Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus

Chen, Zhiheng; Tang, Yamei; Tao, Huai; Li, Cunyan; Zhang, Xianghui; Liu, Yong

doi:10.1016/j.neuropharm.2015.05.030

Cited by 26 publications

(25 citation statements)

References 69 publications

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“…Our findings are consistent with previously reported KOR-mediated reduction in BLA excitability in adolescents (Huge, Rammes, Beyer, Zieglgansberger, & Azad, 2009). Ultimately, these neurophysiological effects would produce an anxiolytic effect in adolescents, consistent with previously demonstrated anxiolytic effects of KOR agonists in stress-naïve adolescents (Alexeeva, Nazarova, & Sudakov, 2012;Anderson, Morales, Spear, & Varlinskaya, 2014;Chen et al, 2015;Collins, Zavala, Nazarian, & McDougall, 2000;Cortez et al, 2010;McDougall, Garmsen, Meier, & Crawford, 1997;Nizhnikov, Pautassi, Varlinskaya, Rahmani, & Spear, 2012;Privette & Terrian, 1995).…”

Section: Introductionsupporting

confidence: 85%

Adolescent forced swim stress increases social anxiety-like behaviors and alters the dynorphin/kappa opioid receptor system in the basolateral amygdala of males

Johnson

Deak

Diaz

2019

Preprint

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Adolescence is a developmental period marked by robust neural alterations and heightened vulnerability to stress, a factor that is highly associated with increased risk for emotional processing deficits, such as anxiety. Stress-induced upregulation of the dynorphin/kappa opioid receptor (DYN/KOR) system is thought to, in part, underlie the negative affect associated with stress. The basolateral amygdala (BLA) is a key structure involved in anxiety, and neuromodulatory systems, such as the DYN/KOR system, can 1) regulate BLA neural activity in an age-dependent manner in stress-naïve animals and 2) underlie stress-induced anxiety in adults. However, the role of the DYN/KOR system in modulating stress-induced anxiety in adolescents is unknown. To test this, we examined the impact of an acute, 2-day forced swim stress (FSS -10 min each day) on adolescent (~postnatal day (P) 35) and adult Sprague-Dawley rats (~P70), followed by behavioral, molecular and electrophysiological assessment 24 hours following FSS. Adolescent males, but not adult males or females of either age, demonstrated social anxiety-like behavioral alterations indexed via significantly reduced social investigation and preference when tested 24 hours following FSS. Conversely, adult males exhibited increased social preference. While there were no FSS-induced changes in expression of genes related to the DYN/KOR system in the BLA, these behavioral alterations were associated with a robust switch in BLA KOR function. Specifically, while the KOR agonist, U69593, significantly increased GABA transmission in the BLA of non-stressed adolescent males, U69593 significantly inhibited BLA GABA transmission in stressed adolescent males, consistent with the observed anxiogenic phenotype in stressed adolescent males. This is the first study to demonstrate a KOR-dependent mechanism that may contribute to stress-induced social anxiety in adolescent males. Importantly, these findings provide evidence for potential KOR-dependent mechanisms that may contribute to pathophysiological interactions with subsequent stress challenges.

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Section: Introductionsupporting

confidence: 85%

Adolescent forced swim stress increases social anxiety-like behaviors and alters the dynorphin/kappa opioid receptor system in the basolateral amygdala of males

Johnson

Deak

Diaz

2019

Preprint

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“…While numerous studies have shown that KORs are G i/o coupled [reviewed by (Bruchas and Chavkin, 2010)], which ultimately reduces neuronal excitability and/or neurotransmitter release in various brain structures (Chen et al, 2015; Crowley et al, 2016; Gilpin et al, 2014; Kang-Park et al, 2013; Karkhanis et al, 2016; Lemos et al, 2012; Li et al, 2012; Rose et al, 2015; Siciliano et al, 2016), studies have also shown that KORs can couple to G s in various cellular models (Baraban et al, 1995; Hampson et al, 2000; Shen and Crain, 1990a, b, 1994) which can increase action potential duration (Shen and Crain, 1990a, b, 1994) and neuronal excitability in dentate granule cells (McDermott and Schrader, 2011). While we have not yet directly investigated these coupling mechanisms, our findings could be explained by a KOR-dependent increase in action potential duration of local GABAergic interneurons, resulting in the observed increase in sIPSC frequency.…”

