The reinforcing effects of intra-cranial self-stimulation (ICS), like those of natural rewards and abused drugs, involve the dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) (Wise, 1996). We previously examined the activity of neurons in the core of the NAc simultaneously with subsecond dopamine release from the same electrode in animals engaged in an ICS task (Cheer et al., 2005). The only neuronal responses observed were time-locked to the electrical stimulation but preferentially mediated by GABA. However, our most recent findings in the NAc shell show coincident changes in firing and subsecond dopamine release occurring at cues signaling reward availability that are functionally linked via D1 receptor activation during ICS (Cheer et al., 2007b, Appendix A). Accumulating evidence suggests that endogenous cannabinoids regulate reward processing in the brain, including ICS, by modulating neurotransmitter levels including GABA and dopamine (Gardner, 2005). Given these findings, we propose three experiments to investigate the mechanisms through which the shell of the NAc encodes reward-related information during ICS. The first experiment will examine the effects of manipulating endogenous cannabinoid signaling on patterned cell firing and subsecond dopamine release in the shell during learning of ICS. Specifically, a cannabinoid receptor antagonist or an endogenous cannabinoid reuptake blocker (Pertwee, 2005) will be injected systemically prior to the start of the first operant session to determine the role of endogenous cannabinoid tone in ICS acquisition, and its impact on the generation of patterned activity and phasic dopamine release. The second experiment will evaluate reinforcement-specific cell firing and subsecond dopamine release in the shell during maintenance of ICS in well-trained animals. For this experiment the cannabinoid receptor antagonist and the endogenous cannabinoid uptake blocker will be delivered during the ICS session to assess whether behavioral execution of ICS and associated neurophysiological and neurochemical responses are controlled by endogenous cannabinoids. The third experiment will assess, with the aid of intracerebral microinjections, whether endogenous cannabinoid signaling specifically in the VTA, modifies ICS execution and associated neural and dopamine release patterns in the NAc. Altogether, these experiments should provide an unprecedented insight into accumbal encoding of reward and its physiological modulation by endogenous cannabinoids.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Sorensen, Roger
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University of Maryland Baltimore
Anatomy/Cell Biology
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Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R et al. (2016) Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids. Eur J Neurosci 43:1661-73
Covey, Dan P; Dantrassy, Hannah M; Zlebnik, Natalie E et al. (2016) Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease. J Neurosci 36:4993-5002
Zlebnik, Natalie E; Cheer, Joseph F (2016) Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions. J Neurosci 36:10230-10238
Zlebnik, Natalie E; Cheer, Joseph F (2016) Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation? Annu Rev Neurosci 39:1-17
Covey, Dan P; Wenzel, Jennifer M; Cheer, Joseph F (2015) Cannabinoid modulation of drug reward and the implications of marijuana legalization. Brain Res 1628:233-43
Wenzel, Jennifer M; Rauscher, Noah A; Cheer, Joseph F et al. (2015) A role for phasic dopamine release within the nucleus accumbens in encoding aversion: a review of the neurochemical literature. ACS Chem Neurosci 6:16-26
Wang, Huikun; Treadway, Tyler; Covey, Daniel P et al. (2015) Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area. Cell Rep 12:1997-2008
Bagot, Rosemary C; Parise, Eric M; Peña, Catherine J et al. (2015) Corrigendum: Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun 6:7626
Hernandez, Giovanni; Cheer, Joseph F (2015) To Act or Not to Act: Endocannabinoid/Dopamine Interactions in Decision-Making. Front Behav Neurosci 9:336
Hernandez, Giovanni; Oleson, Erik B; Gentry, Ronny N et al. (2014) Endocannabinoids promote cocaine-induced impulsivity and its rapid dopaminergic correlates. Biol Psychiatry 75:487-98

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