Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc (Nat Neurosci, 2009, 12:1036-1041)

報告日期: 2009/12/25
報告時間: 15:10/16:00
報告學生: 陳麗仙
講評老師: 許桂森

Cocaine-evoked synaptic plasticity:

persistence in the VTA triggers adaptations in the NAc

Nat Neurosci. 12, 1036-41 (2009)

Manuel Mameli, Briac Halbout, Cyril Creton, David Engblom, Jan Rodriguez Parkitna, Rainer Spanagel & Christian Lu¨scher


Commentator: Kuei-Sen Hsu, Ph.D. (許桂森 老師)

Speaker: Lihsien Chen (陳麗仙)

Date: 12/25 15:10 – 16:00

Place: Room 602



The mesolimbic dopamine neurons and their widespread projections to areas such as the nucleus accumbens, prefrontal cortex and amygdala are involved in both acute and chronic responses to drugs of abuse. Therefore, plasticity at glutamatergic afferents onto DA neuron could participate in the incentive sensitization process thought to underlie addiction. Single cocaine injection induced an increase in the AMPAR/NMDAR ratio of glutamatergic synaptic currents in VTA dopamine neurons for up to 10 days, and the AMPA-EPSCs became rectifying. These results, taken together, indicated that newly-synthesized AMPARs were inserted into the synapse, of which a substantial fraction was devoid of the GluR2 subunit. In contrast, mGluR-mediated Long-term depression (LTD) was found to reverse such a cocaine-induced synaptic plasticity in the VTA and to selectively remove the GluR2-lacking receptors to restore the initial GluR2-dependent transmission. In the NAc, cocaine-evoked plasticity also occurred, but on a slower timescale and with a steeper induction threshold. One cocaine injection is not sufficient to trigger changes in synaptic transmission in this region. However, 5 consecutive days of cocaine injections decreased AMPA/NMDA ratios.

The current study aimed to examine whether the cocaine-induced plasticity in VTA and NAc are independent or hierarchically organized. Authors demonstrated that the persistence of VTA plasticity, due to an mGluR1-dependent mechanism, triggered a synaptic depression in the NAc and that a swift reversal of this plasticity may prevent synaptic alterations in the NAc. Moreover, they used genetically modified mice lacking NMDA receptor (NMDAR) in midbrain DA neurons and found that preventing the induction of cocaine-evoked plasticity in DA neurons of the VTA abolished early and enduring plasticity in the NAc and attenuated cue-induced cocaine seeking after prolonged withdrawal.



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