Adenylyl Cyclase 1 Is Required for Ethanol-Induced Locomotor Sensitization and Associated Increases in NMDA Receptor Phosphorylation and Function in the Dorsal Medial Striatum

Bosse, Kelly E.; Oginsky, Max F.; Susick, Laura L.; Ramalingam, Sailesh; Ferrario, Carrie R.; Conti, Alana C.

doi:10.1124/jpet.117.242321

Cited by 9 publications

(5 citation statements)

References 47 publications

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“…Consistent with this nding, we found that hNB001, which can be used for the treatment of chronic pain in human, also did not affect acute nociceptive responses to mechanical stimuli and noxious thermal stimuli in naive mice. Previous studies showed that AC1 KO or NB001-treated mice exhibited normal motor functions and anxiety-like behavior (34,35). In the present study, hNB001 did not affect motor functions and anxiety-like behavior in naive adult mice (Table 1).…”

Section: Anxiety-like Behaviorsupporting

confidence: 56%

Selective enhancement of fear extinction by inhibiting neuronal adenylyl cyclase 1 (AC1) in aged mice

Shi,

Chen,

et al. 2024

Preprint

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Adenylyl cyclase 1 (AC1) is a selective subtype of ACs, which is selectively expressed in neurons. The activation of AC1 is activity-dependent, and AC1 plays an important role in cortical excitation that contributes to chronic pain and related emotional disorders. Previous studies have reported that human-used NB001 (hNB001, a selective AC1 inhibitor) produced analgesic effects in different animal models of chronic pain. However, the potential effects of hNB001 on learning and memory have been less investigated. In the present study, we found that hNB001 affected neither the induction nor the expression of trace fear, but selectively enhanced the relearning ability during the extinction in aged mice. By contrast, the same application of hNB001 did not affect recent, remote auditory fear memory, or remote fear extinction in either adult or aged mice. Furthermore, a single or consecutive 30-day oral administration of hNB001 did not affect acute nociceptive response, motor function, or anxiety-like behavior in either adult or aged mice. Our results are consistent with previous findings that inhibition of AC1 did not affect general sensory, emotional, and motor functions in adult mice, and provide strong evidence that inhibiting the activity of AC1 may be beneficial for certain forms of learning and memory in aged mice.

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Section: Anxiety-like Behaviorsupporting

confidence: 56%

Selective enhancement of fear extinction by inhibiting neuronal adenylyl cyclase 1 (AC1) in aged mice

Shi,

Chen,

et al. 2024

Preprint

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“…Our findings that activation of G i/o signaling in the dorsal striatum reduces alcohol intake would suggest a role for adenylyl cyclase and cAMP in this behavior. Recently, reductions in cAMP levels in the dorsal striatum by adenylyl cyclase type 1 (AC1) inhibition and AC1-KO have been associated with decreased ethanol-induced locomotor sensitization ( 65 ). Furthermore, blockade of dorsal striatal G s -coupled dopamine D 1 receptors (but not blockade of G i/o -coupled dopamine D 2 ) attenuates alcohol consumption ( 8 ), suggesting indeed that inhibition of cAMP production in the dorsal striatum may contribute to reduced alcohol use.…”

Section: Discussionmentioning

confidence: 99%

Critical Role for Gi/o-Protein Activity in the Dorsal Striatum in the Reduction of Voluntary Alcohol Intake in C57Bl/6 Mice

Robins

Chiang

et al. 2018

Front. Psychiatry

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The transition from non-dependent alcohol use to alcohol dependence involves increased activity of the dorsal striatum. Interestingly, the dorsal striatum expresses a large number of inhibitory G-protein-coupled receptors (GPCRs), which when activated may inhibit alcohol-induced increased activity and can decrease alcohol consumption. Here, we explore the hypothesis that dorsal striatal Gi/o-protein activation is sufficient to reduce voluntary alcohol intake. Using a voluntary, limited-access, two-bottle choice, drink-in-the-dark model of alcohol (10%) consumption, we validated the importance of Gi/o signaling in this region by locally expressing neuron-specific, adeno-associated-virus encoded Gi/o-coupled muscarinic M4 designer receptors exclusively activated by designer drugs (DREADD) in the dorsal striatum and observed a decrease in alcohol intake upon DREADD activation. We validated our findings by activating Gi/o-coupled delta-opioid receptors (DORs), which are natively expressed in the dorsal striatum, using either a G-protein biased agonist or a β-arrestin-biased agonist. Local infusion of TAN-67, an in vitro-determined Gi/o-protein biased DOR agonist, decreased voluntary alcohol intake in wild-type and β-arrestin-2 knockout (KO) mice. SNC80, a β-arrestin-2 biased DOR agonist, increased alcohol intake in wild-type mice; however, SNC80 decreased alcohol intake in β-arrestin-2 KO mice, thus resulting in a behavioral outcome generally observed for Gi/o-biased agonists and suggesting that β-arrestin recruitment is required for SNC80-increased alcohol intake. Overall, these results suggest that activation Gi/o-coupled GPCRs expressed in the dorsal striatum, such as the DOR, by G-protein biased agonists may be a potential strategy to decrease voluntary alcohol consumption and β-arrestin recruitment is to be avoided.

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“…Ethanol affects receptor trafficking through changes e.g. in NMDA receptor phosphorylation and also neurosteroid synthesis is influenced by alcohol [6–14].…”

Section: Introductionmentioning

confidence: 99%

Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures

et al. 2019

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BackgroundThe pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic and sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a γ-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons.MethodWe used electrophysiological recordings from organotypic slice cultures derived from Sprague–Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase.ResultsWhile both substances seem to decrease neocortical action potential firing in a not significantly different (p = 0.659, Mann–Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p < 0.05). Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam for a wide frequency range and a narrow-band de-synchronizing effect for ethanol (p < 0.05, Kolmogorov–Smirnov test).ConclusionDiazepam and ethanol, induce specific patterns of network depressant actions. Diazepam induces cortical network inhibition and increased synchronicity via gamma subunit containing GABAA receptors. Ethanol also induces cortical network inhibition, but without an increase in synchronicity via a wider span of molecular targets.

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Adenylyl Cyclase 1 Is Required for Ethanol-Induced Locomotor Sensitization and Associated Increases in NMDA Receptor Phosphorylation and Function in the Dorsal Medial Striatum

Cited by 9 publications

References 47 publications

Selective enhancement of fear extinction by inhibiting neuronal adenylyl cyclase 1 (AC1) in aged mice

Selective enhancement of fear extinction by inhibiting neuronal adenylyl cyclase 1 (AC1) in aged mice

Critical Role for Gi/o-Protein Activity in the Dorsal Striatum in the Reduction of Voluntary Alcohol Intake in C57Bl/6 Mice

Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures

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