Endocannabinoid Actions on Prefrontal Cortical Presynaptic Terminals Modulate Dopamine Release and Reward-Driven Behavior via Actions in the Nucleus Accumbens Previous work in our group showed that dopamine release in the Nucleus Accumbens (NAc) can be elicited by activation of cholinergic striatal interneurons (ChIs). Activation of nicotinic acetylcholine (ACh)receptors drives this release. We subsequently observed that activation of CB1-type endocannabinoid receptors inhibits this ACh-driven release. This effect can be mimicked by increasing tissue levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG). Furthermore, during short bursts of stimulation of ACh release, 2-AG activation of CB1 receptors limits DA release. However, CB1 receptors are not expressed by either dopaminergic neurons of ChIs. Thus, the CB1 action must be altering a different neuronal subtype. Using a combination of pharmacological and neuronal specific CB1 gene knockout techniques, we found that the CB1 receptors on the axon terminals of glutamatergic afferents from prefrontal cortex (PFC) to NAc mediate the eCB actions that suppress DA release. This helps to explain why the actions of the CB1 agonists occlude and are occluded by agonists of ionotropic glutamate receptors. The neurotransmitter GABA did not appear to have a role in this modulatory action. We also observed that optogenetic stimulation of PFC afferents increased NAc DA release, and release elicited in this way is also inhibited by CB1 activation. The NAc has prominent roles in brain mechanisms related to and driven by reward. To determine if the CB1 receptors on PFC glutamatergic afferents to NAc are involved in reward-driven behavior we examined intracranial self-stimulation (ICSS) driven by stimulation of PFC-NAc afferents. In this behavioral paradigm, mice press a lever to receive optogenetic stimulation of the PFC afferents to NAc. This optical ICSS was inhibited by blockers of dopamine and nicotinic ACh receptors, indicating that these two NAc neurotransmitters participate in driving this behavior. The optical ICSS was also reduced by elevation of endocannabinoids in a CB1-dependent manner. In mice in which CB1 receptors were genetically deleted from PFC afferents, this ICSS was increased. These findings indicate that the CB1 modulation of PFC activity limits reward-driven behavior, via mechanisms that appear to involve interactions with cholinergic and dopaminergic transmission.

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13
Fiscal Year
2018
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Alcohol Abuse and Alcoholism
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Shonesy, Brian C; Parrish, Walker P; Haddad, Hala K et al. (2018) Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Biol Psychiatry 84:304-315
Augustin, Shana M; Lovinger, David M (2018) Functional Relevance of Endocannabinoid-Dependent Synaptic Plasticity in the Central Nervous System. ACS Chem Neurosci 9:2146-2161
Lovinger, David M (2017) Presynaptic Ethanol Actions: Potential Roles in Ethanol Seeking. Handb Exp Pharmacol :
Lovinger, David M; Alvarez, Veronica A (2017) Alcohol and basal ganglia circuitry: Animal models. Neuropharmacology 122:46-55
Abrahao, Karina P; Salinas, Armando G; Lovinger, David M (2017) Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits. Neuron 96:1223-1238
Kupferschmidt, David A; Juczewski, Konrad; Cui, Guohong et al. (2017) Parallel, but Dissociable, Processing in Discrete Corticostriatal Inputs Encodes Skill Learning. Neuron 96:476-489.e5
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
Gremel, C M; Lovinger, D M (2017) Associative and sensorimotor cortico-basal ganglia circuit roles in effects of abused drugs. Genes Brain Behav 16:71-85
Lovinger, David M (2017) An indirect route to repetitive actions. J Clin Invest 127:1618-1621

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