Extrasynaptic Targeting of NMDA Receptors Following D1 Dopamine Receptor Activation and Cocaine Self-Administration

被引:31
|
作者
Ortinski, Pavel I. [1 ]
Turner, Jill R. [2 ]
Pierce, R. Christopher [1 ]
机构
[1] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA
[2] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA
来源
JOURNAL OF NEUROSCIENCE | 2013年 / 33卷 / 22期
基金
美国国家卫生研究院;
关键词
RAT NUCLEUS-ACCUMBENS; VENTRAL TEGMENTAL AREA; DRUG-SEEKING BEHAVIOR; D-ASPARTATE RECEPTORS; MEDIUM SPINY NEURONS; PROTEIN-KINASE-C; D-1; RECEPTOR; GLUTAMATE TRANSMISSION; SYNAPTIC-TRANSMISSION; HIPPOCAMPAL SYNAPSES;
D O I
10.1523/JNEUROSCI.5730-12.2013
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We previously showed that after repeated exposure to cocaine, D1-like dopamine receptor (D1DR) stimulation reverses plastic changes of AMPA receptor-mediated signaling in the nucleus accumbens shell. However, there is little information on the impact of cocaine self-administration on D1-NMDA receptor interactions in this brain region. Here, using whole-cell patch-clamp recordings, we assessed whether cocaine self-administration alters the effects of D1DRstimulation on synaptic and extrasynaptic NMDA receptors (NMDARs). In slices from cocaine-naive rats, pretreatment with a D1DR agonist decreased synaptic NMDAR-mediated currents and increased the contribution of extrasynaptic NMDARs. In contrast, neither cocaine self-administration alone nor cocaine experience followed by D1DR stimulation had an effect on synaptic or extrasynaptic NMDAR signaling. Activation of extrasynaptic NMDARs relies on the availability of extracellular glutamate, which is regulated primarily by glutamate transporters. In cocaine-experienced animals, relative to cocaine-naive rats, administration of a glutamate reuptake blocker, DL-threo-beta-benzyloxyaspartic acid, revealed increased extrasynaptic NMDAR activity and stronger baseline activity of glutamate uptake transporters. In cocaine-naive rats, the D1DR-mediated increase in extrasynaptic NMDAR signaling was independent of the activity of glutamate reuptake transporters. Together, these results indicate that cocaine experience blunts the influence of D1DRs on synaptic and extrasynaptic NMDAR signaling. Additionally, prior cocaine self-administration limits activation of the extrasynaptic NMDAR pool by increasing glutamate reuptake. These findings outline a pattern of adaptive interactions between D1DRs and NMDARs in the nucleus accumbens shell and demonstrate upregulation of extrasynaptic NMDAR signaling as a novel consequence of cocaine self-administration.
引用
收藏
页码:9451 / +
页数:12
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