scholarly journals Kappa Opioid Receptor and Dynorphin Signaling in the Central Amygdala Regulates Alcohol Intake

2019 ◽  
Author(s):  
Daniel W. Bloodgood ◽  
Dipanwita Pati ◽  
Melanie M. Pina ◽  
Sofia Neira ◽  
J. Andrew Hardaway ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Alcohol Drinking ◽  
Alcohol Intake ◽  
Gene Knockout ◽  
Kappa Opioid Receptor ◽  
Conditional Knockout ◽  
Central Nucleus ◽  
Kappa Opioid ◽  
Excessive Alcohol Consumption ◽  
Excessive Alcohol

AbstractExcessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. We then examined the effects of DID on PDYN and KOR modulation of CeA circuit physiology. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

scholarly journals Alcohol Drinking Alters Stress Response to Predator Odor via Extended Amygdala Kappa Opioid Receptor Signaling in Male Mice

2019 ◽  
Author(s):  
Lara S. Hwa ◽  
Sofia Neira ◽  
Meghan E. Flanigan ◽  
Christina M. Stanhope ◽  
Melanie M. Pina ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Stress Responses ◽  
Alcohol Drinking ◽  
Kappa Opioid Receptor ◽  
Predator Odor ◽  
Stria Terminalis ◽  
Receptor Signaling ◽  
Kappa Opioid ◽  
Bed Nucleus ◽  
Heavy Alcohol

AbstractMaladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST compared to drinking or stress alone. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal from heavy drinking. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.Impact StatementHeavy alcohol drinking primes dynorphin / kappa opioid systems in the bed nucleus of the stria terminalis to alter stress responses in mice.

scholarly journals Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lara S Hwa ◽  
Sofia Neira ◽  
Meghan E Flanigan ◽  
Christina M Stanhope ◽  
Melanie M Pina ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Stress Responses ◽  
Alcohol Drinking ◽  
Kappa Opioid Receptor ◽  
Predator Odor ◽  
Stria Terminalis ◽  
Receptor Signaling ◽  
Kappa Opioid ◽  
Bed Nucleus ◽  
Heavy Alcohol

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here, we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic inhibition of the PFC-BNST pathway restored abnormal responses to predator odor in alcohol-exposed mice. These findings suggest that increased corticolimbic drive may promote abnormal stress behavioral responses to predator odor during protracted withdrawal. Various nodes of this PFC-BNST dynorphin-related circuit may serve as potential targets for potential therapeutic mediation as well as biomarkers of negative responses to stress following heavy alcohol drinking.

scholarly journals Activation of the kappa opioid receptor / dynorphin system alters stress and threat responding during acute withdrawal from intermittent alcohol drinking in male mice

2020 ◽  
Author(s):  
Lara S. Hwa ◽  
Sofia Neira ◽  
Dipanwita Pati ◽  
Melanie M. Pina ◽  
Morgan Bowling ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Alcohol Drinking ◽  
Kappa Opioid Receptor ◽  
Predator Odor ◽  
List Type ◽  
Kappa Opioid ◽  
Swim Stress ◽  
Acute Withdrawal ◽  
Stress Behavior ◽  
Forced Swim

AbstractThe dynorphin/kappa opioid receptor (KOR) system in the brain regulates both stressful experiences and negative, aversive states during withdrawal from drugs of abuse. We explored the role of this system during acute withdrawal from long-term alcohol drinking, focusing on the bed nucleus of the stria terminalis (BNST), a region strongly implicated in alcohol-withdrawal induced alterations of behavior. Male C57BL/6J mice were subjected to repeated forced swim tests, home cage exposure to a predator odor, and a visual threat after eight weeks intermittent access to alcohol or water. Systemic injection of KOR antagonist norBNI reversed alcohol-related differences in immobility time during the second swim test and reduced burying behavior in response to predator odor, but did not affect behavioral response to visual threat. In dynorphin-GFP reporter mice, c-Fos immunoreactivity was increased in dynorphin-containing neurons after repeated swim stress and alcohol drinking. Using dynorphin-GFP mice, there was enhanced spontaneous excitatory synaptic drive onto dynorphin neurons in the BNST after alcohol-drinking mice underwent forced swim stress. Finally, knockdown of dynorphin in the BNST using a viral shRNA affected swim stress behavior and responses to TMT in alcohol drinkers and controls, but did not affect alcohol drinking. These studies confirm BNST dynorphin recruitment during acute withdrawal as playing a key role in altered behavioral responses to stressful stimuli.HighlightsIntermittent alcohol drinking changed stress reactions in mice.KOR antagonist norBNI altered stress responses in alcohol drinkers.Alcohol and swim stress increased c-Fos immunoreactivity in BNST dynorphin neurons.Swim stress enhanced excitatory drive onto BNST dynorphin cells in alcohol mice.BNST dynorphin knockdown affected some stress behavior, but not alcohol drinking.

scholarly journals Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Sophia Khom ◽  
Jacques D. Nguyen ◽  
Sophia A. Vandewater ◽  
Yanabel Grant ◽  
Marisa Roberto ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Wistar Rats ◽  
Kappa Opioid Receptor ◽  
Female Rats ◽  
Central Nucleus ◽  
Self Administration ◽  
Kappa Opioid ◽  
Extended Access ◽  
Female Wistar Rats ◽  
Saline Vehicle

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

scholarly journals Dynorphin-kappa opioid receptor activity in the central amygdala modulates binge-like alcohol drinking in mice

2018 ◽  
Vol 44 (6) ◽  
pp. 1084-1092 ◽  
Author(s):  
Rachel I. Anderson ◽  
Marcelo F. Lopez ◽  
William C. Griffin ◽  
Harold L. Haun ◽  
Daniel W. Bloodgood ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Alcohol Drinking ◽  
Kappa Opioid Receptor ◽  
Receptor Activity ◽  
Central Amygdala ◽  
Kappa Opioid

scholarly journals Delineation of dynorphin and kappa opioid receptor circuit elements in alcohol consumption

2021 ◽  
Author(s):  
Melanie Pina ◽  
Dipanwita Pati ◽  
Sofia Neira ◽  
Christina Stanhope ◽  
Alex Mahoney ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Alcohol Intake ◽  
Insular Cortex ◽  
Kappa Opioid Receptor ◽  
Male Mice ◽  
Kappa Opioid ◽  
Excessive Alcohol ◽  
Circuit Elements

Alcohol use disorder is complex and multi-faceted, involving the coordination of multiple signaling systems across numerous brain region. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit elements on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR systems in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was selective for alcohol in male mice, as DYN deletion did not impact their sucrose intake. In male mice, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA only. Alcohol consumption as not affected by insula KOR knockout. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest that there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR circuit elements.

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