The N-type calcium channel is a novel target for treating alcohol use disorders

Newton, Philip M.; Messing, Robert O.

doi:10.4161/chan.3.2.8037

Cited by 11 publications

(7 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The remaining significant pathways in brain revolved around members involved with glutamatergic, calcium and G-protein signaling. Pharmacological inhibition of the N-type voltage gated calcium channel Ca v 2.2 ( Cacna1b ) results in reduced ethanol intoxication, reinforcement, and reward in mice (Newton and Messing, 2009). Kcnj5 , the G βγ -activated inward rectifying potassium channel 4 (GIRK4) contains a binding site for and is activated by ethanol (Aryal et al, 2009), and is necessary for ethanol–induced conditioned place preference in mice (Tipps et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

A Whole Methylome Study of Ethanol Exposure in Brain and Blood: An Exploration of the Utility of Peripheral Blood as Proxy Tissue for Brain in Alcohol Methylation Studies

Clark

Costin

Chan

et al. 2018

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background: Recent reviews have highlighted the potential use of blood-based methylation biomarkers as diagnostic and prognostic tools of current and future alcohol use and addiction. Due to the substantial overlap that often exists between methylation patterns across different tissues, including blood and brain, blood-based methylation may track methylation changes in brain, however, little work has explored the overlap in alcohol related methylation in these tissues. Methods: To study the effects of alcohol on the brain methylome and identify possible biomarkers of these changes in blood, we performed a methylome-wide association study in brain and blood from 40 male DBA/2J mice that received either an acute ethanol or saline intraperitoneal injection. To investigate all 22 million CpGs in the mouse genome, we enriched for the methylated genomic fraction using methyl-CpG binding domain (MBD) protein capture followed by next-generation sequencing (MBD-seq). We performed association tests in blood and brain separately followed by enrichment testing to determine if there was overlapping alcohol related methylation in the two tissues. Results: The top result for brain was a CpG located in an intron of Ttc39b (p=5.65×10−08) and for blood the top result was located in Espnl (p=5.11×10−08). Analyses implicated pathways involved in inflammation and neuronal differentiation, such as CXCR4, Il-7, and Wnt signaling. Enrichment tests indicated significant overlap among the top results in brain and blood. Pathway analyses of the overlapping genes converge on MAPKinase signaling (p=5.6×10−05) which plays a central role in acute and chronic responses to alcohol and glutamate receptor pathways, which can regulate neuroplastic changes underlying addictive behavior. Conclusions: Overall, we have shown some methylation changes in brain and blood after acute ethanol administration and that the changes in blood partly mirror the changes in brain suggesting the potential for DNA methylation in blood to be biomarkers of alcohol use.

show abstract

Section: Discussionmentioning

confidence: 99%

A Whole Methylome Study of Ethanol Exposure in Brain and Blood: An Exploration of the Utility of Peripheral Blood as Proxy Tissue for Brain in Alcohol Methylation Studies

Clark

Costin

Chan

et al. 2018

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

show abstract

“…In this paradigm, Cav1.3 appears to be the most relevant channel (N'gouemo et al, 2015); however, the paradigm is very different from our model of alcohol dependence as well as the brain regions analyzed. Furthermore, there are reports depicting a role of non-LTCCs, that is, N-type (Newton et al, 2008;Newton and Messing, 2009) and T-type calcium channels (Carden et al, 2006;Nordskog et al, 2006), in alcohol-related behavior. Therefore, we analyzed the expression of P/Q-type, N-type, and T-type non-LTCCs in 3-week abstinent rats by qRT-PCR.…”

Section: Discussionmentioning

confidence: 99%

Differential Roles for L-Type Calcium Channel Subtypes in Alcohol Dependence

Uhrig

Vandael

Marcantoni

et al. 2016

Neuropsychopharmacol

View full text Add to dashboard Cite

It has previously been shown that the inhibition of L-type calcium channels (LTCCs) decreases alcohol consumption, although the contribution of the central LTCC subtypes Cav1.2 and Cav1.3 remains unknown. Here, we determined changes in Cav1.2 (Cacna1c) and Cav1.3 (Cacna1d) mRNA and protein expression in alcohol-dependent rats during protracted abstinence and naive controls using in situ hybridization and western blot analysis. Functional validation was obtained by electrophysiological recordings of calcium currents in dissociated hippocampal pyramidal neurons. We then measured alcohol self-administration and cue-induced reinstatement of alcohol seeking in dependent and nondependent rats after intracerebroventricular (i.c.v.) injection of the LTCC antagonist verapamil, as well as in mice with an inducible knockout (KO) of Cav1.2 in Ca/calmodulin-dependent protein kinase IIα (CaMKIIα)-expressing neurons. Our results show that Cacna1c mRNA concentration was increased in the amygdala and hippocampus of alcohol-dependent rats after 21 days of abstinence, with no changes in Cacna1d mRNA. This was associated with increased Cav1.2 protein concentration and L-type calcium current amplitudes. Further analysis of Cacna1c mRNA in the CA1, basolateral amygdala (BLA), and central amygdala (CeA) revealed a dynamic regulation over time during the development of alcohol dependence. The inhibition of central LTCCs via i.c.v. administration of verapamil prevented cue-induced reinstatement of alcohol seeking in alcohol-dependent rats. Further studies in conditional Cav1.2-KO mice showed a lack of dependence-induced increase of alcohol-seeking behavior. Together, our data indicate that central Cav1.2 channels, rather than Cav1.3, mediate alcohol-seeking behavior. This finding may be of interest for the development of new antirelapse medications.

show abstract

“…Much of the vascular, neurovegetative, and neurotransmitter release effects of ACh are mediated by the N‐type calcium channel. The N‐ and T‐type voltage‐gated calcium channel blockers have recently been used in psychiatry to treat disorders such as ethanol addiction (45,46). The proposed psychiatric effects of this class of drugs are inapplicable in our study; none of our patients reported ethanol abuse.…”

Section: Discussionmentioning

confidence: 58%