ABSTRACT
Alcohol abuse and anxiety disorders often occur concurrently, but their underlying cellular mechanisms remain unclear. N-methyl-D-aspartic acid receptors (NMDARs) have recently received attention from those interested in the neurobiology of anxiety. A chronic alcohol exposure rat model (28 consecutive days of 20% alcohol intake and 6 h of withdrawal) was established. Here, we investigated the NMDAR1 (NR1), Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinases (ERK) pathway in the modulation of anxiety-like behaviors in rats exposed to an open field and elevated plus maze (EPM) through systematic injections of memantine (a NMDAR inhibitor). We found that the NR1-CaMKII-ERK signaling pathway was activated after alcohol withdrawal in medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcSh) but not core (NAcC). Memantine treatment greatly ameliorated anxiety-like behavior in the rats experiencing alcohol withdrawal. Moreover, memantine uniformly suppressed the phosphorylation of NR1-CaMKII-ERK pathway induced by alcohol withdrawal. Our results suggest that activation of the NR1-CaMKII-ERK pathway in the mPFC and NAcSh is an important contributor to the molecular mechanisms underlying alcohol withdrawal-induced anxiety behaviors. NMDAR signaling pathway inhibitors are thus potential therapeutics for treating alcohol abuse.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/drug effects , Ethanol/adverse effects , Memantine/pharmacology , Substance Withdrawal Syndrome/drug therapy , Alcoholism/drug therapy , Alcoholism/metabolism , Animals , Anxiety/chemically induced , Anxiety/drug therapy , Anxiety Disorders/drug therapy , Anxiety Disorders/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Extracellular Signal-Regulated MAP Kinases/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Male , Phosphorylation/drug effects , Rats, Sprague-Dawley , Substance Withdrawal Syndrome/metabolismABSTRACT
Prodynorphin (PDYN) binds to k-opioid receptors (KOPr; encoded by OPRK1) and is known to regulate dopaminergic tone, making this system important for drugs addiction. Dynorphin (Dyn)/KORr system are powerful effectors of stress-induced alterations in reward processing and dysphoric states. Thus, We identified 11 potential functional SNPs and one variable number of tandem repeat (VNTR) in this system, performed a case-control association analysis, investigated particular disease phenotypes, assessed the joint effect of variants in two genes, carried out a meta-analysis to analyze the association between this VNTR and Heroin dependence (HD) risk. Eleven single-nucleotide polymorphisms (SNPs) were genotyped using SNaPshot SNP technology. Participants included 566 healthy controls and 541 patients with HD. We found that PDYN polymorphisms modulate the susceptibility to HD. An increased risk of HD was significantly associated with H alleles of PDYN VNTR (χ2 = 10.824, p = 0.001, OR = 1.419, 95% CI = 1.151-1.748). In addition, the results revealed the patients with the HH genotype showed greater number of withdrawal instances (F(2538) = 7.987, p = 0.0004) compared to the patients with the LL genotype. The Meta-analysis showed the pooled effect of the H allele at this locus is a risk factor for HD in Chinese Han. Gene-gene interaction analysis indicated strong interactions between PDYN rs3830064, 68-bp VNTR and OPRK1 rs16918842, rs3802279. These findings support the important role of PDYN polymorphism in HD, and may guide future studies to identify genetic risk factors for HD.
