VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity
VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity
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DOI：
10.1073/pnas.94.18.9938
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发表时间：
1997-09-02
影响因子：
11.1
通讯作者：
Uhl, GR
中科院分区：
文献类型：
--
作者：
Takahashi, N;Miner, LL;Uhl, GR
脑泡单胺转运蛋白（VMAT2）将单胺类神经递质和帕金森诱导的多巴胺神经毒素（如1-甲基-4-苯基-苯吡啶（MPP+））从神经元细胞质泵入突触囊泡，安非他明导致它们从突触囊泡释放。安非他命和MPP+也在非囊泡部位起作用，目前关于囊泡作用对其体内作用的贡献还不确定。为了评估安非他明诱导的运动、安非他明诱导的奖励、多巴胺能神经毒素的隔离和抗性，我们构建了转基因VMAT2敲除小鼠。杂合的VMAT2基因敲除在成年后仍能存活，VMAT2水平只有野生型的一半，同时单胺能标记物、心率和血压的变化较小。体重增加、生育能力、习惯化、被动回避和运动活动与野生型幼崽相似。在这些杂合子中，安非他明增强了运动，但减少了行为奖励，这是通过条件位置偏好来衡量的。MPP+前体n -甲基-4-苯基-1,2,3,6-四氢吡啶给杂合子产生的多巴胺细胞损失是野生型小鼠的两倍多。这些小鼠提供了单胺类药物和神经毒素对突触囊泡作用的贡献的新信息，并表明完整的突触囊泡功能可能对安非他明条件奖励的贡献大于安非他明诱导的运动。
The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP+ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP+ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.