AsianScientist (Mar. 1, 2016) – Researchers in Japan have discovered how the pleasure chemical dopamine behaves in mouse brains that were fed cocaine. Their study, published in Neuron, shows that administration of the highly addictive drug increases dopamine levels in the striatum, or the brain’s reward system, activating a signaling pathway that was previously unknown.
In the future, these findings could contribute to our understanding of the different roles of dopamine in many brain functions.
Dopamine activates a protein called PKA in striatal neurons, which activates many additional substrates to regulate neuronal excitability and control behavior. Now, a research team at Nagoya University in Japan has uncovered the identities of these substrates.
“We stimulated PKA in mouse brain slices to activate these unknown substrates,” explained corresponding author Professor Kozo Kaibuchi of the university’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,” said Kaibuchi.
One of these substrates was Rasgrp2, a protein that is highly expressed in striatal neurons. Rasgrp2 positively regulates another protein called Rap1. The authors set out to discover whether Rap1 was activated by Rasgrp2 in striatal neurons.
Through a range of experiments, they found 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 Associate Professor Taku Nagai.
By measuring neuronal activity directly in the mouse brain slices, Nagai and colleagues discovered that activated Rap1 can increase the activity of dopaminergic neurons in the striatum. In addition, the rewarding effects of cocaine were higher when Rap1 was activated in mouse brains.
“When dopamine levels increase due to cocaine administration, striatal neurons become more excitable, resulting in enhanced responses to excitatory input from other brain regions,” explains Nagai. “This increases the sensitivity of mice to cocaine reward.”
The article can be found at: Nagai et al. (2016) Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo.
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Source: Nagoya University.
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