Effects of Corticotrophin Releasing Factor on Ventral Tegmental Area Neurons

A major hypothesis in the pathology of addiction is that maladaptive behaviors result from a disruption in the homeostatic balance between stress and reward circuitry. Several rodent models of stress (i.e. footshock, foot pinch, restraint stress, and social defeat stress) increase the activity of ventral tegmental area (VTA) neurons and result in an increase in dopamine in midbrain terminal regions. Corticotrophin releasing factor (CRF) is released in the VTA during stress and is reported to increase the firing rate of dopamine neurons, yet decrease dopamine release in the Nucleus Accumbens (NAc) (Wanat et al., 2008; Wanat et al., 2013; Wang et al., 2005). These results suggest that CRF differentially modulates discrete VTA circuits. However, the synaptic action of CRF on specific VTA circuits and its role in influencing behavior has yet to be characterized.We made ex vivo whole cell current clamp recordings to examine the synaptic actions of CRF. We measured responses to varying concentrations (100 nM to 1 mM) of CRF in both TH(+) and TH(-) neurons from throughout the VTA. To analyze circuit specific responses of CRF recordings were made in labeled neurons 7 days after the retrograde fluorescent marker DiI was injected into midbrain terminal regions including medial prefrontal cortex (mPFC), NAc, and amygdala. CRF consistently increased the firing rate of spontaneously active neurons. However, in quiescent neurons we observed both depolarizations and hyperpolarizations. Amygdala-projecting VTA neurons were consistently excited by CRF, whether firing spontaneously or quiescent. Given the importance of kappa opioids receptor (KOR) activation in the inhibition of dopaminergic neurons that project to the amygdala and PFC we also examined the possibility that CRF modulates KOR signaling in the VTA (Margolis et al., 2008). We used whole cell ex vivo electrophysiology and found that exposure to CRF can uncover a novel excitatory response to KOR activation in a subset of VTA neurons. These results provide insight into how stress may alter neuronal responses in VTA neuron populations