Dopamine signaling pathway that controls cocaine reward in mice identified

February 24, 2016
Illustration of the pathway by which dopamine may induce reward. Dopamine activates dopamine receptor 1 (DA1R), which initiates a biochemical chain of events leading to excitation. Credit: Nagoya University

Researchers have thus far been unable to define how dopamine influences cocaine reward. A recent report published in Neuron has shown that cocaine administration increases dopamine levels in the striatum, activating a signaling pathway that was previously unknown.

Dopamine activates a protein called PKA in , which activates many additional substrates to regulate neuronal excitability and control behavior. However, the identities of these PKA substrates are not known. Recently, a research team at Nagoya University has uncovered the answers.

"We stimulated PKA in mouse brain slices to activate these unknown substrates," explains corresponding author Kozo Kaibuchi of the University of Nagoya's Department of Cell Pharmacology. His research team was able to extract these activated proteins from brain slices and identify them. "Using this screening approach, we identified more than 100 candidate substrates of PKA," continues Kaibuchi.

One of these novel candidates was Rasgrp2, a protein that is highly expressed in striatal neurons. Rasgrp2 positively regulates another protein called Rap1 and the authors were intrigued to find out whether Rap1 was activated by Rasgrp2 in striatal neurons. Through a range of experiments, the Nagoya research group found the answer; they demonstrated that cocaine treatment increased the phosphorylation of Rasgrp2 by PKA, which in turn activated Rap1 in striatal neurons.

"We speculated that the Rap1 pathway is involved in the regulation of neuronal functions by dopamine," says lead author Taku Nagai at the university's Department of Neuropsychcopharmacology. By measuring neuronal activity directly in mouse brain slices, Nagai and colleagues discovered that activated Rap1 can increase the activity of in the striatum. In addition, the rewarding effects of cocaine were higher when Rap1 was activated in mouse brains.

"When increase due to cocaine administration, striatal become more excitable, resulting in enhanced responses to excitatory input from other brain regions," explains Nagai. "This increases the sensitivity of mice to reward."

Many of the 100 candidate PKA substrates identified were previously unknown as components of dopamine signaling. Therefore in the future, these findings will significantly contribute to our understanding of the different roles of in many brain functions.

Explore further: Researchers uncover how dopamine transports within the brain

More information: The article "Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo" was published in Neuron, at DOI: 10.1016/j.neoron2015.12.019

Related Stories

Researchers uncover how dopamine transports within the brain

January 25, 2016

Researchers at University of Florida Health have discovered the mechanics of how dopamine transports into and out of brain cells, a finding that could someday lead to more effective treatment of drug addictions and neurological ...

New insights on how cocaine changes the brain

November 25, 2015

The burst of energy and hyperactivity that comes with a cocaine high is a rather accurate reflection of what's going on in the brain of its users, finds a study published November 25 in Cell Reports. Through experiments conducted ...

Is dopamine to blame for our addictions?

December 3, 2015

Most researchers agree that the key difference between human brains and those of other animals is the size and complexity of our cerebral cortex, the brain's outer layer of neural tissue. We therefore tend to focus our attention ...

Morphine and cocaine affect reward sensation differently

October 5, 2012

(Medical Xpress)—A new study by scientists in the US has found that the opiate morphine and the stimulant cocaine act on the reward centers in the brain in different ways, contradicting previous theories that these types ...

Recommended for you

People match confidence levels to make decisions in groups

May 26, 2017

When trying to make a decision with another person, people tend to match their confidence levels, which can backfire if one person has more expertise than the other, finds a new study led by UCL and University of Oxford researchers.

Optic probes shed light on binge-eating

May 26, 2017

Activating neurons in an area of the brain not previously associated with feeding can produce binge-eating behavior in mice, a new Yale study finds.

Study finds gray matter density increases during adolescence

May 26, 2017

For years, the common narrative in human developmental neuroimaging has been that gray matter in the brain - the tissue found in regions of the brain responsible for muscle control, sensory perception such as seeing and hearing, ...

Game study not playing around with PTSD relief

May 26, 2017

Post-traumatic stress disorder (PTSD) patients wrestling with one of its main symptoms may find long-term relief beyond medication thanks to the work of a Western researcher.

Researchers identify brain network organization changes

May 25, 2017

As children age into adolescence and on into young adulthood, they show dramatic improvements in their ability to control impulses, stay organized, and make decisions. Those executive functions of the brain are key factors ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.