Alpha-synuclein is strategically positioned for afferent modulation of midbrain dopamine neurons and is essential for cocaine preference.
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.
['Trubetckaia|Olga|O|', 'Lane|Ariana E|AE|', 'Qian|Liping|L|', 'Zhou|Ping|P|', 'Lane|Diane A|DA|']
D000818:Animals D003042:Cocaine D019970:Cocaine-Related Disorders D004195:Disease Models, Animal D004198:Disease Susceptibility D059290:Dopaminergic Neurons D005110:Extracellular Space D007150:Immunohistochemistry D008297:Male D008636:Mesencephalon D051379:Mice D018345:Mice, Knockout D008954:Models, Biological D009042:Motivation D009043:Motor Activity D012201:Reward D015398:Signal Transduction D051844:alpha-Synuclein
Extracellular signalling molecules Mechanisms of disease Motivation Reward