Summary: A new study reveals insight into the mechanisms underlying alcohol addiction.
The human brain functions on a delicate balance of reinforcing positive behaviors and suppressing negative ones, which takes place in the dorsal striatum, a brain region critical for goal-directed behavior and implicated in drug and alcohol addiction.
According to a new study in Biological Psychiatry, two pathways in the dorsal striatum that regulate this process — the “Go” pathway, which hits the gas for rewarding behaviors, and the “No-Go” pathway, which hits the brakes — have opposite effects to control alcohol drinking behavior. Led by Dr. Jun Wang of Texas A&M Health Science Center, the study reports that alcohol-induced alterations in the signaling of these two pathways reinforce alcohol consumption, possibly leading to alcohol abuse or addiction.
Co-first authors Dr. Yifeng Cheng, Dr. Cathy Huang, and Dr. Tengfei Ma and colleagues trained mice to become heavy drinkers by repeated cycles of consumption and withdrawal of 20% alcohol — slightly higher than the average alcohol content in a glass of wine — and measured the effects on the balance of this delicate control of reward behavior.
“To the best of our knowledge, this article demonstrated, for the first time, that excessive alcohol consumption suppresses activity of the No-Go pathway,” said Wang. By recording the activity of cells, the researchers found substantially increased GABA signaling, the primary inhibitory neurotransmitter of the brain, which quieted the No-Go pathway. Excessive alcohol consumption had the opposite effect in the Go pathway. These cells had increased glutamate signaling, the primary excitatory neurotransmitter in the brain, ramping up the Go signal.
The findings reveal detailed information on the mechanisms underlying control of alcohol consumption. “Both of these effects serve to reinforce alcohol consumption, leading to pathological excessive use of alcohol,” wrote the authors.
Through manipulation of cells specific to each pathway to mimic either increased glutamatergic or GABAergic activity, Cheng and colleagues confirmed that inhibition of cells in the No-Go pathway and excitation of cells in the Go pathway promotes alcohol consumption. The findings indicate that either of these alterations is sufficient to drive alcohol drinking behavior.
The researchers dug deeper into the mechanism and found that activation of dopamine D2 receptors, the type that mediate the No-Go pathway, also reduced GABAergic activity and alcohol consumption. The regulation in GABAergic activity was mediated by a downstream target of D2 receptors called GSK3β, which altered the expression of GABA receptors in the cells.
“These findings identified potential therapeutic targets,” said Wang, referring to GSK3β and GABA signaling in the No-Go pathway, which the researchers hope will aid development of new ways to treat alcohol abuse.
The study may have even broader implications, according to Dr. John Krystal, Editor of Biological Psychiatry. “The balance between signaling in the [Go] and [No-Go] pathways is likely to be a critical factor influencing motivated behavior, generally. This balance might be targeted to treat alcoholism, but also other addictions, mood disorders, and perhaps OCD,” he said.
About this neuroscience research article
Source: Rhiannon Bugno – Elsevier Image Source: NeuroscienceNews.com image is in the public domain. Original Research:Abstract for “Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption” by Yifeng Cheng, Cathy C.Y. Huang, Tengfei Ma, Xiaoyan Wei, Xuehua Wang, Jiayi Lu, and Jun Wang in Biological Psychiatry. Published online May 24 2017 doi:10.1016/j.biopsych.2016.05.016
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[cbtabs][cbtab title=”MLA”]Elsevier “Resetting Balance in Reward Center May Help Treat Alcohol Addiction.” NeuroscienceNews. NeuroscienceNews, 25 May 2017. <https://neurosciencenews.com/addiction-reward-center-6769/>.[/cbtab][cbtab title=”APA”]Elsevier (2017, May 25). Resetting Balance in Reward Center May Help Treat Alcohol Addiction. NeuroscienceNew. Retrieved May 25, 2017 from https://neurosciencenews.com/addiction-reward-center-6769/[/cbtab][cbtab title=”Chicago”]Elsevier “Resetting Balance in Reward Center May Help Treat Alcohol Addiction.” https://neurosciencenews.com/addiction-reward-center-6769/ (accessed May 25, 2017).[/cbtab][/cbtabs]
Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption
Background Repeated exposure to addictive drugs or alcohol triggers glutamatergic and gamma-aminobutyric acidergic (GABAergic) plasticity in many neuronal populations. The dorsomedial striatum (DMS), a brain region critically involved in addiction, contains medium spiny neurons (MSNs) expressing dopamine D1 or D2 receptors, which form direct and indirect pathways, respectively. It is unclear how alcohol-evoked plasticity in the DMS contributes to alcohol consumption in a cell type–specific manner.
Methods Mice were trained to consume alcohol using an intermittent-access two-bottle-choice drinking procedure. Slice electrophysiology was used to measure glutamatergic and GABAergic strength in DMS D1- and D2-MSNs of alcohol-drinking mice and control mice. In vivo chemogenetic and pharmacologic approaches were employed to manipulate MSN activity, and their consequences on alcohol consumption were measured.
Results Repeated cycles of alcohol consumption and withdrawal in mice strengthened glutamatergic transmission in D1-MSNs and GABAergic transmission in D2-MSNs. In vivo chemogenetic excitation of D1-MSNs, mimicking glutamatergic strengthening, promoted alcohol consumption; the same effect was induced by D2-MSN inhibition, mimicking GABAergic strengthening. Importantly, suppression of GABAergic transmission via D2 receptor–glycogen synthase kinase–3β signaling dramatically reduced excessive alcohol consumption, as did selective inhibition of D1-MSNs or excitation of D2-MSNs.
Conclusions Our results suggest that repeated cycles of excessive alcohol intake and withdrawal potentiate glutamatergic strength exclusively in D1-MSNs and GABAergic strength specifically in D2-MSNs of the DMS, which concurrently contribute to alcohol consumption. These results provide insight into the synaptic and cell type–specific mechanisms underlying alcohol addiction and identify targets for the development of new therapeutic approaches to alcohol abuse.
“Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption” by Yifeng Cheng, Cathy C.Y. Huang, Tengfei Ma, Xiaoyan Wei, Xuehua Wang, Jiayi Lu, and Jun Wang in Biological Psychiatry. Published online May 24 2017 doi:10.1016/j.biopsych.2016.05.016