Findings may help explain why drugs for addiction, depression are not always effective.
New research may help explain why drug treatments for addiction and depression don’t work for some patients.
The conditions are linked to reward and aversion responses in the brain. Working in mice, researchers at Washington University School of Medicine in St. Louis have discovered brain pathways linked to reward and aversion behaviors are in such close proximity that they unintentionally could be activated at the same time.
The findings suggest that drug treatments for addiction and depression simultaneously may stimulate reward and aversion responses, resulting in a net effect of zero in some patients.
The research is published online Sept. 2 in the journal Neuron.
“We studied the neurons that cause activation of kappa opioid receptors, which are involved in every kind of addiction — alcohol, nicotine, cocaine, heroin, methamphetamine,” said principal investigator Michael R. Bruchas, PhD, associate professor of anesthesiology and neurobiology. “We produced opposite reward and aversion behaviors by activating neuronal populations located very near one another. This might help explain why drug treatments for addiction don’t always work — they could be working in these two regions at the same time and canceling out any effects.”
Addiction can result when a drug temporarily produces a reward response in the brain that, once it wears off, prompts an aversion response that creates an urge for more drugs.
The researchers studied mice genetically engineered so that some of their brain cells could be activated with light. Using tiny, implantable LED devices to shine a light on the neurons, they stimulated cells in a region of the brain called the nucleus accumbens, producing a reward response. Cells in that part of the bran are dotted with kappa opioid receptors, which are involved in addiction and depression.
The mice returned over and over again to the same part of a maze when the researchers stimulated the brain cells to produce a reward response. But activating cells a millimeter away resulted in robust aversion behavior, causing the mice to avoid these areas.
“We were surprised to see that activation of the same types of receptors on the same types of cells in the same region of the brain could cause different responses,” said first author Ream Al-Hasani, PhD, an instructor in anesthesiology. “By understanding how these receptors work, we may be able to more specifically target drug therapies to treat conditions linked to reward and aversion responses, such as addiction or depression.”
Funding: Funding for this research comes from the National Institute on Drug Abuse, the National Institute on Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH), grant numbers P30 NS057105, R01 DA033396, R01 DA037152 K99/R00 DA038725, TR01 NS081707 R01 DK075623, R37 DK053477, R01 DK089044, R01 DK071051, R01 DK096010, P30DK046200 and P30 DK057521.
Source: Jim Dryden – Washington University School of Medicine
Image Credit: The image credited to Bruchas laboratory, Washington University
Original Research: Abstract for “Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward” by Ream Al-Hasani, Jordan G. McCall, Gunchul Shin, Adrian M. Gomez, Gavin P. Schmitz, Julio M. Bernardi, Chang-O. Pyo, Sung Il Park, Catherine M. Marcinkiewcz, Nicole A. Crowley, Michael J. Krashes, Bradford B. Lowell, Thomas L. Kash, John A. Rogers, and Michael R. Bruchas in Neuron. Published online August 8 2015 doi:10.1016/j.neuron.2015.08.019
Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward
•Optogenetic excitation of nucleus accumbens dynorphin cells elicits dynorphin release
•Discrete accumbens shell dynorphinergic populations drive either aversion or reward
•These two nucleus accumbens subregions can be bi-directionally controlled
•Both aversive and rewarding behaviors require kappa opioid receptors
The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease.
“Distinct Subpopulations of Nucleus Accumbens Dynorphin Neurons Drive Aversion and Reward” by Ream Al-Hasani, Jordan G. McCall, Gunchul Shin, Adrian M. Gomez, Gavin P. Schmitz, Julio M. Bernardi, Chang-O. Pyo, Sung Il Park, Catherine M. Marcinkiewcz, Nicole A. Crowley, Michael J. Krashes, Bradford B. Lowell, Thomas L. Kash, John A. Rogers, and Michael R. Bruchas in Neuron. Published online August 8 2015 doi:10.1016/j.neuron.2015.08.019