Dopamine-independent locomotion following blockade of N-methyl-D-aspartate receptors in the ventral tegmental area

Jennifer L. Cornish, Mistu Nakamura, Peter W. Kalivas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Compounds acting in the ventral tegmental area to increase motor activity are thought to do so by activating mesolimbic dopamine transmission. The present report demonstrates that the microinjection of N-methyl-D-aspartate (NMDA) antagonists into the ventral tegmental area produces a dose-dependent increase in motor activity. This effect was not mimicked by antagonizing either α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid/kainate or metabotropic glutamate receptors in the ventral tegmental area. Three experiments were conducted that indicated that the capacity of NMDA receptor antagonists to elevate motor activity did not involve increased dopamine transmission. 1) The systemic administration of a D1 dopamine receptor antagonist did not inhibit the motor stimulant response to NMDA antagonist injection into the ventral tegmental area except at doses that also inhibited motor activity after an injection of saline into the ventral tegmental area. 2) Stimulating orphanin receptors in the ventral tegmental area selectively inhibits dopamine cells, and this did not alter NMDA antagonist-induced motor activity. Whereas, stimulating γ-aminobutyric acid (GABA)B receptors hyperpolarizes both dopamine and GABA cells in the ventral tegmental area, and this abolished NMDA antagonist-induced motor activity. 3) The microinjection of an NMDA antagonist into the ventral tegmental area did not increase dopamine metabolism in dopamine terminal fields, including the accumbens, striatum, or prefrontal cortex. Also consistent with a lack of dopamine involvement, repeated administration of NMDA antagonist into the ventral tegmental area did not produce behavioral sensitization. These data identify a mechanism to elicit a motor stimulant response from the ventral tegmental area that does not involve activating dopamine transmission.

Original languageEnglish
Pages (from-to)226-233
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume298
Issue number1
Publication statusPublished - 2001
Externally publishedYes

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