br Conclusion These studies broadly demonstrate that

Conclusion These studies broadly demonstrate that dopamine and endocannabinoid signaling in the NAc can have diverse effects on AMPAR-mediated synaptic function depending on previous psychostimulant experience. Here, we examined mechanisms underlying the depotentiation of AMPAR-mediated synaptic transmission in the NAc shell evoked by cocaine re-exposure, finding that plasticity is rapidly induced and persists for up several days before returning to “repotentiated” levels, suggesting that synapses altered by cocaine exposure remain plastic and are capable of undergoing further modifications by re-exposure to cocaine. Both dopamine and eCBs, critical modulators of synaptic plasticity in the NAc, contribute to AMPAR synaptic depotentiation, indicating that cocaine re-exposure engages multiple signaling pathways in the NAc that cooperate in modifying excitatory synaptic strength. Alterations in glutamatergic synaptic transmission induced by experience with cocaine may therefore profoundly alter the responsiveness of MSNs to future stimulation by dopamine, modifying dopamine's capacity to effectively gate activity and plasticity at glutamatergic synapses. Additionally, changes in dopamine receptor isethionate sale and signaling during abstinence or extinction (Anderson and Pierce, 2005) may modify how dopamine and glutamate receptor signaling mechanisms converge and interact at an intracellular level. Endocannabinoid signaling may additionally modulate MSN responsiveness to alterations in glutamatergic signaling induced by cocaine experience. Further studies will be needed to determine the cellular signaling factors mediating the complex effects of these critical neuromodulators on cocaine-induced AMPAR plasticity.
Funding sources This work was supported by the National Institute on Drug Abuse to MJT (R01DA019666, K02 DA035459) and AEI (T32 DA007234), the University of Minnesota Doctoral Dissertation Fellowship to AEI, University of Minnesota MnDRIVE Fellowship to MCH, and the Breyer-Longden Family Research Fund.
Acknowledgments
Introduction The rise in global obesity has prompted a closer examination of the psychological and neurobiological processes that influence over-eating and enhanced motivation to consume palatable foods. Studies in humans support the idea that cravings triggered by stimuli associated with food (i.e., food cues) may contribute to food-seeking and over-eating leading to obesity (Burger and Stice, 2014; Stoeckel et al., 2008 see Stice et al., 2013 for review). For example, food cues induce feelings of hunger, bias food choice, and increase the amount of food consumed (Fedoroff et al., 1997, Jansen et al., 2008, Watson et al., 2014). These cues include sensory properties of food itself, like the crunching sensation of digging your hand into a bag of potato chips, as well as distal cues like packaging, and branding logos (Bouton, 2011). The ability for food cues to trigger cravings is not unique to obese populations, but rather individuals that struggle to maintain a healthy weight are more sensitive to these motivational properties of food cues (Fedoroff et al., 1997, Ferriday and Brunstrom, 2011, Jansen et al., 2008, Lehner et al., 2017; see Small, 2009 for review). This suggests that brain regions mediating incentive motivation, such as the NAc (Berridge et al., 2009, Berridge et al., 2010, Cartoni et al., 2016, Holmes et al., 2010), differ functionally between obesity-susceptible vs. -resistant populations, thereby contributing to overconsumption in susceptible individuals (Burger and Stice, 2014, Stoeckel et al., 2008, Tomasi and Volkow, 2013). This has prompted vibrant discussion about the degree to which these neurobehavioral differences seen in susceptible individuals are similar vs. different to those driving drug-seeking in addiction (Berridge et al., 2010, Ferrario, 2017, Long et al., 2015, Michaud et al., 2017, Stice et al., 2013, Volkow et al., 2013).