Novel Drug Reduces Anxiety-Like Behavior in Mice

Summary: KNT-127 reduced anxiety-like behaviors in mice, researchers report.

Source: Tokyo University of Science

Anxiety, commonly termed as a feeling of fear, dread, and restlessness, is a perfectly normal reaction to stressful situations. However, a state of heightened anxiety, which is the reality for thousands of people who struggle to cope with these feelings, is called anxiety disorder.

Anxiety disorder can invoke debilitating fear or apprehension, even without any immediate threat. Though intensive research over the years has yielded a plethora of information, and effective drugs like selective serotonin reuptake inhibitors have been used to alleviate this condition, a lot remains to be understood about this complex condition and its treatment.

For a group of Japanese researchers from Tokyo University of Science and University of Tsukuba, endeavoring in this line of research is not new. In a previous study, they used a drug called KNT-127, which acts by activating specific receptors in the brain, called “delta opioid receptors.” The researchers found KNT-127 to reduce anxiety-like behavior in mice.

They found that KNT-127 caused the reduction of an excitatory neurotransmitter, called glutamate, in the extracellular regions of a part of the brain that controls several emotional states, called the “prelimbic subregion of the medial prefrontal cortex” (PL-PFC).

The researchers went on to study this phenomenon in a new study published in Biochemical and Biophysical Research Communications.

According to Professor Akiyoshi Saitoh, from the Faculty of Pharmaceutical Sciences, Tokyo University of Science, and corresponding author of this study, there is a good reason to have investigated the glutamate levels specifically in PL-PFC. He says, “The medial prefrontal cortex (mPFC) plays a vital role in the processing of emotional events. It has been shown that activation of the glutamatergic transmission in PL-PFC evoked anxiety-like behavior in rodents.”

Accordingly, Professor Saitoh and his colleagues conducted electrophysiological studies at a single-neuron level in mice. The team measured spontaneous excitatory currents from the glutamate-releasing presynapse region of various important neurons treated with and without KNT-127, in the PL-PFC of mice that had been induced to exhibit anxious behavior.

This is a diagram from the study
KNT-127 suppresses glutamate release in the PL-PFC, resulting in an anxiolytic effect. Credit: Akiyoshi Saitoh, Tokyo University of Science

For neurons treated with KNT-127, the results showed that release of glutamate was reduced at the PL-PFC synapses. Since this excitatory neurotransmitter relays information from one neuron to the other, at the synapse region, the corresponding brain activity was also found to be lowered. Interestingly, the team found that KNT-127 treatment made the PL-PFC neurons less excitable. The researchers considered these findings to be a consequence of the anxiolytic effects of KNT-127.

Overall, this study proposes a novel pathway–and a novel drug candidate–that can be targeted for treating anxiety disorder. Commenting on the clinical potential of drugs like KNT-127, Dr. Daisuke Yamada, one of the investigators in the study from Tokyo University of Science, says, “There is a need for the development of new therapeutic agents that have different mechanisms of action from existing drugs. The results of this study are expected to lead to the development of evidence-based antipsychotics with a new mechanism of action, targeting opioid delta receptors.”

Indeed, the world can hope for groundbreaking anxiolytic drugs to enter the market, taking after the results of this promising study!

About this anxiety research news

Source: Tokyo University of Science
Contact: Tsutomu Shimizu – Tokyo University of Science
Image: The image is credited to Akiyoshi Saitoh, Tokyo University of Science

Original Research: Closed access.
Modulation of glutamatergic synaptic transmission and neuronal excitability in the prelimbic medial prefrontal cortex via delta-opioid receptors in mice” by Akiyoshi Saitoh et al. Biochemical and Biophysical Research Communications


Modulation of glutamatergic synaptic transmission and neuronal excitability in the prelimbic medial prefrontal cortex via delta-opioid receptors in mice

The medial prefrontal cortex (mPFC) plays a vital role in the processing of emotional events. It has been shown that activation of the glutamatergic transmission in prelimbic subregion of the mPFC (PL-PFC) evoked anxiety-like behavior in rodents. We previously reported that local perfusion of a selective agonist to delta-opioid receptor (DOP), KNT-127, attenuated the veratrine-induced elevation of extracellular glutamate in the PL-PFC and anxiety-like behavior in mice.

These results suggested the possibility that KNT-127 suppresses glutamate release from the presynaptic site in the PL-PFC. To examine this possibility directly, we performed whole-cell patch-clamp recording from principal neurons in the PL-PFC and examined the spontaneous and electrically-evoked excitatory postsynaptic currents (EPSC)s.

We found that bath application of KNT-127 significantly decreased the frequency of spontaneous and miniature EPSCs. Conversely, amplitude, rise time, and decay time of spontaneous and miniature EPSCs were not affected by bath application of KNT-127. Also, KNT-127 increased paired-pulse ratios of electrically-evoked EPSCs in the PL-PFC principal neurons tested. Further, we analyzed the firing properties of pyramidal neurons in the PL-PFC and found that KNT-127 treatment significantly reduced the number of action potentials and firing threshold.

These results suggested that KNT-127 suppresses glutamatergic synaptic transmission by inhibiting glutamate release from the presynaptic site and reduces neuronal excitability in the mouse PL-PFC. We propose the possibility that these suppressing effects of KNT-127 on PL-PFC activity are part of the underlying mechanisms of its anxiolytic-like effects.

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