Section: Discussionmentioning

confidence: 99%

“…Although there are no studies that have tested KOR function across development in the BLA, it was previously reported that KOR function is developmentally regulated in the paraventricular nucleus of the thalamus, with a peak effect at 4 weeks of age followed by a robust and stable drop at 8 weeks (Chen et al, 2015). However, Bruchas and colleagues have reported an interaction between CRF and KORs within the BLA of adults, specifically showing that only under stress (when BLA CRF levels are presumably elevated) do KORs become activated within the BLA, as BLA microinfusions of norBNI only altered anxiety-like behaviors in stressed adult mice, but not in unstressed mice (Bruchas et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent regulation of GABA transmission by kappa opioid receptors in the basolateral amygdala of Sprague-Dawley rats

Przybysz

Werner

2017

Neuropharmacology

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Anxiety disorders are one of the most common and debilitating mental illnesses worldwide. Growing evidence indicates an age-dependent rise in the incidence of anxiety disorders from adolescence through adulthood, suggestive of underlying neurodevelopmental mechanisms. Kappa opioid receptors (KORs) are known to contribute to the development and expression of anxiety; however, the functional role of KORs in the basolateral amygdala (BLA), a brain structure critical in mediating anxiety, particularly across ontogeny, are unknown. Using whole-cell patch-clamp electrophysiology in acute brain slices from adolescent (postnatal day (P) 30–45) and adult (P60+) male Sprague-Dawley rats, we found that KOR activation increased the frequency of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in the adolescent BLA, without an effect in the adult BLA or on sIPSC amplitude at either age. The KOR effect was blocked by the KOR antagonist, nor-BNI, which alone did not alter GABA transmission at either age, and the effect of the KOR agonist was TTX-sensitive. Additionally, KOR activation did not alter glutamatergic transmission in the BLA at either age. In contrast, U69593 inhibited sIPSC frequency in the central amygdala (CeA) at both ages, without altering sIPSC amplitude. Western blot analysis of KOR expression indicated that KOR levels were not different between the two ages in either the BLA or CeA. This is the first study to provide compelling evidence for a novel and unique neuromodulatory switch in one of the primary brain regions involved in initiating and mediating anxiety that may contribute to the ontogenic rise in anxiety disorders.

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“…In support of these notably different behavioral effects associated with pharmacological activation and/or suppression of the DYN/KOR system across ontogeny, we recently found that KOR activation in the basolateral amygdala (BLA) of adolescent rats increased GABA transmission, without having an effect in the adult BLA (Przybysz, Werner, & Diaz, 2017). An age-dependent increase followed by a decrease in DYN-mediated hyperpolarization of neurons within the paraventricular nucleus of the thalamus has also been shown (Chen et al, 2015). Hence, there is clear behavioral and cellular evidence consistent with age-dependent differences in the functional role of the DYN/KOR system (Diaz et al, in press).…”

Section: Introductionmentioning

confidence: 95%

Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats

Spear

Diaz

2018

Preprint

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The dynorphin/kappa (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adults, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny.Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development.

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Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus

Cited by 26 publications

References 69 publications

Adolescent forced swim stress increases social anxiety-like behaviors and alters the dynorphin/kappa opioid receptor system in the basolateral amygdala of males

Adolescent forced swim stress increases social anxiety-like behaviors and alters the dynorphin/kappa opioid receptor system in the basolateral amygdala of males

Age-dependent regulation of GABA transmission by kappa opioid receptors in the basolateral amygdala of Sprague-Dawley rats

Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats

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