Electrical stimulation of the ventral tegmental area restores consciousness from sevoflurane-, dexmedetomidine-, and fentanyl-induced unconsciousness in rats.

Background: Dopaminergic neurons in the ventral tegmental area (VTA) are crucially involved in regulating arousal, making them a potential target for reversing general anesthesia. Electrical deep brain stimulation (DBS) of the VTA restores consciousness in animals anesthetized with drugs that primarily enhance GABA receptors. However, it is unknown if VTA DBS restores consciousness in animals anesthetized with drugs that target other receptors.

Return of the Righting Reflex Does Not Portend Recovery of Cognitive Function in Anesthetized Rats.

As the number of individuals undergoing general anesthesia rises globally, it becomes increasingly important to understand how consciousness and cognition are restored after anesthesia. In rodents, levels of consciousness are traditionally captured by physiological responses such as the return of righting reflex (RORR). However, tracking the recovery of cognitive function is comparatively difficult.

Sex, drugs, and anaesthesia research.

In this issue of the British Journal of Anaesthesia, Joksimovic and colleagues report significant sex differences in sensitivity to the behavioural and neurophysiological effects of 3β-OH, a novel neurosteroid anesthetic. Female rats were more sensitive to the effects of 3β-OH than male rats, although the mechanims remain unclear. Sex differences have been understudied in anaesthesia research, and this article by Joksimovic and colleagues emphasizes the need to devote more effort to understanding these differences.

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats.

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABA receptors.

The Neural Circuits Underlying General Anesthesia and Sleep.

General anesthesia is characterized by loss of consciousness, amnesia, analgesia, and immobility. Important molecular targets of general anesthetics have been identified, but the neural circuits underlying the discrete end points of general anesthesia remain incompletely understood. General anesthesia and natural sleep share the common feature of reversible unconsciousness, and recent developments in neuroscience have enabled elegant studies that investigate the brain nuclei and neural circuits underlying this important end point.

D-Amphetamine Accelerates Recovery of Consciousness and Respiratory Drive After High-Dose Fentanyl in Rats.

In the United States, fentanyl causes approximately 60,000 drug overdose deaths each year. Fentanyl is also frequently administered as an analgesic in the perioperative setting, where respiratory depression remains a common clinical problem. Naloxone is an efficacious opioid antagonist, but it possesses a short half-life and undesirable side effects.

Manipulating Neural Circuits in Anesthesia Research.

The neural circuits underlying the distinct endpoints that define general anesthesia remain incompletely understood. It is becoming increasingly evident, however, that distinct pathways in the brain that mediate arousal and pain are involved in various endpoints of general anesthesia. To critically evaluate this growing body of literature, familiarity with modern tools and techniques used to study neural circuits is essential.

The role of loops B and C in determining the potentiation of GABA receptors by midazolam.

Many benzodiazepines are positive allosteric modulators (PAMs) of GABA receptors that cause sedation, hypnosis, and anxiolysis. Benzodiazepines bind GABA receptors at the extracellular interface of the α and γ subunits. Within the α subunit, the benzodiazepine binding site is defined by three highly conserved structural loops, loops A-C.

De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.

GABAA receptors are ligand-gated anion channels that are important regulators of neuronal inhibition. Mutations in several genes encoding receptor subunits have been identified in patients with various types of epilepsy, ranging from mild febrile seizures to severe epileptic encephalopathy. Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.

Rigor, reproducibility, and in vitro cerebrospinal fluid assays: The devil in the details.

Divergent results and misinterpretation of non-significant findings remain problematic in science – especially in retrospective, hypothesis generating, translational research. When such divergence occurs, it is imperative that the cause of the divergence be established. In their recent paper in , Dauvilliers challenged our earlier finding that cerebrospinal fluid (CSF) from some patients with unexplained excessive daytime sleepiness enhances the activation of GABA receptors (GABA-R).

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.

The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies.