agonist NT69L blocked both cocaine- CPP and reinstatement to cocaine preference. NT69L may exert this action by modulating the mesocorticolimbic dopamine and glutamatergic pathways involved in addiction and relapse processes. Therefore, NT agonists may represent a novel therapy for the treatment of addiction to cocaine and possibly to other psychostimulants. © Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. Source

Boules M.,Neuropsychopharmacology Laboratory | Liang Y.,Neuropsychopharmacology Laboratory | Briody S.,Neuropsychopharmacology Laboratory | Miura T.,Neuropsychopharmacology Laboratory | And 9 more authors.
Brain Research | Year: 2010

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 (apomorphine-induced 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 ED50 of 0.14 μg/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, d-amphetamine-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. © 2009 Elsevier B.V. All rights reserved. Source

Boules M.,Neuropsychopharmacology Laboratory | Li Z.,Neuropsychopharmacology Laboratory | Smith K.,Neuropsychopharmacology Laboratory | Fredrickson P.,Neuropsychopharmacology Laboratory | Richelson E.,Neuropsychopharmacology Laboratory
Frontiers in Endocrinology | Year: 2013

Neurotensin (NT) is a tridecapeptide that is found in the central nervous system (CNS) and the gastrointestinal tract. NT behaves as a neurotransmitter in the brain and as a hormone in the gut. Additionally, NT acts as a neuromodulator to several neurotransmitter systems including dopaminergic, sertonergic, GABAergic, glutamatergic, and cholinergic systems. Due to its association with such a wide variety of neurotransmitters, NT has been implicated in the pathophysiology of several CNS disorders such as schizophrenia, drug abuse, Parkinson's disease (PD), pain, central control of blood pressure, eating disorders, as well as, cancer and inflammation. The present review will focus on the role that NT and its analogs play in schizophrenia, endocrine function, pain, psychostimulant abuse, and PD. © 2013 Boules, Li, Smith, Fredrickson and Richelson. Source

Boules M.,Neuropsychopharmacology Laboratory | Oliveros A.,Neuropsychopharmacology Laboratory | Liang Y.,Neuropsychopharmacology Laboratory | Williams K.,Neuropsychopharmacology Laboratory | And 4 more authors.
Neuropeptides | Year: 2011

NT69L is a neurotensin analog that blocks nicotine-induced locomotor activity and has sustained efficacy in a rat model of nicotine-induced sensitization when administered peripherally. Additionally, NT69L attenuates food-reinforcement in rats. The present study tested the effect of acute administration of NT69L on nicotine self-infusion in Sprague-Dawley rats. Rats were trained to self-infuse nicotine intravenously (0.03. mg/kg per infusion) following operant training. Once the rats acquired stable responding to nicotine self-infusion they were pretreated with NT69L (1. mg/kg, i.p.) or saline 30. min before being assessed for nicotine self-infusion. Pretreatment with NT69L significantly attenuated nicotine self-infusion under FR1 (fixed ratio of 1) and FR5 schedule of reinforcement as compared to saline pretreatment. Control rats that were response-independent "yoked" as well as rats that self-infused saline or NT69L showed minimal responses, indicating that nicotine served as a reinforcer.Additionally, NT69L modulated serum corticosterone; brain norepinephrine serotonin; and dopamine receptors mRNA levels altered in the nicotine self-infused rats after a 24. h withdrawal period. Pretreatment with NT69L significantly decreased the nicotine-induced increase in serum corticosterone levels and striatal norepinephrine and increased the nicotine-induced reduction in serotonin in both the striatum and the prefrontal cortex (PFC). NT69L might modulate dopamine neurotransmission implicated in the reinforcing effects of nicotine by modulating tyrosine hydroxylase and dopamine receptor mRNA levels in the PFC and striatum. These data support further study of the effects of NT analogs on attenuating the reinforcing effects of psychostimulants. © 2010 Elsevier Ltd. Source

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