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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA022340-04
Application #
7765484
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2008-03-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$259,875
Indirect Cost
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Covey, Dan P; Mateo, Yolanda; Sulzer, David et al. (2017) Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology 124:52-61
Patel, Sachin; Hill, Mathew N; Cheer, Joseph F et al. (2017) The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav Rev 76:56-66
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; Zlebnik, Natalie E; Cheer, Joseph F (2016) Endocannabinoid Regulation of Cocaine Reinforcement: an Upper or Downer? Neuropsychopharmacology 41:2189-91
Can, Adem; Frost, Douglas O; Cachope, Roger et al. (2016) Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens. J Neurochem 139:576-585
Can, Adem; Zanos, Panos; Moaddel, Ruin et al. (2016) Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters. J Pharmacol Exp Ther 359:159-70
Cockerham, Renee; Liu, Shaolin; Cachope, Roger et al. (2016) Subsecond Regulation of Synaptically Released Dopamine by COMT in the Olfactory Bulb. J Neurosci 36:7779-85
Zlebnik, Natalie E; Cheer, Joseph F (2016) Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions. J Neurosci 36:10230-10238
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
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

Showing the most recent 10 out of 35 publications