Corticotropin-releasing Factor Regulates Somatodendritic Dopamine Release By Inhibiting Voltage-dependent Ca2+ Channels

Abstract

Corticotrophin-releasing factor (CRF) is the main regulator of the body's stress axis. Even though it is known that CRF plays a key role in the modulation of drug addiction by acting on dopamine (DA) neurons, the mechanism of CRF action on these neurons is not clear yet. In a previous study, we showed that the application of CRF-related peptide, urocortin, reversibly inhibits T-type Ca2+ channels via the activation of CRF-R1 from MN9D cells, a model for DA neurons (Kim et al., 20007). Here, we tested the effect of CRF on DA neurons isolated from rat substantia nigra. Urocortin (100 nM) acutely inhibited not only low-threshold T-type Ca2+ current, but also high-threshold Ca2+ current by 50.0+4.7% via the activation of CRF-R1, similar to MN9D cells. Since Ca2+ influx through voltage-activated Ca2+ channels (VOCC) plays a pivotal role as the final signal for rapid stimulus-evoked release of neurotransmitters and hormones, we tested the effect of CRF on DA release. We found that DA neurons spontaneously released DA in resting condition. Removing extracellular Ca2+, and the application of blockers for VOCC inhibited the frequency of secretion events. Activation of VOCC by stimulation with high-K+ containing saline increased the frequency, which were sensitive to blockers for L-, and T-type Ca2+ channels. The application of urocortin reversibly inhibited the frequency of DA release by about 40%, while the presence of VOCC blockers prevented further inhibition by urocortin. The presence of antagonist for CRF-R or specific antagonist for CRF-R1 prevented the inhibitory effects of urocortin on DA release. These results indicate that the activation of CRF-R1 induces the decrease of cytoplasmic Ca2+ via the inhibition of VOCC, which causes the inhibition of somatodendritic DA release from isolated substantia nigra DA neurons.