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

Uhrig, Stefanie; Vandael, David; Marcantoni, Andrea; Dedic, Nina; Bilbao, Ainhoa; Vogt, Miriam A.; Hirth, Natalie; Broccoli, Laura; Bernardi, Rick E.; Shi, Kai; Gass, Peter; Bartsch, Dušan; Spanagel, Rainer; Deussing, Jan M.; Sommer, Wolfgang; Carbone, Emilio; Hansson, Anita C.

doi:10.1038/npp.2016.266

Cited by 37 publications

(30 citation statements)

References 62 publications

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“…No effect after chronic treatment of the blockers [309] Self-administration Verapamil Prevented cue-primed reinstatement following 21 days of abstinence [20] Withdrawal following chronic ethanol consumption…”

Section: Nifedipine and Verapamilmentioning

confidence: 99%

“…Verapamil has also been shown to block alcohol-seeking behavior in response to alcohol-associated cues following abstinence using selfadministration [20], and mice deficient in Ca v 1.2 in forebrain glutamatergic neurons show a deficit in alcohol-seeking behavior [20]. These behavioral findings are consistent with the previous report showing that protracted abstinence from alcohol increases Ca v 1.2 but not Ca v 1.3 in the amygdala and hippocampus [20], 2 brain regions involved in mediating the effects of alcohol [334][335][336]. Separately, nitrendipine has been shown to reduce withdrawal symptoms when administered during chronic ethanol exposure [310,311].…”

Section: Nifedipinementioning

confidence: 99%

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From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms

2017

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The L-type calcium channels (LTCCs) Ca1.2 and Ca1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Ca1.2 and Ca1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca1.2- and Ca1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

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Section: Nifedipine and Verapamilmentioning

confidence: 99%

Section: Nifedipinementioning

confidence: 99%

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms

2017

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“…Together, these data suggest that changes in KOR may underlie the effects of alcohol dependence on measures of anxiety and on increased motivation to seek alcohol during early and protracted withdrawal. Stress-and cue-induced relapse to alcohol is also enhanced during protracted withdrawal after intermittent exposure to alcohol vapor or intragastric injections of alcohol (Liu and Weiss, 2002;de Guglielmo et al, 2015;Uhrig et al, 2017). The function of KOR in enhanced stress-induced alcohol seeking, during early or protracted withdrawal after alcohol dependence induction is not known.…”

Section: Introductionmentioning

confidence: 99%

Effect of chronic alcohol vapor exposure on reinstatement of alcohol seeking induced by U50,488

et al. 2019

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Alcohol dependence and stress are associated with relapse to alcohol during abstinence, but the underlying mechanisms are poorly understood. Kappa opioid receptors (KOR) are involved in alcohol reward and in the effects of stress. Previously, in non-dependent rats, we showed that KOR in the bed nucleus of the stria terminalis (BNST) mediate reinstatement of alcohol seeking induced by the selective KOR agonist U50,488. Here, we determine the effects of chronic, intermittent exposure to alcohol vapor on U50,488-induced reinstatement of alcohol seeking. We also study brain mechanisms involved using the neuronal activity marker Fos and phosphorylated p38 MAPK (p-p38), an intracellular messenger implicated in the effects of KOR stimulation. We trained male Long-Evans rats to self-administer alcohol (12% w/v) and exposed them to alcohol vapor (14 h vapor/10 h air) daily for 24 d or to the control condition, extinguished alcohol-reinforced responding and determined the dose response for U50,488-induced reinstatement. We then determined the effects of vapor exposure on U50,488-induced Fos and p-p38 expression. Vaporexposed rats were more sensitive to U50,488-induced reinstatement. U50,488 increased Fos expression in brain areas involved in stress-induced relapse, and Fos activation in the ventral BNST was greater in vapor exposed rats. Vapor exposed rats had increased basal p-p38 expression in the dorsal BNST, LC and NTS. Our findings suggest that changes in the neuronal responses to KOR stimulation in the ventral BNST may be involved in the increased sensitivity to U50,488 accompanying dependence.

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“…However, interest in this medication has waned given risk for severe liver toxicity in a minority of patients and an associated FDA black box warning in 2002 (48). Verapamil (CYP3A4) has been found to prevent cue-induced reinstatement of alcohol seeking in rats, suggesting it may be a promising compound for relapse prevention (49). Methyrapone (CYP3A4) has been found to prevent alcohol withdrawal associated working memory deficits and reestablish prefrontal cortex activity in withdrawn mice (50).…”

Section: Promising Molecular Targetsmentioning

confidence: 99%

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity

Gray

Murphy

Leggio

2019

Preprint

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Novel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. We utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify high-confidence risk genes (HRGs) for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280). We subsequently used the Target Central Resource Database (TCRD) to search for drug-protein interactions for these HRGs and previously identified risk genes for alcohol consumption. We identified several HRGs for alcohol consumption that are novel contributions to the previously published alcohol consumption GWAS. Namely, ACVR2A, codes for activin receptor type-2A, which is critical for liver function, and PRKCE, codes for protein kinase C epsilon, which has been linked to alcohol consumption. Furthermore, several previously identified risk genes for alcohol consumption code for proteins that are implicated in liver function and are targeted by drugs that are promising candidates for managing hepatotoxicity (e.g., metformin), highlighting potential candidates for drug repurposing. This study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight promising molecular targets and drugs for treating AUD and ALD.

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

Cited by 37 publications

References 62 publications

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms

Effect of chronic alcohol vapor exposure on reinstatement of alcohol seeking induced by U50,488

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity

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