Cocaine chemogenetics blunts drug-seeking by synthetic physiology.

Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness.

The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors.

Esketamine represents a new class of drugs for treating mood disorders. Unlike traditional monoaminergic-based therapies, esketamine primarily targets N-methyl-D-aspartate receptors (NMDAR). However, esketamine is a complex drug with low affinity for NMDAR and can also bind to other targets, such as opioid receptors.

Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?

Ketamine is a racemic compound and medication comprised of ()-ketamine and ()-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders such as anxiety, obsessive-compulsive, and opioid use disorders.

Dopamine dynamics in chronic pain: music-induced, sex-dependent, behavioral effects in mice.

Introduction: Chronic pain is a debilitating disease that is usually comorbid to anxiety and depression. Current treatment approaches mainly rely on analgesics but often neglect emotional aspects. Nonpharmacological interventions, such as listening to music, have been incorporated into clinics to provide a more comprehensive management of chronic pain.

A combination of Δ-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer's disease.

A combination of Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer's disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ-THC and CBD are not fully understood. Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD.

A non-canonical striatopallidal Go pathway that supports motor control.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function.

Converging circuits between pain and depression: the ventral tegmental area as a therapeutic hub.

Chronic pain and depression are highly prevalent pathologies and cause a major socioeconomic burden to society. Chronic pain affects the emotional state of the individuals suffering from it, while depression worsens the prognosis of chronic pain patients and may diminish the effectiveness of pain treatments. There is a high comorbidity rate between both pathologies, which might share overlapping mechanisms.

In vivo photopharmacology with light-activated opioid drugs.

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone.

Expression of the excitatory opsin ChRERα can be traced longitudinally in rat and nonhuman primate brains with PET imaging.

Optogenetics is a widely used technology with potential for translational research. A critical component of such applications is the ability to track the location of the transduced opsin in vivo. To address this problem, we engineered an excitatory opsin, ChRERα (hChR2(134R)-V5-ERα-LBD), that could be visualized using positron emission tomography (PET) imaging in a noninvasive, longitudinal, and quantitative manner.

Anterior hypothalamic parvalbumin neurons are glutamatergic and promote escape behavior.

The anterior hypothalamic area (AHA) is a critical structure for defensive responding. Here, we identified a cluster of parvalbumin-expressing neurons in the AHA (AHA) that are glutamatergic with fast-spiking properties and send axonal projections to the dorsal premammillary nucleus (PMD). Using in vivo functional imaging, optogenetics, and behavioral assays, we determined the role of these AHA neurons in regulating behaviors essential for survival.

Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release.

Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade.

In vivo photopharmacology with a caged mu opioid receptor agonist drives rapid changes in behavior.

Photoactivatable drugs and peptides can drive quantitative studies into receptor signaling with high spatiotemporal precision, yet few are compatible with behavioral studies in mammals. We developed CNV-Y-DAMGO-a caged derivative of the mu opioid receptor-selective peptide agonist DAMGO. Photoactivation in the mouse ventral tegmental area produced an opioid-dependent increase in locomotion within seconds of illumination.

Mu Opioid Receptor Activation Mediates (S)-ketamine Reinforcement in Rats: Implications for Abuse Liability.

Background: (S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid receptors (MORs) and kappa opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine's in vivo pharmacology is unknown.

Methods: We investigated the extent to which (S)-ketamine interacts with opioid receptors in rats by combining in vitro and in vivo pharmacological approaches, in vivo molecular and functional imaging, and behavioral procedures relevant to human abuse liability.

photopharmacology with light-activated opioid drugs.

Unlabelled: Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors , we developed PhOX and PhNX, photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone.

The SARS-CoV-2 spike protein binds and modulates estrogen receptors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor α (ERα).

Adolescent nicotine administration increases nicotinic acetylcholine receptor binding and functional connectivity in specific cortico-striatal-thalamic circuits.

Nicotine exposure is associated with regional changes in brain nicotinic acetylcholine receptors subtype expression patterns as a function of dose and age at the time of exposure. Moreover, nicotine dependence is associated with changes in brain circuit functional connectivity, but the relationship between such connectivity and concomitant regional distribution changes in nicotinic acetylcholine receptor subtypes following nicotine exposure is not understood. Although smoking typically begins in adolescence, developmental changes in brain circuits and nicotinic acetylcholine receptors following chronic nicotine exposure remain minimally investigated.

Essential role of P-glycoprotein in the mechanism of action of oliceridine.

Mu opioid receptor (MOR) agonists comprise the most effective analgesics, but their therapeutic utility is limited by adverse effects. One approach for limiting such effects has been to develop "biased" MOR agonists that show preference for activating G protein over β-Arrestin signaling. However, the notion of biased agonism has been challenged by recent studies.

6-O-(2-[F]Fluoroethyl)-6-O-Desmethyl-Diprenorphine ([F]FE-DPN) Preferentially Binds to Mu Opioid Receptors In Vivo.

Purpose: 6-O-(2-[F]Fluoroethyl)-6-O-desmethyl-diprenorphine ([F]FE-DPN) is regarded as a non-selective opioid receptor radiotracer.

Procedure: Here, we report the first characterization of [F]FE-DPN synthesized from the novel precursor, 6-O-(2-tosyloxyethoxy)-6-O-desmethyl-3-O-trityl-diprenorphine (TE-TDDPN), using a one-pot, two-step nucleophilic radiosynthesis to image opioid receptors in rats and mice using positron emission tomography.

Results: We also show that [F]FE-DPN and [H]DPN exhibit negligible brain uptake in mu opioid receptor (MOR) knockout mice.

Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search.

The off-label use of racemic ketamine and the FDA approval of (S)-ketamine are promising developments for the treatment of depression. Nevertheless, racemic ketamine and (S)-ketamine are controlled substances with known abuse potential and their use is associated with undesirable side effects. For these reasons, research efforts have focused on identifying alternatives.

The SARS-CoV-2 spike protein binds and modulates estrogen receptors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 (ACE2) at the cell surface, which constitutes the primary mechanism driving SARS-CoV-2 infection. Molecular interactions between the transduced S and endogenous proteins likely occur post-infection, but such interactions are not well understood. We used an unbiased primary screen to profile the binding of full-length S against >9,000 human proteins and found significant S-host protein interactions, including one between S and human estrogen receptor alpha (ERα).