Targeting Diacylglycerol Lipase to Reduce Alcohol Consumption

ABSTRACTAlcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking, and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. Lastly, DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent a novel approach to reduce alcohol consumption across the spectrum of AUD severity.

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Timing in reward and decision processes

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0468 ◽

2014 ◽

Vol 369 (1637) ◽

pp. 20120468 ◽

Cited By ~ 28

Author(s):

Maria A. Bermudez ◽

Wolfram Schultz

Keyword(s):

Frontal Cortex ◽

Temporal Discounting ◽

Decision Processes ◽

Reward Processing ◽

Dopamine Neurons ◽

Error Signal ◽

Reward Delivery ◽

Midbrain Dopamine ◽

The Brain ◽

Timing Processes

Sensitivity to time, including the time of reward, guides the behaviour of all organisms. Recent research suggests that all major reward structures of the brain process the time of reward occurrence, including midbrain dopamine neurons, striatum, frontal cortex and amygdala. Neuronal reward responses in dopamine neurons, striatum and frontal cortex show temporal discounting of reward value. The prediction error signal of dopamine neurons includes the predicted time of rewards. Neurons in the striatum, frontal cortex and amygdala show responses to reward delivery and activities anticipating rewards that are sensitive to the predicted time of reward and the instantaneous reward probability. Together these data suggest that internal timing processes have several well characterized effects on neuronal reward processing.

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A striatal plasticity that supports the long-term preservation of motor function in Parkinsonian mice.

10.1101/2022.01.10.475638 ◽

2022 ◽

Author(s):

Joe C Brague ◽

Rebecca P Seal

Keyword(s):

Dopamine Neurons ◽

Neuron Activity ◽

Motor Deficits ◽

Projection Neurons ◽

Motor Symptoms ◽

Indirect Pathway ◽

Novel Approach ◽

Midbrain Dopamine ◽

Nigrostriatal Dopamine Neurons

Motor deficits of Parkinsons disease (PD) such as rigidity, bradykinesia and akinesia result from a progressive loss of nigrostriatal dopamine neurons. No therapies exist that slow their degeneration and the most effective treatments for the motor symptoms: L-dopa -the precursor to dopamine, and deep brain stimulation can produce dyskinesias and are highly invasive, respectively. Hence, alternative strategies targeted to slow the progression or delay the onset of motor symptoms are still highly sought. Here we report the identification of a long-term striatal plasticity mechanism that delays for several months, the onset of motor deficits in a mouse PD model. Specifically, we show that a one-week transient daily elevation of midbrain dopamine neuron activity during depletion preserves the connectivity of direct but not indirect pathway projection neurons. The findings are consistent with the balance theory of striatal output pathways and suggest a novel approach for treating the motor symptoms of PD.

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