Apr 24, 2020

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

BioRxiv : the Preprint Server for Biology
Elyssa B. MargolisW. Martin

Abstract

Activation of the kappa opioid receptor ( KOR ) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area ( VTA )dopaminergic neurons, contributing to aversive responses [1,2] ; therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX -395750, PF -04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U- 69,593. BTRX -335140 and BTRX -395750 fully blocked U-69,593 currents (IC 50 = 1.3 {+/-} 0.9 and 4.6 {+/-} 0.9 nM, respectively). JNJ-67953964 showed an IC 50 of 0.3 {+/-} 1.3 nM. PF- 04455242 ( IC 50 = 19.6 {+/-} 16 nM) exhibited partial antagonist activity ( ~ 60% maximal blockade ) .In 50% of neurons, 1 m M PF -04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DO...Continue Reading

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Genome-Wide Association Study
Study
Meta-Analysis (Publications)
Meta Analysis (Statistical Procedure)
Longitudinal Studies
Family Research
Brain
Genetic Pleiotropy
Genomics
Disease Susceptibility

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