科研之友
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摘要
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.
- 出版日期2007-11
