Corticotropin releasing factor and dopamine interactions in a heterogeneous ventral tegmental area: How can aversive experiences heighten cocaine self-administration?.
Abstract: Stress rapidly and potently excites certain dopamine neurons in the
ventral tegmental area (VTA), promoting phasic dopamine increases in the medial prefrontal
cortex (mPFC) and nucleus accumbens shell (NAcSh). Repeated stressful episodes have been
linked to addiction both clinically and preclinically, so stress-induced activation of this
mesocorticolimbic dopamine system may trigger ... read morelong-term changes leading to later heightened
vulnerability to addiction. One possible mediator of this VTA dopamine activation is the
stress neuropeptide corticotropin releasing factor (CRF), but the interactions of CRF and
VTA dopamine neurons during stress have received only limited attention. This dissertation
explores interactions of CRF and dopamine neurons in the VTA during acute stress (Aim 1)
and repeated stress (Aim 2), as well as how these interactions can affect later
reward-related behaviors and neurochemistry (Aim 3). Specifically, this work demonstrates
that extracellular dopamine is increased in both the mPFC and NAcSh during acute social
defeat, which is paralleled by increased extracellular CRF within the posterior, but not
anterior VTA. Intra-VTA antagonism of CRF-R2, but not CRF-R1, prevents acute social defeat
stress-induced dopamine efflux in the NAcSh, but not mPFC. Repeated stress results in
increased tonic CRF within the VTA, and a shift to a phasic response in the anterior, but
not posterior, VTA during stress. Additionally, the non-habituated dopaminergic increases
in both the mPFC and NAcSh during repeated defeat are prevented with intra-VTA CRF-R2
antagonism. However, intra-VTA antagonism of both CRF-R1 and CRF-R2 prior to social defeat
prevents the induction of neural cross-sensitization to cocaine as well as escalated
cocaine self-administration during a 24 h "binge". Finally, this work shows that VTA CRF
and its receptors play a long-lasting role in cocaine seeking, such that increased
extracellular CRF tone within the VTA of previously stressed animals drives augmented
context-induced reinstatement to cocaine seeking after abstinence, an effect which can be
prevented with intra-VTA antagonism of both CRF-R1 and CRF-R2 prior to reinstatement
testing. Together, these data establish a fundamental role of CRF and its receptors in the
VTA in mediating dopaminergic function during stress, promoting long lasting neural
adaptations of mesocorticolimbic circuitry traditionally associated with
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Psychology.
Advisor: Klaus Miczek.
Committee: Joseph DeBold, Jamie Maguire, and Alexa Veenema.
Keyword: Psychology.read less