Ultrasonic potentiation of ketamine neuromodulation.
Kanchan Sinha Roy, Payton Martinez, Sedona N. Ewbank, Kenneth Shinozuka, Mahaveer Purohit, Yun Xiang, Raag D. Airan
bioRxiv : the preprint server for biology August 4, 2026 preprint DOI: 10.64898/2026.07.29.741494 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study |
|---|---|
| Population | Awake rats |
| Interventions | Free ketamine Focused ultrasound (FUS) |
| Dose | 0.75 mg/kg SonoKet; 10 mg/kg free ketamine; 0.75 mg/kg free ketamine |
| Measures | solid-phase microextraction (SPME) coupled to LC-MS/MS measuring ketamine, metabolites, glutamate, GABA, serotonin (5-HT), and dopamine |
| Topics | Esketamine Ketamine |
| Key findings | Focused ultrasound potentiated ketamine-induced neurotransmitter release, and SonoKet uncaging produced synergistically greater, region-specific neurochemical responses at a fraction of the ketamine dose (0.75 mg/kg vs 10 mg/kg free ketamine). |
Abstract
The psychiatric utility of ketamine is limited by its dissociative and systemic side effects. Recently, to enable precision ketamine pharmacotherapy, we introduced SonoKet, ketamine-loaded acoustically activatable liposomes that enable focused ultrasound (FUS)-targeted ketamine delivery to millimeter-sized brain regions. In initial studies, we observed that SonoKet uncaging targeted ketamine to the ultrasound-treated brain region, while inducing greater electrophysiologic and behavioral functional effects than dose-matched free ketamine. To further define these uncaging-potentiated neuromodulatory effects, we used solid-phase microextraction (SPME) coupled to LC-MS/MS to investigate the effect of ultrasound and SonoKet uncaging on key neurotransmitters in real-time. SPME probes were used to sample ketamine, its metabolites, and glutamate, GABA, serotonin (5-HT), and dopamine in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and retrosplenial cortex (RsC) of awake rats. Sampling occurred before and after intravenous administration of either SonoKet, free ketamine, or saline, with FUS targeted to either a frontolimbic or caudal brain region. FUS alone did not yield significant changes in neurotransmitter concentration, nor did it affect the pharmacodistribution of free ketamine. In contrast, FUS generally increased the neurotransmitter response to free ketamine, suggesting an ultrasonic potentiation of ketamine neuromodulation. SonoKet (0.75 mg/kg) uncaging with FUS elicited further elevations in glutamate, GABA, and 5-HT within the FUS-targeted region, along with an increase in dopamine in the NAc when the frontolimbic region was sonicated. These increases were similar to or higher than those induced by 10 mg/kg free ketamine alone or 0.75 mg/kg free ketamine combined with FUS, especially with frontolimbic SonoKet uncaging. Altogether, FUS potentiates ketamine-induced neuromodulation, with spatially specific and synergistically greater effects when ketamine is spatially localized via ultrasonic uncaging. This strategy could augment ketamine pharmacotherapy for psychiatric diseases, while limiting its dissociative and abuse liabilities. Focused ultrasound potentiated ketamine-driven glutamate, serotonin, and dopamine releaseLocalized ketamine delivery with SonoKet uncaging drove synergistically greater region-specific neurochemical responsesUncaging boosts ketamine effects at a fraction of the ketamine dose.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 9
- Ketamine use: a review Addiction July 21, 2011
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Deep posteromedial cortical rhythm in dissociation Nature September 16, 2020
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- A REVIEW OF KETAMINE ABUSE AND DIVERSION Depression and Anxiety August 1, 2016
and 4 more in the library