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Joseph Cheer"Endogenous cannabinoids and the pursuit of reward"

Abstract :

Dopamine has emerged as a major neurotransmitter for controlling pleasure, impulses, and craving¬all processes that, while important for survival of an animal, can be subverted in pathological ways, including drug abuse. Thus, perturbations in dopamine release can lead to drug abuse behaviors. Like many drugs of abuse, THC (the main psychoactive component of marijuana) and other cannabinoids stimulate dopamine release, thought to be important in positively reinforcing the continued use of drugs. In addition, and unexpectedly, endogenous cannabinoids appear to be crucial in facilitating the release of dopamine by other abused drugs. Thus, blocking the effects of endogenous cannabinoids might be beneficial in treating drug abuse. My contribution to these lines of work has been broad and significant.

The nervous system operates on the millisecond time scale, but previous analytical techniques have only allowed for measurement of dopamine released over the course of minutes. This meant that the most important details of dopamine release were invisible to scientists. We have refined the measurement of dopamine in the context of cannabinoid administration, allowing its measurement on the time scale of milliseconds. This technical advance allowed us to make key discoveries showing that cannabinoids rapidly increase dopamine release in the brain areas involved in addictive processes. Furthermore, we showed that other commonly abused drugs rapidly increase dopamine only if endogenous cannabinoids can interact with their receptors. This provided "proof of principle" that blocking these receptors may be of broad therapeutic benefit in treating a number of addictive processes, both chemical (e.g., cocaine, alcohol, nicotine, methamphetamine) as well as behavioral (e.g., compulsive gambling, overeating).

We also designed a unique sensor that allows for the simultaneous measurement of subsecond dopamine release and electrophysiology (to measure the function of individual neurons). This approach has further advanced our understanding of the role of dopamine and endogenous cannabinoids in addictive processes as it allows the linking of specific neuronal activity to dopamine release. We have successfully combined this combined approach with the addition of iontophoresis to be enable a spatially resolved characterization of accumbal encoding of reward. We are currently exploring the use of transgenic mice, to take advantage of recently described in vivo optogenetic techniques to further delineate the impact of endogenous cannabinoid signaling on specific subsets of synapses to examine their role in reward-directed behaviors. These complementary techniques allow our research group to investigate the specific neural circuitry that mediates reward learning and decision-making and how signaling at cannabinoid receptors underlies these processes normally and in disease.

Selected publications

Morra JT, Glick SD, Cheer JF. (2010) Neural encoding of psychomotor activation in the nucleus accumbens core, but not the shell, requires cannabinoid receptor signaling. Journal of Neuroscience 30: 5102-5107

Cheer JF; Heien MLAV; Ariansen JL; Aragona BJ, Carelli RM and Wightman RM. (2007) Coordinated accumbal dopamine release and neural activity drive goal-directed behavior. Neuron 54: 237-244

Cheer JF; Wassum KM; Sombers LA; Heien MLAV; Ariansen JL; Aragona BJ; Phillips PEM and Wightman RM (2007) Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation. Journal of Neuroscience 27: 791-795

Cheer JF; Heien MLAV; Garris PA; Carelli RM and Wightman RM (2005) Simultaneous dopamine and single-unit recordings reveal accumbens GABAergic responses: implications for intracranial self-stimulation. Proceedings of the National Academy of Sciences of the United States of America 102: 19150-19155

Scientific focus :

Research in my lab is aimed at understanding the pysiological function of the endogenous cannabinoid system with a particular emphasis on normal motivated behaviors as well as its potential therapeutic role in pathological states such as addiction. 

Martine Cador