Optogenetically modulating ventral tegmental area dopamine neuron activity alters dopamine transporter sensitivity to cocaine

Abstract ID 100184 Poster Board 312 Accumulating evidence suggests that greater dopamine transporter (DAT) sensitivity to cocaine is associated with escalation of cocaine taking and exaggerated motivation for cocaine. Across several experiments, we have shown that pharmacological manipulations known to alter ventral tegmental area (VTA) dopamine neuron activity result in rapid changes in DAT sensitivity to cocaine in the nucleus accumbens, suggesting that dopamine cell body activity can regulate DAT function at distal sites. Consistent with this hypothesis, we recently demonstrated that chemogenetic activation and inhibition of VTA dopamine neurons leads to increased and decreased DAT sensitivity to cocaine respectively, further suggesting the likelihood that dopamine neuron activity influences DAT function. Despite this evidence, all of our previous studies employed G-protein coupled receptor (GPCR) manipulations and thus, it is unclear whether changes in DAT function are mediated through alterations in DA neuron activity or GPCR signaling cascades. To initially address this issue, we used optogenetics to activate VTA dopamine neurons in vivo and measured resulting changes in dopamine transmission in brain slices containing the nucleus accumbens core using fast scan cyclic voltammetry. Tyrosine hydroxylase-Cre rats received bilateral injections of channelrhodopsin in the VTA, and three weeks later, received optostimulation of VTA dopamine neurons. We then measured dopamine release and uptake at baseline, as well as DAT sensitivity to cocaine. We found that activation of VTA dopamine neurons did not affect baseline release or uptake. However, we did observe that activation of dopamine neurons increased DAT sensitivity to cocaine, similar to what we observed with chemogenetic manipulations. Ongoing studies are investigating whether optoinhibition of VTA dopamine neurons decreases DAT sensitivity to cocaine. Although the mechanisms through which dopamine neuron activity alters DAT function remain unclear, our results suggest that changes in DAT sensitivity to cocaine are not dependent on GPCR signaling cascades. Consequently, these findings further support the tenet that simply manipulating the activity of VTA dopamine neurons is sufficient to alter DAT function, which we propose will impact motivated behavior. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. 2041772. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.