The Role of Oxidative Stress in Amphetamine- and Dopamine-induced Toxic Effects in the Rat Striatum

• Main Authors: Wang, Hui-Chun, 王惠君
• Other Authors: Tung, Che-Se
• Format: Others
• Language: zh-TW
• Published: 1999
• Online Access: http://ndltd.ncl.edu.tw/handle/20060779552639367394

碩士 === 國防醫學院 === 生理學研究所 === 87 === Repeated or high doses of d-amphetamine (AMPH) and its analogs have been shown to cause degeneration of striatal dopamine (DA) nerve terminals. This phenomenon is characterized by long-term DA depletion, and decreases of DA transporter number and of the tyrosine hydroxylase activity in the striatum of rats. Endogenous dopamine, excitatory amino acid and oxidative stress are proposed to mediate DA neuron toxicity elicited by AMPH and its analogs. Thus, tyrosine hydroxylase inhibitor pretreatment can attenuate AMPH-induced hydroxyl radical formation. Several antioxidants, glutamate receptor antagonists and nitric oxide synthase (NOS) inhibitors significantly attenuate the depletion of striatal DA in rats treated with AMPH. The present study further examined the role of oxidative stress in AMPH- and dopamine-induced striatal DA depletion. Male Sprague-Dawley rats were treated with 7.5 mg/Kg AMPH plus 10 mg/Kg desipramine (DMI) intraperitoneally. 2,3-DHBA serves as a maker of hydroxyl radical derived from salicylate hydroxylation. Our results demonstrated that repeated systemic administration of two doses of AMPH plus DMI resulted in a significant of decreased DA content and increased of 2,3-DHBA, nitric oxide (NO) and malondialdehyde (MDA) levels in striatum 7 day later. N-acetylcysteine (NAC), an antioxidative agent, significantly attenuated AMPH-induced striatal MDA content and also protected against long-term striatal dopamine depletion. Acute perfusion of sodium nitroprusside (SNP) and DA elevated 2,3-DHBA concentration in the striatum. N-tetra-butyl-a-phenylnitrone (PBN), a radical scavenger, reduced 2,3-DHBA formation caused by DA. Additionally, intrastriatal injection of a high dose of DA induced ipsilateral rotational behavior as measured 10 days later. It also increased 2,3-DHBA and MDA levels, and depleted dopamine content in the striatum. In conclusion, this study provides evidence that oxidative stress is involved in the AMPH- and DA-induced toxicity. In addition, NO and DA both participate in the formation of hydroxyl radicals which produce oxidative stress.