Carbonic anhydrase 4 disruption decreases synaptic and behavioral adaptations induced by cocaine withdrawal

Gupta, Subhash Chandra; Ghobbeh, Ali; Taugher-Hebl, Rebecca J.; Fan, Rong; Hardie, Jason B.; LaLumiere, Ryan T.; Wemmie, John A.

doi:10.1126/sciadv.abq5058

Cited by 4 publications

(17 citation statements)

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“…Because NAcc is thought to be an important site of ASIC action in cocaine seeking ( Kreple et al, 2014 ; Gupta et al, 2022 ), we assessed expression of ASIC2A and ASIC2B subunits at this site. We dissected out NAcc bilaterally from wild-type and Asic2 −/− mice and assessed ASIC2 expression via western blot.…”

Section: Resultsmentioning

confidence: 99%

“…A number of previous studies have also reported effects of cocaine withdrawal on spines in NAcc MSNs, however results of these studies have varied. While some have reported increased dendritic spines in NAcc following cocaine withdrawal ( Christian et al, 2017 ; Gupta et al, 2022 ), others have reported decreased spine density ( Dumitriu et al, 2012 ). Some have reported effects only in specific populations of MSNs, stratified by presynaptic input or dopamine receptor (D1R/D2R) classification ( Lee et al, 2006 ; Kim et al, 2011 ; MacAskill et al, 2014 ; Siemsen et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

“…ASIC1A and ASIC2 subunits have been localized to post-synaptic dendritic spines and synaptosomes (Zha et al, 2006;Zha et al, 2009), where they are positioned to respond to synaptically released protons. Consistent with this possibility, ASIC-dependent synaptic currents have been identified during synaptic transmission in a variety of neuron types, including NAcc MSNs (Du et al, 2014;Kreple et al, 2014;González-Inchauspe et al, 2017;Gupta et al, 2022). Inhibiting or genetically disrupting ASIC1A eliminated this current, while disrupting ASIC2 subunits reduced these currents by ~50% (Kreple et al, 2014), suggesting that both ASIC1A and ASIC2 subunits contribute to the synaptically-evoked currents.…”

Section: Introductionmentioning

confidence: 90%

“…Dye application was performed similarly to Gupta et al (2022) and imaging similarly to Dumitriu et al (2012) . Following 7 days of saline or 7 days of cocaine (10 mg/kg i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…Our previous work implicated ASICs in cocaine- and opioid-reinforced synaptic and behavioral effects ( Kreple et al, 2014 ; Gupta et al, 2022 ). ASICs are cation channels activated by extracellular acidosis.…”

Section: Introductionmentioning

confidence: 99%

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Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse

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Gupta

Fan

et al. 2023

Front. Mol. Biosci.

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Drugs of abuse produce rearrangements at glutamatergic synapses thought to contribute to drug-reinforced behaviors. Acid-Sensing Ion Channels (ASICs) have been suggested to oppose these effects, largely due to observations in mice lacking the ASIC1A subunit. However, the ASIC2A and ASIC2B subunits are known to interact with ASIC1A, and their potential roles in drugs of abuse have not yet been investigated. Therefore, we tested the effects of disrupting ASIC2 subunits in mice exposed to drugs of abuse. We found conditioned place preference (CPP) to both cocaine and morphine were increased in Asic2−/− mice, which is similar to what was observed in Asic1a−/− mice. Because nucleus accumbens core (NAcc) is an important site of ASIC1A action, we examined expression of ASIC2 subunits there. By western blot ASIC2A was readily detected in wild-type mice, while ASIC2B was not, suggesting ASIC2A is the predominant subunit in nucleus accumbens core. An adeno-associated virus vector (AAV) was used to drive recombinant ASIC2A expression in nucleus accumbens core of Asic2−/− mice, resulting in near normal protein levels. Moreover, recombinant ASIC2A integrated with endogenous ASIC1A subunits to form functional channels in medium spiny neurons (MSNs). However, unlike ASIC1A, region-restricted restoration of ASIC2A in nucleus accumbens core was not sufficient to affect cocaine or morphine conditioned place preference, suggesting effects of ASIC2 differ from those of ASIC1A. Supporting this contrast, we found that AMPA receptor subunit composition and the ratio of AMPA receptor-mediated current to NMDA receptor-mediated current (AMPAR/NMDAR) were normal in Asic2−/− mice and responded to cocaine withdrawal similarly to wild-type animals. However, disruption of ASIC2 significantly altered dendritic spine morphology, and these effects differed from those reported previously in mice lacking ASIC1A. We conclude that ASIC2 plays an important role in drug-reinforced behavior, and that its mechanisms of action may differ from ASIC1A.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

