These proteins, report University of North Carolina researchers, inhibit the release of the neurotransmitter glutamate in a part of the brain that regulates emotion. KORs have been of great interest as a drug target for the treatment of addiction and anxiety disorders.
Thomas L. Kash, PhD, associate professor of pharmacology and the lead author of the study, used mice to show the effects of KORs on behavior.
“When KORs are inactivated, glutamate is released properly and mice showed significant signs of feeling less anxious,” said Kash. “But when kappa opioid receptors are activated, this glutamate release associated with ‘safety’ was tamped down. There were clear signs of more anxiety. So, in essence, KORs shut off an anxiety-reducing pathway in the brain.”
Humans also have kappa opioid receptors that work in the same way.
Several pharmaceutical companies are already working on developing KOR antagonists as a treatment for anxiety and drug abuse, Kash said. The new study adds to a growing body of literature showing how these drugs may work.
Profiling neurons to define new target proteins for drug development is among the next logical steps in this line of research. Kash also said that future projects could include the study of forms of anxiety that are more pathological, such as those associated with excessive alcohol intake or opiate abuse.
“Kappa opioid receptors (KORs) are involved in a variety of aversive behavioral states, including anxiety. To date, a circuit-based mechanism for KOR-driven anxiety has not been described.
Here, we show that activation of KORs inhibits glutamate release from basolateral amygdala (BLA) inputs to the bed nucleus of the stria terminalis (BNST) and occludes the anxiolytic phenotype seen with optogenetic activation of BLA-BNST projections. In addition, deletion of KORs from amygdala neurons results in an anxiolytic phenotype.
Furthermore, we identify a frequency-dependent, optically evoked local dynorphin-induced heterosynaptic plasticity of glutamate inputs in the BNST. We also find that there is cell type specificity to the KOR modulation of the BLA-BNST input with greater KOR-mediated inhibition of BLA dynorphin-expressing neurons.
Collectively, these results provide support for a model in which local dynorphin release can inhibit an anxiolytic pathway, providing a discrete therapeutic target for the treatment of anxiety disorders.”
Nicole A. Crowley, Daniel W. Bloodgood, J. Andrew Hardaway, Alexis M. Kendra, Jordan G. McCall, Ream Al-Hasani, Nora M. McCall, Waylin Yu, Zachary L. Schools, Michael J. Krashes, Bradford B. Lowell, Jennifer L. Whistler, Michael R. Bruchas, Thomas L. Kash Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit Cell Reports, 2016; DOI: 10.1016/j.celrep.2016.02.069