Maladaptive forms of reward seeking that support drug abuse and obesity exact an enormous toll on individual and economic health. A mounting body of preclinical and clinical work demonstrates that the endocannabinoid system powerfully regulates the motivational impact of rewards. While pharmacotherapies targeting endocannabinoid function to treat disordered reward seeking are efficacious, this approach has been hindered due to non-specific drug actions and unacceptable side effects. Here, I aim to identify mechanisms by which endocannabinoids regulate reward seeking through interactions with dopamine system function to identify precise neuronal targets for future cannabinoid-based therapies. I will test the hypothesis that synthesis of the endocannabinoid 2-arachidonoylglycerol by dopamine neurons is required for dopamine neurons to encode the incentive value of reward-predicting cues and motivate reward seeking. This work will employ two cutting-edge techniques, fast-scan cyclic voltammetry and optogenetics, paired with conditional and inducible mutagenesis to selectively target the enzyme responsible for 2-arachidonoylglycerol synthesis within dopamine neurons. Our ability to target dopamine neuron function in real-time during behavior and manipulate specific elements of the endocannabinoid system will provide novel information concerning how endocannabinoid signaling motivates reward seeking, potentially enabling the development of more targeted pharmacotherapies.
In the United States, nearly 35% (78.6 million) of the population is clinically obese and 8.2% (21.6 million) suffer from drug abuse, exacting an annual economic cost of $147 billion and $700 billion, respectively. Extensive clinical and preclinical work demonstrates that endocannabinoid signaling powerfully regulates the motivational impact of rewards, but the utility of endocannabinoid-targeted treatments for disorders such as obesity or drug abuse has been hindered due to non-specific drug actions and unacceptable side effects. The current proposal will provide evidence for guiding novel treatments by investigating precisely how endocannabinoids influence reward seeking through interactions with dopamine neurons.
|Covey, Dan P; Dantrassy, Hannah M; Yohn, Samantha E et al. (2018) Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington's disease. Neuropsychopharmacology 43:2056-2063|
|Mateo, Yolanda; Johnson, Kari A; Covey, Dan P et al. (2017) Endocannabinoid Actions on Cortical Terminals Orchestrate Local Modulation of Dopamine Release in the Nucleus Accumbens. Neuron 96:1112-1126.e5|
|Covey, Dan P; Mateo, Yolanda; Sulzer, David et al. (2017) Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology 124:52-61|