Neurotensin and Dynorphin Bi-Directionally Modulates CeA Inhibition of oval BNST Neurons in Male Mice

AbstractNeuropeptides are often co-expressed in neurons but their neurophysiological effects are commonly studied individually. Multiple neuropeptides may therefore be simultaneously released to coordinate proper neural circuit function. Here, we triggered the release of endogenous neuropeptides in brain slices from male mice to better understand the modulation of central amygdala (CeA) inhibitory inputs onto oval (ov) BNST neurons. We found that locally-released neurotensin (NT) and dynorphin (Dyn) antagonistically regulated CeA inhibitory inputs onto ovBNST neurons. NT and Dyn respectively increased and decreased CeA-to-ovBNST inhibitory inputs through NT receptor 1 (NTR1) and kappa opioid receptor (KOR). Additionally, NT and Dyn mRNAs were highly co-localized in ovBNST neurons suggesting that they may be released from the same cells. Together, we showed that NT and Dyn are key modulators of CeA inputs to ovBNST, paving the way to determine whether different conditions or states can alter the neuropeptidergic regulation of this particular brain circuit.

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Kappa-opioid receptor-dependent changes in dopamine and affective behavior occur differentially across the nucleus accumbens shell rostro-caudal axis

10.1101/2020.05.09.085761 ◽

2020 ◽

Author(s):

Breanne E. Pirino ◽

Mary B. Spodnick ◽

Andrew T. Gargiulo ◽

Genevieve R. Curtis ◽

Jessica R. Barson ◽

...

Keyword(s):

Nucleus Accumbens ◽

Opioid Receptor ◽

Dopamine Release ◽

Neural Circuit ◽

Ex Vivo ◽

Kappa Opioid Receptor ◽

Affective Behavior ◽

Kappa Opioid ◽

Affective Behaviors ◽

The Impact

ABSTRACTNeural circuit engagement within the nucleus accumbens (NAc) shell is implicated in the regulation of both negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote dysphoric behavior, while dopamine was viewed as interacting with reward behavior, and KOR activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have, separately, been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to other affective behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behavior using approach-avoidance assays. We report here that activation of KORs in the caudal NAc shell significantly inhibits dopamine release, stimulates novelty-induced rearing behavior, increases avoidance behavior, and reduces locomotor activity. In contrast, activation of KORs in the rostral NAc shell inhibits dopamine release to a lesser extent and instead increases approach behavior. Taken together, these results indicate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behaviors, and they suggest that this might be due to differences in KOR control over dopamine release.

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

10.1101/2020.04.24.059352 ◽

2020 ◽

Author(s):

Elyssa B. Margolis ◽

Tanya L. Wallace ◽

Lori Jean Van Orden ◽

William J. Martin

Keyword(s):

Opioid Receptor ◽

Therapeutic Potential ◽

Outward Current ◽

Complete Recovery ◽

Kappa Opioid Receptor ◽

Dopamine Neurons ◽

Kappa Opioid ◽

Opioid Receptor Antagonists ◽

Neurobehavioral Disorders ◽

Circuit Function

AbstractActivation 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 (IC50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively). JNJ-67953964 showed an IC50 of 0.3 ± 1.3 nM. PF-04455242 (IC50 = 19.6 ± 16 nM) exhibited partial antagonist activity (∼60% maximal blockade). In 50% of neurons, 1 μM 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 (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within disorder-relevant circuits implicated in neurobehavioral disorders.

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Kappa Opioid Receptor-Mediated Dysregulation of Gamma-Aminobutyric Acidergic Transmission in the Central Amygdala in Cocaine Addiction

Biological Psychiatry ◽

10.1016/j.biopsych.2013.04.028 ◽

2013 ◽

Vol 74 (7) ◽

pp. 520-528 ◽

Cited By ~ 35

Author(s):

Marsida Kallupi ◽

Sunmee Wee ◽

Scott Edwards ◽

Timothy W. Whitfield ◽

Christopher S. Oleata ◽

...

Keyword(s):

Opioid Receptor ◽

Kappa Opioid Receptor ◽

Cocaine Addiction ◽

Central Amygdala ◽

Kappa Opioid

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Nalmefene, a Mu Opioid Receptor Antagonist/Kappa Opioid Receptor Partial Agonist, Potentiates Cocaine Motivation But Not Intake with Extended Access Self-Administration in Adult Male Mice

Neuropharmacology ◽

10.1016/j.neuropharm.2021.108590 ◽

2021 ◽

pp. 108590

Author(s):

Kyle A. Windisch ◽

Michelle Morochnik ◽

Brian Reed ◽

Mary Jeanne Kreek

Keyword(s):

Receptor Antagonist ◽

Opioid Receptor ◽

Partial Agonist ◽

Mu Opioid Receptor ◽

Kappa Opioid Receptor ◽

Male Mice ◽

Self Administration ◽

Kappa Opioid ◽

Mu Opioid ◽

Extended Access

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

PLoS ONE ◽

10.1371/journal.pone.0232864 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0232864

Author(s):

Elyssa B. Margolis ◽

Tanya L. Wallace ◽

Lori Jean Van Orden ◽

William J. Martin

Keyword(s):

Opioid Receptor ◽

Therapeutic Potential ◽

Outward Current ◽

Complete Recovery ◽

Kappa Opioid Receptor ◽

Dopamine Neurons ◽

Kappa Opioid ◽

Opioid Receptor Antagonists ◽

Neurobehavioral Disorders ◽

Circuit Function

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 (Margolis et al. 2003, 2006); 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 (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 μM 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 (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.

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