Publication Date

2019

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Neuroscience

Advisors

Adam C. Hall

Keywords

GABA receptors, Anesthesia, Patch-clamp, Neuropharmacology

Abstract

GABAA receptors are the most widely distributed inhibitory receptors in the mammalian CNS and are the primary targets for anesthetics. Propofol is an intravenous anesthetic that acts to positively modulate GABAA receptor currents and therefore enhance inhibitory signals. It is commonly used to induce short term anesthesia as its actions allow for several events to occur in the brain that alter cognition, sensation, motor responses, and autonomic control (Garcia et al., 2010). Despite its fast distribution from blood to tissues and rapid metabolic clearance from blood, the use of propofol is associated with several adverse effects including propofol infusion syndrome (PRIS) (Kam & Cardone, 2007). The search for more potent and less toxic anesthetic agents is therefore clinically relevant and a main focus of the Hall lab. Further, the relationship between the structure of potential anesthetics and their effect on GABAA receptor responses can contribute to an understanding of binding domains on GABAA receptors and potentially serve to improve potency and reduce toxicity.

Phenol analogs of propofol containing aliphatic substituents at the 2,6 positions ortho to the hydroxyl group have the potential to act as anesthetics at the GABAA receptor (Krasowski et al., 2001b). Previous research in the Hall lab revealed that 2,6 di-sec-butylphenol has the potential to act as an anesthetic as it was found to directly activate, to enhance, and to inhibit GABAA receptor responses in a dose-dependent manner (Leet, 2018). In the current study, whole-cell patch clamp electrophysiology techniques were used to characterize enhancement of GABAA receptor currents by 2-ethyl, 6-methylphenol; 2-propyl, 6-methylphenol; 2-allyl, 6 methylphenol; 2-sec-butyl, 6-methylphenol; 2-tert-butyl, 6-methylphenol; and 2cyclopentylphenol in WSS-1 cells stably expressing α1β3γ2s GABAA receptors. Results indicate that, relative to propofol, the six aforementioned phenol analogs act to weakly enhance GABAA receptor currents in a dose-dependent manner. Greater enhancement of GABAA receptor currents by 2-propyl, 6-methylphenol, 2-sec-butyl, 6-methyl-phenol, and 2-allyl, 6-methylphenol compared to 2-ethyl, 6-methylphenol, 2-tert-butyl, 6-methylphenol, and 2-cyclopentylphenol suggests that phenol analogs with longer aliphatic chains confer greater GABAergic activity.

Rights

©2019 Lauren Chelsea Bondi. Access limited to the Smith College community and other researchers while on campus. Smith College community members also may access from off-campus using a Smith College log-in. Other off-campus researchers may request a copy through Interlibrary Loan for personal use.

Language

English

Comments

70 pages : color illustrations. Includes bibliographical references (pages 67-70)

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