Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montreal, QC, H3C 3J7, Canada.
CNS Research Group, Faculty of Medicine, Université de Montréal, Montreal, QC, H3C 3J7, Canada.
Psychopharmacology (Berl). 2018 Jan;235(1):317-328. doi: 10.1007/s00213-017-4773-8. Epub 2017 Oct 31.
Taking high and increasing amounts of cocaine is thought to be necessary for the development of addiction. Consequently, a widely used animal model of drug self-administration involves giving animals continuous drug access during long sessions (LgA), as this produces high and escalating levels of intake. However, human cocaine addicts likely use the drug with an intermittent rather than continuous pattern, producing spiking brain cocaine levels.
Using an intermittent-access (IntA) cocaine self-administration procedure in rats, we studied the relationship between escalation of cocaine intake and later incentive motivation for the drug, as measured by responding under a progressive ratio schedule of cocaine reinforcement.
First, under IntA, rats escalated their cocaine use both within and between sessions. However, escalation did not predict later incentive motivation for the drug. Second, incentive motivation for cocaine was similar in IntA-rats limited to low- and non-escalating levels of drug intake (IntA-Lim) and in IntA-rats that took high and escalating levels of drug. Finally, IntA-Lim rats took much less cocaine than rats given continuous drug access during each self-administration session (LgA-rats). However, IntA-Lim rats later responded more for cocaine under a progressive ratio schedule of reinforcement.
Taking large and escalating quantities of cocaine does not appear necessary to increase incentive motivation for the drug. Taking cocaine in an intermittent pattern-even in small amounts-is more effective in producing this addiction-relevant change. Thus, beyond the amount of drug taken, the temporal kinetics of drug use predict change in drug use over time.
人们认为,吸食高剂量和不断增加的可卡因是导致成瘾的必要条件。因此,一种广泛使用的药物自我给药动物模型涉及在长时间(LgA)内给予动物持续的药物接触,因为这会产生高且不断上升的摄入量。然而,人类可卡因成瘾者可能会间歇性而不是连续性地使用药物,从而导致大脑可卡因水平飙升。
我们使用大鼠的间歇性可卡因自我给药程序,研究可卡因摄入量的增加与随后对药物的激励动机之间的关系,这是通过在可卡因强化的递增比率方案下的反应来衡量的。
首先,在 IntA 下,大鼠在单次和多次用药过程中都增加了可卡因的使用量。然而,可卡因的递增并不预示着后来对药物的激励动机。其次,可卡因的激励动机在 IntA 组中是相似的,这些大鼠限制在低摄入量和非递增水平(IntA-Lim),以及摄入高剂量和递增水平的药物。最后,与连续接受每次自我给药期间的药物接触(LgA 大鼠)的大鼠相比,IntA-Lim 大鼠摄入的可卡因要少得多。然而,IntA-Lim 大鼠在递增比率强化方案下对可卡因的反应更多。
摄入大量且不断增加的可卡因似乎并不需要增加对药物的激励动机。以间歇性模式吸食可卡因,即使是小剂量,也更有效地产生这种与成瘾相关的变化。因此,除了药物的摄入量之外,药物使用的时间动力学也预测了药物使用随时间的变化。