Acute cocaine induces fast activation of D1 receptor and progressive deactivation of D2 receptor striatal neurons: in vivo optical microprobe [Ca2+]i imaging.
Acute cocaine induces fast activation of D1 receptor and progressive deactivation of D2 receptor striatal neurons: in vivo optical microprobe [Ca2+]i imaging.
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DOI：
10.1523/jneurosci.2369-11.2011
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发表时间：
2011-09-14
期刊：
影响因子：
--
通讯作者：
Du C
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文献类型：
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作者：
Luo Z;Volkow ND;Heintz N;Pan Y;Du C
可卡因诱导大脑纹状体区域的多巴胺快速增加，这被认为是可卡因回报效应的基础。多巴胺D1和D2受体都参与了可卡因的奖赏，但纹状体中可卡因效应的动态下游后果尚不完全清楚。在本研究中，我们使用D1R和D2R基因控制下表达EGFP的转基因小鼠和微探针光学成像技术，分别观察了纹状体D1R和D2R表达神经元对急性可卡因刺激后细胞内钙([Ca~(2+)]i)反应的动态变化。急性可卡因(8 mg/kg)给药后8.3±2.3min，纹状体D1R表达神经元[Ca~(2+)]_i迅速升高(10.6±3.2%)，此后恢复平稳，这种快速升高可被D1R拮抗剂(SCH_(23390))阻断。相反，可卡因使D2R表达神经元的[Ca~(2+)]i持续下降(10.4±5.8%)，这种缓慢的下降可被D2R拮抗剂(雷氯普利)阻断。由于纹状体D1R表达神经元的激活(直接通路)增强了可卡因的奖赏，而D2R表达神经元的激活抑制了可卡因的奖赏(间接通路)，这表明可卡因的奖赏效应既包括对D1R的快速刺激(导致直接途径神经元的突然激活)，也包括对D2R的较慢刺激(导致间接途径神经元更长时间的失活)。我们还提供了D2R和D1R在纹状体对急性可卡因注射反应中相互作用的直接体内证据。
Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine’s reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca2+]i) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R versus D2R expressing neurons in striatum. Acute cocaine (8 mg/kg ip) rapidly increased [Ca2+]i in D1R expressing neurons (10.6±3.2%) in striatum within 8.3±2.3min after cocaine administration after which the increases plateaued; these fast [Ca2+]i increases were blocked by pretreatment with a D1R antagonist (SCH 23390). In contrast cocaine induced progressive decreases in [Ca2+]i in D2R expressing neurons (10.4±5.8%) continuously throughout the 30min that followed cocaine administration; these slower [Ca2+]i decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R expressing neurons (direct-pathway) enhances cocaine reward whereas activation of D2R expressing neurons suppresses it (indirect-pathway), this suggests that cocaine’s rewarding effects entail both its fast stimulation of D1R (resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R (resulting in longer lasting deactivation of indirect-pathway neurons). We also provide direct in-vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration.