alpha-synuclein and Cocaine-Related-Disorders

Alpha-synuclein (α-syn) is an abundant neuroprotein elevated in cocaine addicts, linked to drug craving, and recruited to axon terminals undergoing glutamatergic plasticity - a proposed mechanism for substance abuse. However, little is known about normal α-syn function or how it contributes to substance abuse. We show that α-syn is critical for preference of hedonic stimuli and the cognitive flexibility needed to change behavioral strategies, functions that are altered with substance abuse. Electron microscopic analysis reveals changes in α-syn targeting of ventral tegmental area axon terminals that is dependent upon the duration of cocaine exposure. The dynamic changes in presynaptic α-syn position it to control neurotransmission and fine-tune the complex afferent inputs to dopamine neurons, potentially altering functional dopamine output. Cocaine also increases postsynaptic α-syn where it is needed for normal ALIX function, multivesicular body formation, and cocaine-induced exosome release indicating potentially similar α-syn actions for vesicle release pre- and post-synaptically.

Topics: alpha-Synuclein; Animals; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Disease Susceptibility; Dopaminergic Neurons; Extracellular Space; Immunohistochemistry; Male; Mesencephalon; Mice; Mice, Knockout; Models, Biological; Motivation; Motor Activity; Reward; Signal Transduction

Alpha synuclein is increased in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. Recent studies have shown increased alpha synuclein protein expression in serum of alcoholic patients that is linked with severity of alcohol craving. The aim of this study was to analyze the serum levels of alpha synuclein in healthy subjects and in recently abstinent cocaine abusers. Alpha synuclein protein expression was measured by enzyme-linked immunosorbent assay in serum specimens obtained from 38 recently abstinent cocaine dependent patients and 14 control subjects. The presence of cocaine dependence disorder was based on the Structured Clinical Interview (DSM-IV). Drug severity was assessed by the Addiction Severity Index ratings and composite measures. Scores of the intensity and frequency of cocaine craving episodes were obtained from the Minnesota Cocaine Craving Questionnaire. The serum concentrations of alpha synuclein in cocaine dependent patients were significantly higher as compared with age-matched drug-free controls (p<0.001). Alpha synuclein levels in blood were significantly correlated with the intensity (r=0.60, p<0.001) and frequency (r=0.64, p<0.001) of cocaine craving and with 30 days of cocaine use in the prior month before entry to treatment (r=0.56, p<0.005). However, there was no correlation between the serum protein levels of alpha synuclein and age in either group. This report is the first demonstration of altered alpha synuclein levels in peripheral blood from cocaine abusers. These data agree with previous reports in postmortem brain of cocaine abusers and provide support for an association between alpha synuclein and cocaine dependence.

Topics: Adult; alpha-Synuclein; Cocaine-Related Disorders; Disruptive, Impulse Control, and Conduct Disorders; Dopamine; Female; Humans; Interview, Psychological; Male; Mass Screening; Surveys and Questionnaires

Direct protein interactions between the dopamine transporter and alpha-synuclein demonstrate that dopamine uptake function is modulated by alpha-synuclein. We report here that chronic cocaine abuse results in an increase in alpha-synuclein expression in the human striatum. Immunoblot analysis in the ventral putamen showed that alpha-synuclein protein was increased in striatal synaptosomes from cocaine users compared with age-matched drug-free controls. [H]-Dopamine transporter uptake was increased in parallel with 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane binding to the dopamine transporter. The increase in alpha-synuclein protein was more marked in the ventromedial sectors of the striatum than in the dorsal caudate nucleus. These results demonstrate concomitant regulation of alpha-synuclein and dopamine transporter binding and function in human striatal synaptic terminals isolated from cocaine abusers. Overexpression of alpha-synuclein may play a role in cocaine-induced plasticity and regulation of dopamine synaptic tone.

Topics: Adaptation, Physiological; alpha-Synuclein; Chronic Disease; Cocaine-Related Disorders; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Homeostasis; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Presynaptic Terminals; Synucleins

Alpha-synuclein is a presynaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease. The native protein is a major component of nigral Lewy bodies in Parkinson's disease, and full-length alpha-synuclein accumulates in Lewy neurites. Here we present evidence that alpha-synuclein levels are elevated in midbrain dopamine (DA) neurons of chronic cocaine abusers. Western blot and immunoautoradiographic studies were conducted on postmortem neuropathological specimens from cocaine users and age-matched drug-free control subjects. The results demonstrated that alpha-synuclein levels in the DA cell groups of the substantia nigra/ventral tegmental complex were elevated threefold in chronic cocaine users compared with normal age-matched subjects. The increased protein levels in chronic cocaine users were accompanied by changes in the expression of alpha-synuclein mRNA in the substantia nigra and ventral tegmental area. Although alpha-synuclein expression is prominent in the hippocampus, there was no increase in protein expression in this brain region. The levels of beta-synuclein, a possible negative regulator of alpha-synuclein, also were not affected by cocaine exposure. Alpha-synuclein protein levels were increased in the ventral tegmental area, but not the substantia nigra, in victims of excited cocaine delirium who experienced paranoia, marked agitation, and hyperthermia before death. The overexpression of alpha-synuclein may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse. However, the accumulation of alpha-synuclein protein with long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson's disease.

Topics: alpha-Synuclein; beta-Synuclein; Blotting, Western; Cocaine-Related Disorders; Dopamine; Gene Expression Regulation; Humans; Mesencephalon; Nerve Tissue Proteins; Neurons; RNA, Messenger; Synucleins; Transcription, Genetic