Rodríguez Manuel J, Pugliese Marco, Mahy Nicole
Unitat de Bioquímica, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Curr Drug Abuse Rev. 2009 Jan;2(1):99-112. doi: 10.2174/1874473710902010099.
Positive and negative reinforcing systems are part of the mechanism of drug dependence. Drugs with abuse potential may change the manner of response to negative emotional stimuli, activate positive emotional reactions and possess primary reinforcing properties. Catecholaminergic and peptidergic processes are of importance in these mechanisms. Current research needs to understand the types of adaptations that underlie the particularly long-lived aspects of addiction. Presently, glutamate is candidate to play a role in the enduring effects of drugs of abuse. For example, it participates in the chronic pathological changes of corticostriatal terminals produced by methamphetamine. At the synaptic level, a link between over-activation of glutamate receptors, C(a2+) increase and neuronal damage has been clearly established leading to neurodegeneration. Thus, neurodegeneration can start after an acute over-stimulation whose immediate effects depend on a diversity of calcium-activated mechanisms. If sufficient, the initial insult results in calcification and activation of a chronic on-going process with a progressive loss of neurons. At present, long-term effects of drug dependence underlie an excitotoxicity process linked to a polysynaptic pathway that dynamically regulates synaptic glutamate. Retaliatory mechanisms include energy capability of the neurons, inhibitory systems and cytoplasmic calcium precipitation as part of the neuron-glia interactions. This paper presents an integrated view of these molecular and cellular mechanisms to help understand their relationship and interdependence in a chronic pathological process that suggest new targets for therapeutic intervention.
正性和负性强化系统是药物依赖机制的一部分。具有滥用潜力的药物可能会改变对负性情绪刺激的反应方式，激活正性情绪反应，并具有主要的强化特性。儿茶酚胺能和肽能过程在这些机制中具有重要意义。当前的研究需要了解成瘾特别长期存在方面所基于的适应类型。目前，谷氨酸是在滥用药物的持久效应中发挥作用的候选物质。例如，它参与甲基苯丙胺引起的皮质纹状体终末的慢性病理变化。在突触水平，谷氨酸受体过度激活、细胞内钙离子浓度升高与神经元损伤之间的联系已被明确确立，从而导致神经退行性变。因此，神经退行性变可在急性过度刺激后开始，其即时效应取决于多种钙激活机制。如果刺激足够，初始损伤会导致钙化并激活一个持续的慢性过程，伴有神经元的逐渐丧失。目前，药物依赖的长期效应基于与动态调节突触谷氨酸的多突触通路相关的兴奋性毒性过程。报复机制包括神经元的能量能力、抑制系统以及作为神经元 - 胶质细胞相互作用一部分的细胞质钙沉淀。本文提出了这些分子和细胞机制的综合观点，以帮助理解它们在一个慢性病理过程中的关系和相互依存性，该过程提示了治疗干预的新靶点。
