A spontaneous deletion of α‐Synuclein is associated with an increase in CB1 mRNA transcript and receptor expression in the hippocampus and amygdala: Effects on alcohol consumption

Abstract

α-Synuclein (α-syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between α-syn and CB1 receptors has recently been established in Parkinson’s disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the α-syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the α-syn gene (C57BL/6Snca−/−) and their respective controls (C57BL/6Snca+/+). These animals were monitored for spontaneous alcohol consumption (3–10%) and their response to a hypnotic-sedative dose of alcohol (3 g/kg) was also assessed. Compared with the C57BL/6Snca+/+ mice, we found that the C57BL/6Snca−/− mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6Snca−/− mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between α-syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions.

Ethanol (EtOH)‐Related Behaviors in α‐Synuclein Mutant Mice and Association of SNCA SNPs with Anxiety in EtOH‐Dependent Patients

“…The insensitivity to the anxiolytic effects of EtOH could be related to the reduced propensity to drink EtOH in Snca mutant mice. Our results are in accordance with those of a previous study showing no modification of consumption of either 3 to 6% EtOH solution or saccharin solution (Lopez‐Jimenez et al., ). However, the same study showed a 2‐fold increase in EtOH intake at the 10% concentration in EtOH by Snca mutant mice, but it is important to note that they used younger mice (5‐ to 7‐weeks old) compared with mice in our study.…”

Enhanced motivation to alcohol in transgenic mice expressing human α‐synuclein

“…The results reported here are not in perfect accord with a previous study reporting increased alcohol consumption in Snca −/− mice (López‐Jiménez et al . ). First of all, it is not known whether αSYN knockout is expected to inversely affect systemic behaviors because the potential effects of Thy1‐driven expression of human A30P mutant αSYN on synaptic activity are likely very complex.…”

“…In addition, the C57BL/6J OlaHsd strain used by López‐Jiménez et al . () is not a targeted knockout, but a spontaneous mutant mouse line with a larger genomic deletion, ablating also a neighboring gene (Specht and Schoepfer ). Moreover, there are several differences in the experimental design.…”

Issues in the Study of Alcohol Consumption in Genetically Modified Mice

“…escalation). Thus, although WT mice did not show escalation under such a regimen, escalation of ethanol intake was seen over just one week of continuous access to 10% ethanol in α-synuclein null mutant mice [10]. Intermittent access paradigms more often lead to escalation of ethanol intake [19].…”

“…A similar effect was found in prodynorphin KO mice [4]. A number of other studies in genetically modified mice have identified differences in ethanol preference or consumption only at certain ethanol concentrations, including dopamine D2 receptor (DRD2) KO mice [5], µ opioid receptor KO mice [6], dopamine transporter KO mice [7], vesicular monoamine transporter 2 (VMAT2) KO mice [7], dopamine β-hydroxylase KO mice [8], corticotrophin releasing factor receptor type 1 (CRF 1 ) KO mice [9], α-synuclein null mutant mice [10] and Cyclin D2 KO mice [11]. In most cases differences in ethanol consumption were more likely to be observed for higher ethanol concentrations, often above the concentration that is typically used in single concentration studies.…”