ALTERATIONS IN LOCOMOTOR-ACTIVITY AFTER MICROINJECTIONS OF GBR-12909,SELECTIVE DOPAMINE ANTAGONISTS OR NEUROTENSIN INTO THE MEDIAL PREFRONTAL CORTEX

It has been postulated that increased dopamine (DA) activity in the me dial prefrontal cortex (mPFC) exerts an inhibitory influence over DA r elease in the nucleus accumbens and, thus, also over locomotor activit y. Experiments were designed to examine the role of mPFC DA and neurot ensin (NT), a neuropeptide which interacts with DA, in spontaneous loc omotor activity. LS/IBG mice were injected bilaterally with either GBR -12909, a selective DA uptake blocker, the DA D1 receptor antagonist R -(+)-SCH-23390, the DA D2 receptor antagonist epidepride, NT or a comb ination of drugs. GBR-12909 produced a U-shaped dose-response curve wi th a maximum inhibition of 47% of control. Postmortem tissue levels of DA, 5-hydroxytryptamine, norepinephrine and their major metabolites w ere determined after microinjections of GBR-12909. Tissue levels of th ese compounds were not significantly affected by GBR-12909. However, t he ratios of homovanilic acid/DA and homovanilic acid + 3,4-dihyroxyph enylacetic acid/DA were significantly decreased, whereas the 5-hydroxy indoleacetic acid/5-hydroxytryptamine ratio was not affected by GBR-12 909, suggesting a selective effect on DAergic processes. By itself, R- (+)-SCH-23390 had no effect on locomotor activity except at a very hig h dose which caused locomotor inhibition (49% of control). Epidepride caused a dose-dependent inhibition of locomotor activity with a maximu m inhibition of 49% of control. When coinjected with an inhibitory dos e of GBR-12909, both epidepride and R-(+)-SCH-23390 attenuated the GBR -12909 effect in a dose-dependent manner. A broad range of doses of NT was found to have no consistent effect on locomotor activity, However , when coinjected with an inhibitory dose of GBR-12909, NT attenuated the GBR-12909-induced inhibition in a dose-dependent manner. The resul ts suggest that stimulation of DA receptors in the mPFC, both DA D1 an d DA D2 receptors mediates locomotor inhibition. Furthermore, stimulat ion of NT receptors appears to antagonize the effects of DA.