The Novel Neurotensin Analog NT69L Blocks Phencyclidine (PCP)-induced Increases in Locomotor Activity and PCP-induced Increases in Monoamine and Amino Acids Levels in the Medial Prefrontal Cortex

Overview

Journal Brain Res

Specialty Neurology

Date 2009 Dec 2

PMID 19948149

Citations 13

Authors

Zhimin Li

Mona Boules

Katrina Williams

Joanna Peris

Elliott Richelson

Affiliations

Soon will be listed here.

Abstract

Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy. Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia. Another current animal model utilizes non-competitive antagonists of the NMDA/glutamate receptor, such as the psychotomimetic phencyclidine (PCP). In the present study, we investigated the effects of NT69L on PCP-induced behavioral and biochemical changes in the rat. The top of an activity chamber was modified to allow us to perform microdialysis in rat brain, while simultaneously recording the locomotor activity of a rat. PCP injection significantly increased activity as well as the extracellular concentration of norepinephrine (NE), 5-HT, dopamine (DA), and glutamate in the medial prefrontal cortex (mPFC). Pretreating with NT69L blocked the PCP-induced hyperactivity as well as the increase of DA, 5-HT, NE, and glutamate in mPFC. Interestingly and unexpectedly, NT69L markedly increased glycine levels, while PCP was without effect on glycine levels. Thus, NT69L showed antipsychotic-like effects in this glutamate-based animal model for studying schizophrenia. Previous work from our group suggests that NT69L also has antipsychotic-like effects in dopaminergic and serotonergic rodent models. Taken together, these data suggest that NT69L in particular and NT receptor agonists in general, will be useful as broad-spectrum antipsychotic drugs.

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References

Berendse H, Galis-de Graaf Y, Groenewegen H . Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol. 1992; 316(3):314-47. DOI: 10.1002/cne.903160305. View

Sanz B, Exposito I, Mora F . Effects of neurotensin on the release of glutamic acid in the prefrontal cortex and striatum of the rat. Neuroreport. 1993; 4(10):1194-6. View

Boules M, Iversen I, Oliveros A, Shaw A, Williams K, Robinson J . The neurotensin receptor agonist NT69L suppresses sucrose-reinforced operant behavior in the rat. Brain Res. 2006; 1127(1):90-8. DOI: 10.1016/j.brainres.2006.10.025. View

CLEGHORN J, Franco S, Szechtman B, Kaplan R, Szechtman H, Brown G . Toward a brain map of auditory hallucinations. Am J Psychiatry. 1992; 149(8):1062-9. DOI: 10.1176/ajp.149.8.1062. View

Carraway R, Leeman S . The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem. 1973; 248(19):6854-61. View

Bowser M, Kennedy R . In vivo monitoring of amine neurotransmitters using microdialysis with on-line capillary electrophoresis. Electrophoresis. 2001; 22(17):3668-76. DOI: 10.1002/1522-2683(200109)22:17<3668::AID-ELPS3668>3.0.CO;2-M. View

Zavitsanou K, Ward P, Huang X . Selective alterations in ionotropic glutamate receptors in the anterior cingulate cortex in schizophrenia. Neuropsychopharmacology. 2002; 27(5):826-33. DOI: 10.1016/S0893-133X(02)00347-0. View

Boules M, Warrington L, Fauq A, McCormick D, Richelson E . A novel neurotensin analog blocks cocaine- and D-amphetamine-induced hyperactivity. Eur J Pharmacol. 2001; 426(1-2):73-6. DOI: 10.1016/s0014-2999(01)01197-9. View

Breslin N, Suddath R, Bissette G, Nemeroff C, Lowrimore P, Weinberger D . CSF concentrations of neurotensin in schizophrenia: an investigation of clinical and biochemical correlates. Schizophr Res. 1994; 12(1):35-41. DOI: 10.1016/0920-9964(94)90082-5. View

10.

Boules M, Fredrickson P, Richelson E . Bioactive analogs of neurotensin: focus on CNS effects. Peptides. 2006; 27(10):2523-33. DOI: 10.1016/j.peptides.2005.12.018. View

11.

Tamminga C, Lewitt P, Chase T . Cholecystokinin and neurotensin gradients in human CSF. Arch Neurol. 1985; 42(4):354-5. DOI: 10.1001/archneur.1985.04060040064013. View

12.

Petrie K, Schmidt D, Bubser M, Fadel J, Carraway R, Deutch A . Neurotensin activates GABAergic interneurons in the prefrontal cortex. J Neurosci. 2005; 25(7):1629-36. PMC: 6725935. DOI: 10.1523/JNEUROSCI.3579-04.2005. View

13.

Breier A, Buchanan R, Waltrip 2nd R, Listwak S, Holmes C, Goldstein D . The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy. Neuropsychopharmacology. 1994; 10(1):1-7. DOI: 10.1038/npp.1994.1. View

14.

Weinberger D . Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987; 44(7):660-9. DOI: 10.1001/archpsyc.1987.01800190080012. View

15.

Wang R, Boules M, Tiner W, Richelson E . Effects of repeated injections of the neurotensin analog NT69L on dopamine release and uptake in rat striatum in vitro. Brain Res. 2004; 1025(1-2):21-8. DOI: 10.1016/j.brainres.2004.07.069. View

16.

Lada M, Kennedy R . Quantitative in vivo monitoring of primary amines in rat caudate nucleus using microdialysis coupled by a flow-gated interface to capillary electrophoresis with laser-induced fluorescence detection. Anal Chem. 1996; 68(17):2790-7. DOI: 10.1021/ac960178x. View

17.

Wachi M, Okuda M, Togashi S, Fuwano S, Miyashita O . Effects of phencyclidine administration on behavior and brain neurotensin-like immunoreactivity in rats. Brain Res. 1985; 333(2):393-6. DOI: 10.1016/0006-8993(85)91601-4. View

18.

Hertel P, Mathe J, Nomikos G, Iurlo M, Mathe A, Svensson T . Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat. Behav Brain Res. 1995; 72(1-2):103-14. DOI: 10.1016/0166-4328(96)00138-6. View

19.

Smith A, Watson C, Frantz K, Eppler B, Kennedy R, Peris J . Differential increase in taurine levels by low-dose ethanol in the dorsal and ventral striatum revealed by microdialysis with on-line capillary electrophoresis. Alcohol Clin Exp Res. 2004; 28(7):1028-38. DOI: 10.1097/01.alc.0000131979.78003.34. View

20.

Prus A, Huang M, Li Z, Dai J, Meltzer H . The neurotensin analog NT69L enhances medial prefrontal cortical dopamine and acetylcholine efflux: potentiation of risperidone-, but not haloperidol-, induced dopamine efflux. Brain Res. 2007; 1184:354-64. DOI: 10.1016/j.brainres.2007.09.092. View