Abstract:Opioid receptors can display spontaneous agonist-independent G-protein signaling (basal signaling/constitutive activity). While constitutive κ-opioid receptor (KOR) activity has been documented in vitro, it is unknown if KORs are constitutively active in native systems. Using [35S] GTPγS coupling assay that measures receptor functional state, we identified the presence of medial prefrontal cortex (mPFC) KOR constitutive activity in young rats that declined with age. Furthermore, basal signaling showed an age-r… Show more
“…In this study, our data support the latter mechanism: a single exposure to an acute stressor causes a lasting constitutive activation of VTA κORs that suppresses plasticity at inhibitory synapses correlated with stress-induced drug-seeking (Figure 7). While previous studies have demonstrated constitutive activity of κORs in cultured cells and in the rat brain (Wang et al, 2007; Sirohi and Walker, 2015), ours is the first demonstration of experience-induced changes in constitutive activity of these receptors. This represents a novel mechanism of regulation by acute stress of the dynorphin-κOR system, and sheds new light on signaling pathways involved in reinstatement of drug seeking.10.7554/eLife.23785.011Figure 7.Constitutive activation of κORs by stress.( A ) During stress, dynorphin binding to the κOR triggers a shift to a constitutively active state.…”
Stressful experiences potently activate kappa opioid receptors (κORs). κORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of κORs. This is mediated by activation of the receptor during the stressor followed by a persistent, ligand-independent constitutive activation of the κOR itself. This lasting change in function is not seen at κORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of different subsets of κORs. We also provide evidence that constitutive activity of κORs governs the prolonged reinstatement to cocaine-seeking observed after cold water swim stress. Together, our studies indicate that stress-induced constitutive activation is a novel mechanism of κOR regulation that plays a critical role in reinstatement of drug seeking.DOI:
http://dx.doi.org/10.7554/eLife.23785.001
“…In this study, our data support the latter mechanism: a single exposure to an acute stressor causes a lasting constitutive activation of VTA κORs that suppresses plasticity at inhibitory synapses correlated with stress-induced drug-seeking (Figure 7). While previous studies have demonstrated constitutive activity of κORs in cultured cells and in the rat brain (Wang et al, 2007; Sirohi and Walker, 2015), ours is the first demonstration of experience-induced changes in constitutive activity of these receptors. This represents a novel mechanism of regulation by acute stress of the dynorphin-κOR system, and sheds new light on signaling pathways involved in reinstatement of drug seeking.10.7554/eLife.23785.011Figure 7.Constitutive activation of κORs by stress.( A ) During stress, dynorphin binding to the κOR triggers a shift to a constitutively active state.…”
Stressful experiences potently activate kappa opioid receptors (κORs). κORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of κORs. This is mediated by activation of the receptor during the stressor followed by a persistent, ligand-independent constitutive activation of the κOR itself. This lasting change in function is not seen at κORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of different subsets of κORs. We also provide evidence that constitutive activity of κORs governs the prolonged reinstatement to cocaine-seeking observed after cold water swim stress. Together, our studies indicate that stress-induced constitutive activation is a novel mechanism of κOR regulation that plays a critical role in reinstatement of drug seeking.DOI:
http://dx.doi.org/10.7554/eLife.23785.001
“…The release of DYN opioid peptides and KOR activation putatively regulate acute elevations in N 2 O-induced mesolimbic dopamine release [31] . Although, maturational decline in KOR constitutive activity occurs in rats [32] , which could differentially affect KORs ligand efficacy and impart consequential age-related effects. Age-dependent decline in KOR activity or its desensitization likely explain the N 2 O-induced, DYN-mediated activation of the nonopioid targets responsible for amyloidogenesis, including modulation of glutamate receptors [33] and caspase activation.…”
Introduction
Dysregulated lipid metabolism and nutrient status are thought to play a role in the pathophysiology of Alzheimer's disease (AD). However, the precise involvement is not well understood, and it remains unclear exactly how such dysregulated lipid metabolism and altered nutrient status, especially changes in phosphatidylcholine, B12, and folate, are connected to the hallmark pathology in AD (i.e., amyloidogenesis).
Methods
We have postulated that genetic susceptibility (i.e., APOE ε4/ε4) to environmental exposure to emissions of nitrous oxide (N
2
O) could underlie the onset of AD and its early neuropsychiatric correlates
Results and Discussion
The current theoretical editorial describes, using clinical, preclinical, and in vitro evidences, how this model contributes not only to amyloidogenesis but also other nonopioid effects, specifically altered lipid metabolism, depletion of vitamin B12, and disruption of the folate-mediated one carbon metabolic pathway.
“…Given that Agostini et al report non-significant differences in humoral immunity among aMCI converters versus non-converters yet a higher avidity index (which could be indicative not necessarily of robust host immune response, but of greater accumulation of viral antigen and, thereby, more favorable geometric interaction with antibody, as avidity is determined by antigen-antibody complexing), alternative explanations beyond robust host immunity must be considered in the link between HSV-1 reactivation and AD. 2 It is hypothesized here that chronic, trace N 2 O-induced DYN release promotes HSV-1 reactivation through specific immunosuppression, whereas high viral load (indicative of higher avidity) depletes N 2 O-induced, DYN-mediated non-opioid reactivity (presumably enhanced due to the age-related decline in the activity of cognate receptors 12 ), and this protects against DYN neurotoxicity and conversion to widespread neurodegeneration among aMCI. It is also interesting to speculate whether HSV reactivation in AD occurs proportionately to the maturational decline in the constitutive activity of KOR, which could differentially affect KOR ligand efficacy and impart consequential nonopioid, AD-related effects (i.e.…”
Section: Environmental Nitrous Oxide Exposure Ad Pathology and Hsv-1mentioning
confidence: 99%
“…This model of N 2 O-induced neurodegeneration is likely to be more pronounced in the aged cohort due to the constitutive decline in the activity of cognate KOR receptors for DYN peptide that has been shown in the Wistar rat, compounding the non-opioid action of DYN. 12 The Wistar rat has also been previously shown to have particular susceptibility to the chronic effects of N 2 O, including "shrinkage and vacuolation of neurons in cerebral cortex." 15…”
Section: Animal Models To Test Trace N 2 O-induced Hsv Reactivationmentioning
Many have described the molecular mechanisms underpinning the viral etiology of Alzheimer's disease. This commentary challenges this premise by discussing evidence that Herpes simplex virus reactivation reduces progression to Alzheimer's disease, and also proposing that viral reactivation is a compensatory reaction to other causal exposures in Alzheimer's disease pathophysiology.
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