Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy.
Experimental Psychopharmacology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research IRCCS, Italy.
Addict Biol. 2021 Sep;26(5):e13012. doi: 10.1111/adb.13012. Epub 2021 Jan 28.
Previous studies have shown that adolescent exposure to cocaine increases drug use in adulthood, albeit incubation of cocaine seeking was found to be attenuated in rats trained to self-administer cocaine during adolescence. We here hypothesize that adolescent exposure to cocaine could alter the rewarding properties of the psychostimulant in adulthood. By employing two of the most widely used animal-experimental-preclinical models to investigate drug addiction, we evaluated whether contingent versus non-contingent cocaine self-administration during adolescence modulates its rewarding threshold in adulthood evaluated by conditioned place preference (CPP). Cocaine self-administration during adolescence increases the rewarding threshold in adulthood; CPP for cocaine was observed at the higher (20 mg/kg), but not at the lower (10 mg/kg), dose employed. Rats exposed to either contingent or non-contingent cocaine during adolescence exhibited the same behavior in the CPP paradigm suggesting that, under our experimental conditions, cocaine rewarding properties are shaped by the psychostimulant itself and not by its motivational effects. From a mechanistic standpoint, the preference for the 20 mg/kg cocaine-paired side in a CPP paradigm appears to depend, at least partially, upon the formation of GluA2-lacking Ca -permeable AMPA receptors and the consequent increase of αCaMKII activity in the NAc, both of which are instead reduced when the 10 mg/kg dose was used. In conclusion, contingent or non-contingent cocaine exposure during adolescence desensitizes adult animals to a rewarding dose of cocaine (10 mg/kg) elevating the rewarding threshold necessary (20 mg/kg) to drive conditioned place preference, an effect that may predispose to higher consumption of cocaine during adulthood.
先前的研究表明，青少年接触可卡因会增加成年后的药物使用，尽管在青春期接受可卡因自我给药训练的大鼠中，可卡因寻求的潜伏期被发现减弱。我们假设青少年时期接触可卡因会改变成年后这种精神兴奋剂的奖赏特性。通过使用两种最广泛使用的动物实验-临床前模型来研究药物成瘾，我们评估了青春期期间偶然或非偶然的可卡因自我给药是否会调节其通过条件性位置偏好（CPP）评估的成年奖赏阈值。青春期期间的可卡因自我给药会增加成年后的奖赏阈值；在较高（20mg/kg）而非较低（10mg/kg）剂量下观察到可卡因的 CPP。在青春期接触偶然或非偶然可卡因的大鼠在 CPP 范式中表现出相同的行为，这表明在我们的实验条件下，可卡因的奖赏特性是由该精神兴奋剂本身塑造的，而不是由其动机效应塑造的。从机制的角度来看，在 CPP 范式中对 20mg/kg 可卡因配对侧的偏好似乎至少部分取决于 GluA2 缺失的 Ca 通透性 AMPA 受体的形成，以及随后 NAc 中 αCaMKII 活性的增加，而当使用 10mg/kg 剂量时，这两种受体都会减少。总之，青春期偶然或非偶然的可卡因暴露会使成年动物对奖赏剂量的可卡因（10mg/kg）脱敏，从而提高产生条件性位置偏好所需的奖赏阈值（20mg/kg），这种效应可能会导致成年期可卡因的消耗量增加。
