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The Journal of Neuroscience, February 16, 2005, 25(7):1629-1636; doi:10.1523/JNEUROSCI.3579-04.2005

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Behavioral/Systems/Cognitive
Neurotensin Activates GABAergic Interneurons in the Prefrontal Cortex

Kimberly A. Petrie,¹ Dennis Schmidt,¹ Michael Bubser,¹ Jim Fadel,¹ Robert E. Carraway,² and Ariel Y. Deutch¹

¹Departments of Pharmacology and Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee 37212, and ²Department of Physiology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655

Converging data suggest a dysfunction of prefrontal cortical GABAergic interneurons in schizophrenia. Morphological and physiological studies indicate that cortical GABA cells are modulated by a variety of afferents. The peptide transmitter neurotensin may be one such modulator of interneurons. In the rat prefrontal cortex (PFC), neurotensin is exclusively localized to dopamine axons and has been suggested to be decreased in schizophrenia. However, the effects of neurotensin on cortical interneurons are poorly understood. We used in vivo microdialysis in freely moving rats to assess whether neurotensin regulates PFC GABAergic interneurons. Intra-PFC administration of neurotensin concentration-dependently increased extracellular GABA levels; this effect was impulse dependent, being blocked by treatment with tetrodotoxin. The ability of neurotensin to increase GABA levels in the PFC was also blocked by pretreatment with 2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-yl)carbonylamino]tricyclo(3.3.1.1.^3.7)decan-2-carboxylic acid (SR48692), a high-affinity neurotensin receptor 1 (NTR1) antagonist. This finding is consistent with our observation that NTR1 was localized to GABAergic interneurons in the PFC, particularly parvalbumin-containing interneurons. Because neurotensin is exclusively localized to dopamine axons in the PFC, we also determined whether neurotensin plays a role in the ability of dopamine agonists to increase extracellular GABA levels. We found that D₂ agonist-elicited increases in PFC GABA levels were blocked by pretreatment with SR48692, consistent with data indicating that D₂ autoreceptor agonists increase neurotensin release from dopamine-neurotensin axons in the PFC. These findings suggest that neurotensin plays an important role in regulating prefrontal cortical interneurons and that it may be useful to consider neurotensin agonists as an adjunct in the treatment of schizophrenia.

Key words: dopamine; GABA; interneuron; neurotensin; prefrontal cortex; schizophrenia

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Received Aug 31, 2004; revised December 10, 2004; accepted January 3, 2005.

This article has been cited by other articles:

				S. Li, J. D. Geiger, and S. Lei Neurotensin Enhances GABAergic Activity in Rat Hippocampus CA1 Region by Modulating L-Type Calcium Channels J Neurophysiol, May 1, 2008; 99(5): 2134 - 2143. [Abstract] [Full Text] [PDF]

				M. M. Torregrossa and P. W. Kalivas Neurotensin in the Ventral Pallidum Increases Extracellular {gamma}-Aminobutyric Acid and Differentially Affects Cue- and Cocaine-Primed Reinstatement J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 556 - 566. [Abstract] [Full Text] [PDF]

				K.-Y. Tseng and P. O'Donnell Dopamine Modulation of Prefrontal Cortical Interneurons Changes during Adolescence Cereb Cortex, May 1, 2007; 17(5): 1235 - 1240. [Abstract] [Full Text] [PDF]

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