Abstract
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.
Highlights
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
The lack of cocaine-conditioned place preference (CPP) in αsyn KO mice was surprising given that these mice showed locomotor sensitization demonstrating a progressive activation of dopamine neurons across cocaine trials
We show that α-syn is necessary for the preference for rewarding stimuli and for the cognitive flexibility needed to change previously learned behavioral strategies
Summary
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. Compulsive drug use and unremitting craving even in the absence of drugs are some of the hallmarks of substance abuse disorders, making this disorder extremely difficult to overcome[1,2] These relatively permanent changes in behavior have been attributed to drug-induced maladaptive glutamatergic plasticity of dopamine neurons in the ventral tegmental area (VTA), neurons responsible for reward and motivated behaviors[3,4]. Α-syn KO mice demonstrated greater perseverative errors than WT mice They had increased attempts to enter the original escape hole position (F (1,14) = 6.63, p = 0.02) and spent a greater amount of time in the quadrant containing the original escape hole position (F(1, 14) = 18.94, p = 0.001; Fig. 2b). The predilection for SCM was not as strong in α-syn KO mice, which demonstrated diminished SCM intake as
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