Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4)

Franklin, Kelle M.; Hauser, Sheketha R.; Lasek, Amy W.; McClintick, Jeanette N.; Ding, Zheng Ming; McBride, William J.; Bell, Richard L.

doi:10.1007/s00213-014-3852-3

Cited by 38 publications

(28 citation statements)

References 60 publications

(84 reference statements)

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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: 88%

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: 88%

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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“…2). In rodents, inhibition of PDE activity leads to sustained activation of PKA and to a reduction in alcohol intake in several alcohol-consumption paradigms 124, 125, 126 . Moreover, TP-10, a specific inhibitor of the PDE10A isoform, reduces relapse-like alcohol self-administration in rats 127 , and PDE10A levels correlate with the levels of alcohol consumption in rats during stress-induced relapse 128, 129 .…”

Section: Stop Pathways Gate Drinkingmentioning

confidence: 99%

Molecular mechanisms underlying alcohol-drinking behaviours

2016

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The main characteristic of alcohol use disorder is the consumption of large quantities of alcohol despite the negative consequences. The transition from the moderate use of alcohol to excessive, uncontrolled alcohol consumption results from neuroadaptations that cause aberrant motivational learning and memory processes. Here, we examine studies that have combined molecular and behavioural approaches in rodents to elucidate the molecular mechanisms that keep the social intake of alcohol in check, which we term ‘stop pathways’, and the neuroadaptations that underlie the transition from moderate to uncontrolled, excessive alcohol intake, which we term ‘go pathways’. We also discuss post-transcriptional, genetic and epigenetic alterations that underlie both types of pathways.

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“…PDE4B protein is also abundant in the ventral pallidum, the target region of the striatopallidal pathway, and this region has a similar enrichment of PDE4B relative to the other isoforms that the striatum does (Cherry and Davis, 1999). In drug naïve selectively bred alcohol preferring rats, PDE4A mRNA was elevated and PDE4B2 mRNA was reduced in the accumbens relative to the non-preferring rats (Franklin et al, 2015). …”

Section: The Pde4 Family Of Phosphodiesterasesmentioning

confidence: 99%

“…In the rat VTA, presence of mRNA differed somewhat from the substantia nigra, where PDE4A was the most abundant isoform (Perez-Torres et al, 2000). In drug naïve selectively bred high alcohol drinking (HAD1) rats, PDE4B2 mRNA was elevated in the ventral tegmental area relative to the low alcohol drinking (LAD1) rats (Franklin et al, 2015). …”

Section: The Pde4 Family Of Phosphodiesterasesmentioning

confidence: 99%

“…PDE4B and 4D were enriched in the medial amygdala, and in the basolateral amygdala, PDE4D was the only isoform detected (Perez-Torres et al, 2000). In the drug naïve selectively bred alcohol preferring rats, PDE4B1 mRNA was decreased in the central amygdala relative to the non-preferring rats (Franklin et al, 2015). …”

Section: The Pde4 Family Of Phosphodiesterasesmentioning

confidence: 99%

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Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities

Olsen

Liu

2016

Front. Biol.

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Background Long-term exposure to drugs of abuse causes an up-regulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 (PDE4) is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse. Objective Here, we review the current knowledge about central nervous system (CNS) distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction. Methods A systematic literature search was performed using the Pubmed. Results Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice. Conclusions Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.

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Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4)

Cited by 38 publications

References 60 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

Molecular mechanisms underlying alcohol-drinking behaviours

Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities

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