Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice

Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Harris, R. Adron

doi:10.3389/fnins.2014.00129

Cited by 64 publications

(66 citation statements)

References 59 publications

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“…Recent studies in rodent models have demonstrated decreased drinking behavior in animals given phosphodiesterase inhibitors (Hu et al, 2011;Wen et al, 2012;Blednov et al, 2014;Franklin et al, 2015). Together, these studies suggest that phosphodiesterase inhibition provides a promising target for the treatment of alcohol use disorders.…”

Section: Discussionmentioning

confidence: 89%

Ethanol Regulation of Synaptic GABAA 4 Receptors Is Prevented by Protein Kinase A Activation

Carlson

Bohnsack

Morrow

2016

Journal of Pharmacology and Experimental Therapeutics

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Ethanol alters GABA A receptor trafficking and function through activation of protein kinases, and these changes may underlie ethanol dependence and withdrawal. In this study, we used subsynaptic fraction techniques and patch-clamp electrophysiology to investigate the biochemical and functional effects of protein kinase A (PKA) and protein kinase C (PKC) activation by ethanol on synaptic GABA A a4 receptors, a key target of ethanol-induced changes. Rat cerebral cortical neurons were grown for 18 days in vitro and exposed to ethanol and/or kinase modulators for 4 hours, a paradigm that recapitulates GABAergic changes found after chronic ethanol exposure in vivo. PKA activation by forskolin or rolipram during ethanol exposure prevented increases in P2 fraction a4 subunit abundance, whereas inhibiting PKA had no effect. Similarly, in the synaptic fraction, activation of PKA by rolipram in the presence of ethanol prevented the increase in synaptic a4 subunit abundance, whereas inhibiting PKA in the presence of ethanol was ineffective. Conversely, PKC inhibition in the presence of ethanol prevented the ethanol-induced increases in synaptic a4 subunit abundance. Finally, we found that either activating PKA or inhibiting PKC in the presence of ethanol prevented the ethanol-induced decrease in GABA miniature inhibitory postsynaptic current decay t 1 , whereas inhibiting PKA had no effect. We conclude that PKA and PKC have opposing effects in the regulation of synaptic a4 receptors, with PKA activation negatively modulating, and PKC activation positively modulating, synaptic a4 subunit abundance and function. These results suggest potential targets for restoring normal GABAergic functioning in the treatment of alcohol use disorders.

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Section: Discussionmentioning

confidence: 89%

Ethanol Regulation of Synaptic GABAA 4 Receptors Is Prevented by Protein Kinase A Activation

Carlson

Bohnsack

Morrow

2016

Journal of Pharmacology and Experimental Therapeutics

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“…Mice treated with either LV-Cre-EGFP or LV-EGFP-Empty were given continuous access to water and ascending concentrations of ethanol solutions (3%, 6%, 8%, 10%, 12%, 14%, and 16%, v/v) at 2 d intervals (Blednov et al, 2014). The position of administration tubes was changed daily to control for position preferences.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

Truitt

Blednov

Benavidez

et al. 2016

eNeuro

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Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. The nuclear factor-κB (NF-κB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKβ mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-κB, leading to activation of NF-κB. The role of IKKβ as a potential regulator of excessive alcohol drinking had not previously been investigated. Based on previous findings that the overactivation of innate immune/inflammatory signaling promotes ethanol consumption, we hypothesized that inhibiting IKKβ would limit/decrease drinking by preventing the activation of NF-κB. We studied the systemic effects of two pharmacological inhibitors of IKKβ, TPCA-1 and sulfasalazine, on ethanol intake using continuous- and limited-access, two-bottle choice drinking tests in C57BL/6J mice. In both tests, TPCA-1 and sulfasalazine reduced ethanol intake and preference without changing total fluid intake or sweet taste preference. A virus expressing Cre recombinase was injected into the nucleus accumbens and central amygdala to selectively knock down IKKβ in mice genetically engineered with a conditional Ikkb deletion (IkkbF/F). Although IKKβ was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKKβ in either brain region reduced ethanol intake and preference in the continuous access two-bottle choice test without altering the preference for sucrose. Pharmacological and genetic inhibition of IKKβ decreased voluntary ethanol consumption, providing initial support for IKKβ as a potential therapeutic target for alcohol abuse.

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“…These drugs are thought to reduce inflammation by increasing cAMP concentration resulting in reduced NF-κB activation (Jimenez et al, 2001). Recently, these agents have been found to reduce ethanol intake in rodents (Bell et al, 2015; Blednov et al, 2014; Hu et al, 2011). A phase I clinical trial involving the PDE4 inhibitor ibudilast was recently completed but has not yet been reported.…”

Section: New Treatments Strategies Based On Immune Pharmacologymentioning

confidence: 99%

The role of neuroimmune signaling in alcoholism

et al. 2017

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Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies.

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Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice

Cited by 64 publications

References 59 publications

Ethanol Regulation of Synaptic GABAA 4 Receptors Is Prevented by Protein Kinase A Activation

Ethanol Regulation of Synaptic GABAA 4 Receptors Is Prevented by Protein Kinase A Activation

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

The role of neuroimmune signaling in alcoholism

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