title: Alpha-synuclein in the nucleus accumbens induces changes in cocaine behaviour in rats.
abstract: The mesolimbic dopaminergic system is widely recognized to be critical to the neurobiology of cocaine reward and addiction. The neuronal protein, alpha-synuclein, is an important regulator in dopaminergic transmission. It interacts with the dopamine transporter, and regulates dopaminergic content, neurotransmission and synaptic strength of dopaminergic neurons. Alpha-synuclein levels are elevated in midbrain dopamine neurons of chronic cocaine abusers, and its expression is increased in psychostimulant-treated animals [M.S. Brenz-Verca et al. (2003) J. Neurosci., 18, 1923-1938]. This suggests a role for alpha-synuclein in psychostimulant-induced behavioural effects. To investigate this hypothesis, we tested the effect of stimulation and silencing of alpha-synuclein expression in the nucleus accumbens (NAcc) on two cocaine-induced behavioural effects in the rat. For this purpose, animals were administered with lentiviruses driving alpha-synuclein overexpression under the control of a doxycycline regulatable promoter and/or with three lentiviruses expressing target-specific siRNAs, aimed at silencing alpha-synuclein mRNA expression. Animals were then tested for cocaine-induced locomotion (15 mg/kg i.p.) or cocaine-induced intravenous self-administration (SA; 0.7 mg/kg, 1 h/day). Overexpression of alpha-synuclein in the NAcc induced a 45% increase in locomotor activity and a 1.9-fold increase of cocaine SA, which could be abolished when the same animal was fed doxycycline. Furthermore, local inhibition of alpha-synuclein in the NAcc resulted in significant hypolocomotion activity and a decrease in SA. Our results demonstrate that alpha-synuclein is able to modulate cocaine-induced behavioural effects. This suggests that targeting alpha-synuclein function could provide new therapeutic strategies to treat cocaine abuse, for which there is no available treatment.
authors.affiliation: Institute of Biochemistry, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Boyer
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dreyer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002461:Cell Line, Transformed; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004318:Doxycycline / Q000378:metabolism; D006639:Histidine / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012646:Self Administration / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D006639:Histidine; D003042:Cocaine; D004318:Doxycycline