“…Dye application was performed similarly to Gupta et al (2022) and imaging similarly to Dumitriu et al (2012) . Following 7 days of saline or 7 days of cocaine (10 mg/kg i.p.)…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse

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Gupta

Fan

et al. 2023

Front. Mol. Biosci.

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Predicting potential therapeutic targets and small molecule drugs for early-stage lung adenocarcinoma

Yu,

Li,

Luo

et al. 2024

Biomedicine & Pharmacotherapy

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Effects of acid-sensing ion channel-1A (ASIC1A) on cocaine-induced synaptic adaptations

et al. 2023

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Chronic drug abuse is thought to induce synaptic changes in nucleus accumbens medium spiny neurons (MSNs) that promote subsequent craving and drug-seeking behavior. Accumulating data suggest acid-sensing ion channels (ASICs) may play a critical role. In drug naïve mice, disrupting the ASIC1A subunit produced a variety of synaptic changes reminiscent of wild-type mice following cocaine withdrawal, including increased AMPAR/NMDAR ratio, increased AMPAR rectification, and increased dendrite spine density. Importantly, these changes in Asic1a−/− mice were normalized by a single dose of cocaine. Here we sought to understand the temporal effects of cocaine exposure in Asic1a−/− mice and the cellular site of ASIC1A action. Six hours after cocaine exposure, there was no effect. However, 15 h, 24 h and 4 days after cocaine exposure there was a significant reduction in AMPAR/NMDAR ratio in Asic1a−/− mice. Within 7 days the AMPAR/NMDAR ratio had returned to baseline levels. Cocaine-evoked changes in AMPAR rectification and dendritic spine density followed a similar time course with significant reductions in rectification and dendritic spines 24 h after cocaine exposure in Asic1a−/− mice. To test the cellular site of ASIC1A action on these responses, we disrupted ASIC1A specifically in a subpopulation of MSNs. We found that effects of ASIC1A disruption were cell autonomous and restricted to neurons in which the channels are disrupted. We further tested whether ASIC1A disruption differentially affects MSNs subtypes and found AMPAR/NMDAR ratio was elevated in dopamine receptor 1-expressing MSNs, suggesting a preferential effect for these cells. Finally, we tested if protein synthesis was involved in synaptic adaptations that occurred after ASIC1A disruption, and found the protein synthesis inhibitor anisomycin normalized AMPAR-rectification and AMPAR/NMDAR ratio in drug-naïve Asic1a−/− mice to control levels, observed in wild-type mice. Together, these results provide valuable mechanistic insight into the effects of ASICs on synaptic plasticity and drug-induced effects and raise the possibility that ASIC1A might be therapeutically manipulated to oppose drug-induced synaptic changes and behavior.

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Carbonic anhydrase 4 disruption decreases synaptic and behavioral adaptations induced by cocaine withdrawal

Cited by 4 publications

References 60 publications

Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse

Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse

Predicting potential therapeutic targets and small molecule drugs for early-stage lung adenocarcinoma

Effects of acid-sensing ion channel-1A (ASIC1A) on cocaine-induced synaptic adaptations

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