Biology subjects

Sinha Roy, K.

Publications and source records attributed to Sinha Roy, K..

3 recordsLinked to original sources

bioRxiv2026

Ultrasonic potentiation of ketamine neuromodulation

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. HighlightsO_LIFocused ultrasound potentiated ketamine-driven glutamate, serotonin, and dopamine release C_LIO_LILocalized ketamine delivery with SonoKet uncaging drove synergistically greater region-specific neurochemical responses C_LIO_LIUncaging boosts ketamine effects at a fraction of the ketamine dose C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/741494v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@15c75c8org.highwire.dtl.DTLVardef@138d06eorg.highwire.dtl.DTLVardef@fc0c56org.highwire.dtl.DTLVardef@18e233b_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Cognitive engagement induces area-specific fingerprints of dopamine, acetylcholine, serotonin, glutamate and GABA in prefrontal cortex and striatum

Cholinergic, dopaminergic and serotonergic neuromodulation has pervasive effects on circuit functions in prefrontal cortex (PFC) and striatum and interact with glutamatergic and GABAergic transmission. But how these neurochemicals interact during cognitive engagement is largely unknown and inferred from studying few neuromodulators at a time. Here, we sampled the extracellular availabilities of five neurochemicals in the PFC and striatum of nonhuman primates and tested how they changed when subjects switched from rest to engage in a cognitive set shifting task using miniaturized probes for diffusion-based solid-phase microextraction. Cognitive engagement was best predicted by GABAergic and cholinergic changes in the PFC, and dopaminergic and cholinergic changes in the striatum. Glutamate co-modulated with acetylcholine across states in both the PFC and striatum, while serotonin changes in PFC and striatum correlated consistent with common external modulation. These findings document an area-specific multi-neuromodulatory fingerprint of an adaptive cognitive state in the fronto-striatal network of the nonhuman primate brain. TeaserEngaging in a cognitive task reshapes neurochemical profiles across the fronto-striatal network of the primate brain

neuroscience↗

bioRxiv2023

Acoustomechanically activatable liposomes for ultrasonic drug uncaging

Ultrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest. One Sentence SummaryIncorporating a few percent sucrose into a liposome transforms it into an immediately translatable vehicle for noninvasive, on-demand ultrasound-targeted drug delivery.

bioengineering↗