Sensitization and Stimulant Self-Administration

描述（由申请人提供）：精神运动兴奋剂如安非他明在人类和实验动物中产生运动和支持自我给药。反复接触这些药物会产生长期的增强作用，称为致敏作用。因此，了解导致致敏的神经元事件和作为致敏基础的神经适应，可能对理解药物使用的升级（从偶然的药物实验过渡到药物渴望和滥用的特征）具有特别的意义。

DESCRIPTION (provided by applicant): Psychomotor stimulants like amphetamine produce locomotion and support self-administration in humans and laboratory animals. Repeated exposure to these drugs produces long-term enhancements, termed sensitization, in their ability to produce these effects. Understanding the neuronal events that lead to and the neuroadaptation that underlie sensitization may thus have particular bearing for understanding the escalation of drug use that is characteristic of the transition from casual experimentation with drugs to drug craving and abuse. The dopamine projections to the nucleus accumbens are known, via their impact on other neurotransmitter systems, to be critical for the production of locomotor and self-administration behaviors by amphetamine. This, together with the fact that repeated exposure to amphetamine sensitizes its ability to increase extracellular dopamine in the nucleus accumbens, suggests an important relation between sensitized dopamine neuron reactivity and the enhanced pursuit and self-administration of drugs observed in sensitized animals. Using a model of enhanced drug self-administration in the sensitized rat, the proposed experiments will examine different ways in which the expression of these sensitized responses aimed at obtaining amphetamine can be prevented. The experiments will focus on identified intracellular signaling pathways using calcium/calmodulin-dependent protein kinase II (CaMKII), as well as conditioned inhibitors, environmental stimuli specifically unpaired with the drug. Their contribution to dopaminergic and glutamatergic neuroadaptation underlying enhanced amphetamine self-administration and reinstatement will specifically be assessed. Because both CaMKII and conditioned inhibitors selectively regulate the expression of sensitized but not acute responding to amphetamine, they each may represent an attractive target for the inhibition of enhanced amphetamine self-administration and reinstatement.