Increased mesocorticolimbic dopamine during acute and repeated social defeat stress: modulation by corticotropin releasing factor receptors in the ventral tegmental area

Elizabeth N. Holly, Joseph F. DeBold, Klaus A. Miczek

Stress activates a subset of dopamine neurons in the ventral tegmental area (VTA), increasing extracellular dopamine in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcSh). The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1 and CRF-R2) are located within the VTA and directly and indirectly influence dopaminergic activity. However, it has yet to be shown in vivo whether VTA CRF receptor activation is necessary for acute and repeated stress-induced dopamine efflux. With intra-VTA CRF-R1 and CRF-R2 antagonism during social defeat, we assessed whether blockade of these receptors could prevent stress-induced dopamine increases in the mPFC and NAcSh using in vivo microdialysis. Rats were microinjected with a CRF-R1 or CRF-R2 antagonist into the VTA prior to social defeat stress on days 1, 4, 7, and 10. In vivo microdialysis for dopamine in the mPFC and NAcSh was performed during stress on days 1 and 10. During the first social defeat, extracellular dopamine was significantly elevated in both the mPFC and NAcSh, and this increase in the NAcSh was blocked by intra-VTA CRF-R2, but not CRF-R1, antagonism. During the final social defeat, the dopaminergic increase was neither sensitized nor habituated in the mPFC and NAcSh, and intra-VTA CRF-R2, but not CRF-R1, antagonism prevented the dopamine increase in both brain regions. These findings show that CRF-R2 in the VTA is necessary for acute and repeated stress-induced dopamine efflux in the NAcSh, but is only recruited into mPFC-projecting dopamine neurons with repeated stress exposure.