Dela Peña Ike, Gevorkiana Ruzanna, Shi Wei-Xing
Departments of Pharmaceutical and Administrative Sciences, Loma Linda University Schools of Pharmacy and Medicine, Loma Linda, CA 92350, USA.
Departments of Pharmaceutical and Administrative Sciences, Loma Linda University Schools of Pharmacy and Medicine, Loma Linda, CA 92350, USA.
Eur J Pharmacol. 2015 Oct 5;764:562-570. doi: 10.1016/j.ejphar.2015.07.044. Epub 2015 Jul 21.
The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.
可卡因和苯丙胺类精神兴奋剂产生强化作用的确切机制尚未完全明确。然而,人们普遍认为,这些药物通过增强大脑中的多巴胺神经传递来发挥作用,尤其是在伏隔核等边缘区域,其方式是诱导多巴胺转运体介导的逆向转运和/或通过多巴胺转运体阻断多巴胺的再摄取。在此,我们提供证据表明,除了多巴胺转运体之外,非多巴胺转运体介导的机制也参与精神兴奋剂诱导的多巴胺释放,并对这些药物的行为效应,如运动激活和奖赏,产生影响。因此,精神兴奋剂可增加前额叶皮质中的去甲肾上腺素释放,后者进而改变多巴胺神经元的放电模式,导致依赖动作电位的多巴胺释放发生变化。这些改变将进一步影响伏隔核中多巴胺释放的时间模式,从而改变该区域的信息处理。因此,根据其与多巴胺释放的时间关系,伏隔核神经元的突触输入可能会被多巴胺增强或抑制。伏隔核中某些形式的突触可塑性可能也需要特定的多巴胺释放时间模式。总之,精神兴奋剂通过涉及去甲肾上腺素和前额叶皮质的非多巴胺转运体介导机制所诱导的这些效应,可能对这些药物的强化特性也有重要贡献。