Phosphodiesterase regulation of alcohol drinking in rodents

Logrip, Marian L.

doi:10.1016/j.alcohol.2015.03.007

Cited by 42 publications

(35 citation statements)

References 113 publications

(141 reference statements)

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“…Our study not only confirms the association between PDE10A with alcohol use, but it also identifies a dose-independent relationship between alcohol consumption, increased PDE10A –DMR methylation levels and a correlated decrease in exon 2b expression in the NAcc. We postulate that the downregulation of the associated PDE10A TVs contribute to maintaining the alcohol-induced high levels of cAMP/cGMP reported by others (Logrip, 2015). …”

Section: Discussionsupporting

confidence: 60%

“…Among the DMRs identified, we selected two ( PDE10A and FZD5 ) for validation studies based on their differing alcohol-dose patterns and their roles in two signaling pathways prominently associated with alcohol use, cAMP and Wnt, respectively. In addition, these two genes have been previously identified in alcohol studies in rodents and humans (Logrip, 2015; Wang et al, 2016), although the relationship between alcohol dose, DNA methylation and gene expression had not been described. Using BSAS and a larger sample set, we confirmed the significant DNA methylation difference between ANs, L/BDs and H/VHDs (Figure 2c; Figure 3c).…”

Section: Resultsmentioning

confidence: 99%

“…Remarkably, the L/BD regional cluster analysis identified 9 DMRs, 4 of which mapped to genes with known links to alcohol use ( PDE10A, CCBE1, FZD5, MZF1 ) (Driver et al, 2015; Edenberg et al, 2010; Logrip, 2015; Wang et al, 2016). The other 5 DMRs map to 4 genes of relevance to synaptic signaling ( PKD2L2, FXDY5, TRAPPC9, MACROD1 ) (Fiederling et al, 2011; Georgolios et al, 2012; Hu et al, 2005; Spanagel et al, 2014; Wu et al, 2011) although this is the first report to specifically link them to sustained levels of voluntary alcohol drinking.…”

Section: Discussionmentioning

confidence: 99%

“…The other alcohol dose-independent DMR mapped to PDE10A , encoding cyclic nucleotide phosphodiesterase10A, a dual-specificity phosphodiesterase able to deactivate both cAMP and cGMP. Inhibition of PDE10A activity in the dorsolateral striatum was reported to significantly reduce alcohol and saccharin self-administration in rodent models (Logrip, 2015), highlighting its role in regulating motivated behaviors. While inhibition of PDE10A in the NAcc had no effect on rodent alcohol use (Logrip et al, 2014), the contribution of alternative PDE10A TVs are unknown.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

Cervera-Juanes

Wilhelm

Park

et al. 2017

Alcohol

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Alcohol use disorders encompass a range of drinking levels and behaviors, including low, binge and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression and the predicted neural effects in the nucleus accumbens of male rhesus macaques categorized as “low” or “binge” drinkers, compared to “alcohol-naïve” and “heavy” drinkers based on drinking patterns during a 12 month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol naïve (AN), low/binge (L/BD) and heavy/very heavy (H/VHD) drinking subjects (n=24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to PDE10A and PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However two other DMRs, linked to the CCBE1 and FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining 5 DMRs also differentiated L/BDs and ANs, however H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to FZD5 and PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and identifies synaptic genes that may play a role in preventing the escalation of alcohol use.

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Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

Cervera-Juanes

Wilhelm

Park

et al. 2017

Alcohol

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“…Regulation of alcohol drinking by many different subtypes of PDEs and the underlying signaling mechanisms involved have been recently reviewed in great detail (Logrip, 2015). In this review, we will review recent progress of studying behavioral effects of PDE4 inhibitors on alcohol drinking.…”

Section: Effects Of Pde4 Inhibitors On Drug-associated Behaviorsmentioning

confidence: 99%

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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Aerobic exercise as a promising nonpharmacological therapy for the treatment of substance use disorders

Marrero-Cristobal

Gelpi-Dominguez

Morales-Silva

et al. 2021

J of Neuroscience Research

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Substance use disorder (SUD) is a complex condition that involves the induction of molecular and physiological alterations by the use and abuse of illicit substances. The prevalence of illicit drug use has caused this disorder to grow exponentially over the past 5 years (National Institute of Drug Abuse, 2020). To date, there are several FDA-approved pharmacological treatments for substances that may cause dependency, such as heroin, morphine, alcohol, and nicotine, directed to the attenuation of drug craving, and increase time to relapse. Known as medication-assisted treatment, such FDA-approved pharmaceutical interventions can be used to increase the effectiveness of other substance abuse treatments, including the use of buprenorphine (commonly used in opioid use disorder, OUD).Buprenorphine works as a partial agonist that binds to the opioid receptors in the brain, allowing a partial activation of the receptor when it is activated with opioids, and thus reducing the rewarding effects (James & Williams, 2020). Another FDA-approved treatment for OUD is naloxone, a known opioid receptor antagonist that reduces activation and prevents other endogenous ligands to bind to that receptor (Becker & Chartoff, 2019;James & Williams, 2020). These types of pharmacological treatments are still not available for substances such as cocaine, methamphetamines, or cannabis which limit treatment options. The percentage cocaine users aged

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Phosphodiesterase regulation of alcohol drinking in rodents

Cited by 42 publications

References 113 publications

Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

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

Aerobic exercise as a promising nonpharmacological therapy for the treatment of substance use disorders

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