Neurotensin activates GABAergic interneurons in the prefrontal cortex.
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 [EC] .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.
Petrie
Kimberly A
KA
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37212, USA.
Schmidt
Dennis
D
Bubser
Michael
M
Fadel
Jim
J
Carraway
Robert E
RE
Deutch
Ariel Y
AY
D000818:Animals; D001369:Axons / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D008297:Male; D017551:Microdialysis; D009496:Neurotensin / Q000378:metabolism / Q000494:pharmacology*; D010320:Parvalbumins / Q000032:analysis; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000502:physiology*
D018491:Dopamine Agonists; D010320:Parvalbumins; D011720:Pyrazoles; D011804:Quinolines; D017448:Receptors, Dopamine D2; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; C079087:SR 48692; D019257:Quinpirole; D009496:Neurotensin; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D004298:Dopamine
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