Powell S B, Geyer M A, Preece M A, Pitcher L K, Reynolds G P, Swerdlow N R
Department of Psychiatry, 9500 Gilman Drive, 0804, University of California, San Diego, La Jolla, CA 92093, USA.
Neuroscience. 2003;119(1):233-40. doi: 10.1016/s0306-4522(03)00122-2.
Rearing rats in social isolation from weaning into adulthood leads to deficits in prepulse inhibition and alterations in monoamine systems that modulate prepulse inhibition. For example, rats reared in social isolation have elevated dopamine levels in the nucleus accumbens. Previous studies in rats have shown that nucleus accumbens dopamine depletion with 6-hydroxydopamine blocks the prepulse inhibition-disruptive effects of amphetamine, an indirect dopamine agonist. We tested the hypothesis that prepulse-inhibition deficits in isolation-reared rats are dependent on elevated dopamine levels in the nucleus accumbens. Specifically, we examined whether nucleus accumbens dopamine depletion would attenuate the isolation-induced disruption of prepulse inhibition. Isolation-housed female Long-Evans rats exhibited deficient prepulse inhibition. At 9 weeks post weaning, bilateral injections of 6-hydroxydopamine (8 microg/side) or ascorbic acid vehicle (0.1%) into the nucleus accumbens of social and isolation-reared rats were performed (8-10 rats per group). One week after surgery, prepulse inhibition deficits were exhibited by isolation-reared rats that received vehicle infusion into the nucleus accumbens, but not by those that received 6-hydroxydopamine infusions into the nucleus accumbens. 6-Hydroxydopamine infusions did not significantly change prepulse inhibition in socially reared rats. Behavioral and neurochemical evidence of nucleus accumbens dopamine depletion included: 1) a blockade of amphetamine-stimulated locomotor activity in nucleus accumbens 6-hydroxydopamine-infused isolated and socially reared rats; and 2) high performance liquid chromatography measurements demonstrating a significant depletion of accumbens dopamine and its major metabolites, in addition to decreases in dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid levels in the frontal cortex and anterior caudate. These data indicate that dopamine in the nucleus accumbens plays an essential role in the prepulse inhibition deficits associated with isolation rearing in female Long-Evans rats. The implication of a central role of nucleus accumbens dopamine in prepulse inhibition deficits in an animal model provides further evidence for a link between overactive dopamine function and sensorimotor-gating deficits in patients with schizophrenia.
从断奶到成年一直将大鼠饲养在社会隔离环境中，会导致前脉冲抑制功能缺陷以及调节前脉冲抑制的单胺系统发生改变。例如，在社会隔离环境中饲养的大鼠伏隔核中的多巴胺水平会升高。先前对大鼠的研究表明，用6-羟基多巴胺使伏隔核中的多巴胺耗竭，可阻断苯丙胺（一种间接多巴胺激动剂）对前脉冲抑制的破坏作用。我们检验了这样一个假设：隔离饲养的大鼠的前脉冲抑制缺陷依赖于伏隔核中升高的多巴胺水平。具体而言，我们研究了伏隔核多巴胺耗竭是否会减弱隔离诱导的前脉冲抑制破坏。隔离饲养的雌性Long-Evans大鼠表现出前脉冲抑制缺陷。在断奶后9周，对群居饲养和隔离饲养的大鼠双侧伏隔核注射6-羟基多巴胺（8微克/侧）或抗坏血酸载体（0.1%）（每组8-10只大鼠）。手术后一周，接受载体注入伏隔核的隔离饲养大鼠表现出前脉冲抑制缺陷，而接受6-羟基多巴胺注入伏隔核的大鼠则没有。6-羟基多巴胺注入并未显著改变群居饲养大鼠的前脉冲抑制。伏隔核多巴胺耗竭的行为和神经化学证据包括：1）在注入6-羟基多巴胺的隔离饲养和群居饲养大鼠中，苯丙胺刺激的伏隔核运动活动受到阻断；2）高效液相色谱测量显示，伏隔核多巴胺及其主要代谢产物显著耗竭，同时额叶皮质和前尾状核中的多巴胺、高香草酸和3,4-二羟基苯乙酸水平也降低。这些数据表明，伏隔核中的多巴胺在雌性Long-Evans大鼠与隔离饲养相关的前脉冲抑制缺陷中起重要作用。在动物模型中伏隔核多巴胺在前脉冲抑制缺陷中起核心作用这一发现，为精神分裂症患者多巴胺功能亢进与感觉运动门控缺陷之间的联系提供了进一步证据。
