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

Compounds acting in the ventral tegmental area to increase motor activity a re thought to do so by activating mesolimbic dopamine transmission. The pre sent report demonstrates that the microinjection of N-methyl-D-aspartate (N MDA) antagonists into the ventral tegmental area produces a dose-dependent increase in motor activity. This effect was not mimicked by antagonizing ei ther alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate or m etabotropic glutamate receptors in the ventral tegmental area. Three experi ments were conducted that indicated that the capacity of NMDA receptor anta gonists to elevate motor activity did not involve increased dopamine transm ission. 1)The systemic administration of a D1 dopamine receptor antagonist did not inhibit the motor stimulant response to NMDA antagonist injection i nto the ventral tegmental area except at doses that also inhibited motor ac tivity after an injection of saline into the ventral tegmental area. 2) Sti mulating orphanin receptors in the ventral tegmental area selectively inhib its dopamine cells, and this did not alter NMDA antagonist-induced motor ac tivity. Whereas, stimulating gamma -aminobutyric acid (GABA)(B) receptors h yperpolarizes both dopamine and GABA cells in the ventral tegmental area, a nd this abolished NMDA antagonist-induced motor activity. 3) The microinjec tion 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 inv olvement, repeated administration of NMDA antagonist into the ventral tegme ntal area did not produce behavioral sensitization. These data identify a m echanism to elicit a motor stimulant response from the ventral tegmental ar ea that does not involve activating dopamine transmission.