Regulation of α-Synuclein Expression in Limbic and Motor Brain Regions of Morphine-Treated Mice

Abstract

Chronic exposure to opiates produces dependence and addiction, which may result from neuroadaptations in the dopaminergic reward pathway and its target brain regions. The neuronal protein ␣-synuclein has been implicated in neuronal plasticity and proposed to serve as a negative regulator of dopamine neurotransmission. Thus, ␣-synuclein could mediate some effects of opiates in the brain. The present study investigated the influence of acute and chronic morphine administration on ␣-synuclein mRNA and protein expression in the brains of mice. Downregulation of ␣-synuclein mRNA was observed in the basolateral amygdala, dorsal striatum, nucleus accumbens, and ventral tegmental area of mice withdrawn from chronic morphine treatment. The changes were the most pronounced after longer periods of withdrawal (48 h). In contrast, levels of ␣-synuclein protein, as assessed by Western blotting, were significantly increased in the amygdala and striatum/accumbens (but not in the mesencephalon) of morphine-withdrawn mice. In both brain regions, levels of ␣-synuclein were elevated for as long as 2 weeks after treatment cessation. Because ␣-synuclein is a presynaptic protein, the detected opposite changes in its mRNA and protein levels are likely to take place in different populations of projection neurons whose somata are in different brain areas. Axonal localization of ␣-synuclein was confirmed by immunofluorescent labeling. An attempt to identify postsynaptic neurons innervated by ␣-synuclein-containing axon terminals revealed their selective apposition to calbindin D28K-negative projection neurons in the basolateral amygdala. The observed changes in ␣-synuclein levels are discussed in connection with their putative role in mediating suppression of dopaminergic neurotransmission during opiate withdrawal.

Association of Alcohol Craving With α‐Synuclein (SNCA)

“…Mash et al (2003) reported that a-synuclein levels were 3 fold increased in the midbrain dopamine neurons of chronic cocaine abusers compared with controls. a-Synuclein mRNA levels are also elevated in mice withdrawn from chronic morphine treatment (Ziolkowska et al, 2005). Analyses of SNPs in the noncoding exon 1 0 and intron 1 of SNCA in a sample of methamphetamine dependent patients and matched controls did not detect significant association (Kobayashi et al, 2004).…”

Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala

“…Observations indicate that morphine abuse is a dopaminedependent disorder in which the positive reinforcing value of the drug is mediated through the activation of the mesocorticolimbic dopaminergic system (Di Chiara, 1999). This activation also has been proposed to be responsible for disturbances in motivational and emotional processes underlying addiction (Ziolkowska et al, 2005). However, the morphine-induced adaptive alterations in different parts of the mesocorticolimbic dopaminergic system remain to be studied.…”

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

“…α-Synuclein is also found in other regions of neurons, in astrocytes, and in oligodendroglia (6)(7)(8)(9)(10)(11). Overexpression of and mutations in α-synuclein are associated with early onset Parkinson's disease (12)(13)(14)(15) and other neurodegenerative diseases (16)(17)(18)(19)(20).…”

“…To address the potential role for α-synuclein in brain 20:4n-6 uptake and metabolism, we used steady-state kinetic modeling of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]20:4n-6 metabolism in vivo coupled with studies using enzyme assays and mRNA expression of key fatty acid metabolic enzymes. These data show, for the first time, a mechanistic explanation for the impact of α-synuclein deficiency on brain lipid metabolism.…”