Biochemical and behavioral anxiolytic-like effects of R(+)HA-966 at the level of the ventral tegmental area in rats.

ABSTRACT

RATIONALE R(+) HA-966, a weak partial agonist at the glycine/NMDA receptor complex, has been shown to have anxiolytic-like actions on restraint stress-induced mesoprefrontal dopamine metabolism. OBJECTIVE: This study investigates the putative anxiolytic, R(+) HA-966, applied locally at the level of the mesocorticolimbic dopamine cell bodies in the ventral tegmental area (VTA), on the acquisition and expression of conditioned fear. METHODS: Ten to 14 days after cannula implantation, rats were subjected to the acquisition session (10x5 s tone paired with 0.5 s, 0.8 mA footshock) followed about 24 h later by the expression session (ten tones only) of a conditioned fear protocol. Rats were treated with R(+) HA-966 (15 microg/VTA) or saline before either the acquisition or expression sessions. Other rats were injected with saline or R(+) HA-966 (10 microg/side), intra-medial prefrontal cortex, on the expression day. RESULTS: R(+)HA-966, intra-VTA, prevented stress-induced changes in mesoprefrontal, but not mesoaccumbal, dopamine metabolism and was associated with a reduction in fearful responses to physical (footshock) and psychological (conditioned fear) stressors. Additionally, rats treated with R(+)HA-966 intra-VTA before the acquisition session were less fearful at the beginning of the expression session. Local injection of R(+)HA-966 into medial prefrontal cortex did not have anxiolytic-like behavioral or biochemical actions but diminished the expression of exploratory behavior in non-stress, control rats. CONCLUSIONS: These studies indicate that the stress-induced activation of the mesoprefrontal dopamine neurons is necessary for the normal expression of fearful behaviors.