Ettenberg Aaron, Bernardi Rick E
Behavioral Pharmacology Laboratory, Department of Psychology, University of California, Santa Barbara, CA 93106-9660, USA.
Pharmacol Biochem Behav. 2007 May;87(1):171-8. doi: 10.1016/j.pbb.2007.04.014. Epub 2007 May 4.
In prior work, we have demonstrated that the behavioral effects of cocaine adhere to the predictions of the opponent-process theory of drug action. Animals develop conditioned place preferences for distinct locations paired with the immediate effects of IV cocaine, but learn to avoid places paired with the effects present 15-min post-injection. It was of interest to assess the putative role of 5-HT in producing the negative properties of cocaine since cocaine acts to inhibit the reuptake of serotonin (5-HT) and since such actions have been associated with anxiogenic consequences. Male rats were administered a reinforcing dose of cocaine (1.0 mg/kg IV) and then placed - either immediately or after a 15-min delay - into one side of a two-compartment (black-white) conditioned place preference (CPP) box for 5-min. On alternate days, the animals received IV saline injections and were placed in the opposite side of the CPP box. This continued for eight days after which animals had experienced 4 pairings of cocaine with one side (black or white) of the CPP apparatus, and 4 saline pairings with the opposite side. Other groups of rats were treated identically except that 30-min prior to placement into the apparatus, these animals received an IP injection of saline or buspirone (a partial 5-HT1A agonist) at a dose that we have shown to be anxiolytic (2.5 mg/kg IP). Control animals experienced either buspirone or saline pretreatments without cocaine. Our results confirm that animals increase the time spent on the side paired with the immediate effects of cocaine (compared to baseline), but tend to avoid the side paired with effects present 15-min post-injection. Buspirone had no effect on the immediate rewarding properties of cocaine, but completely reversed the negative properties present 15-min post-cocaine. These results are consistent with the view that attenuation of 5-HT neurotransmission (via the autoreceptor agonist properties of buspirone) can reverse the negative impact of IV cocaine.
在先前的研究中，我们已经证明可卡因的行为效应符合药物作用的对手过程理论的预测。动物会对与静脉注射可卡因的即时效应配对的不同位置产生条件性位置偏好，但学会避开与注射后15分钟出现的效应配对的位置。评估5-羟色胺（5-HT）在产生可卡因负面特性中的假定作用很有意义，因为可卡因会抑制血清素（5-HT）的再摄取，且此类作用与焦虑后果有关。给雄性大鼠注射一剂强化剂量的可卡因（1.0毫克/千克，静脉注射），然后立即或在延迟15分钟后，将其放入两室（黑白）条件性位置偏好（CPP）箱的一侧5分钟。隔天，给动物静脉注射生理盐水，并将其置于CPP箱的另一侧。此过程持续八天，之后动物经历了4次可卡因与CPP装置一侧（黑色或白色）的配对，以及4次生理盐水与另一侧的配对。其他几组大鼠的处理方式相同，只是在放入装置前30分钟，这些动物腹腔注射生理盐水或丁螺环酮（一种5-HT1A部分激动剂），剂量为我们已证明具有抗焦虑作用的剂量（2.5毫克/千克，腹腔注射）。对照动物在没有可卡因的情况下接受丁螺环酮或生理盐水预处理。我们的结果证实，动物会增加在与可卡因即时效应配对的一侧停留的时间（与基线相比），但倾向于避开与注射后15分钟出现的效应配对的一侧。丁螺环酮对可卡因的即时奖赏特性没有影响，但完全逆转了可卡因注射后15分钟出现的负面特性。这些结果与以下观点一致，即5-HT神经传递的减弱（通过丁螺环酮的自身受体激动剂特性）可以逆转静脉注射可卡因的负面影响。
