Der-Ghazarian Taleen S, Call Tanessa, Scott Samantha N, Dai Kael, Brunwasser Samuel J, Noudali Sean N, Pentkowski Nathan S, Neisewander Janet L
School of Life Sciences, Arizona State University, Tempe, AZ, United States.
Front Syst Neurosci. 2017 Oct 10;11:73. doi: 10.3389/fnsys.2017.00073. eCollection 2017.
5-HT receptors (5-HTRs) modulate behavioral effects of cocaine. Here we examined the effects of the 5-HTR agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP94253) on spontaneous and cocaine-induced locomotion and on cocaine-primed reinstatement of conditioned place preference (CPP) in male mice given daily repeated injections of either saline or cocaine (15 mg/kg, IP) for 20 days. In the locomotor activity experiment, testing occurred both 1 and 20 days after the final injection. In the CPP experiment, mice underwent conditioning procedures while receiving the last of their daily injections, which were given either during or ≥2 h after CPP procedures. The CPP procedural timeline consisted of baseline preference testing (days 12-13 of the chronic regimen), conditioning (days 14-19, 2 daily 30-min sessions separated by 5 h), CPP test (day 21), extinction (days 22-34; no injections), CPP extinction test (day 35), and reinstatement test (day 36). Mice that had not extinguished received additional extinction sessions prior to reinstatement testing on day 42. On test days, mice were pretreated with either saline or CP94253 (10 mg/kg, IP). Testing began 30 min later, immediately after mice were primed with either saline or cocaine (5 mg/kg for locomotion; 15 mg/kg for reinstatement). We found that CP94253 increased spontaneous locomotion in mice receiving repeated injections of either saline or cocaine when tested 1 day after the last injection, but had no effect on spontaneous locomotion after 20 days abstinence from repeated injections. Surprisingly, cocaine-induced locomotion was sensitized regardless of whether the mice had received repeated saline or cocaine. CP94253 attenuated expression of the sensitized locomotion after 20 days abstinence. A control experiment in noninjected, drug-naïve mice showed that CP94253 had no effect on spontaneous or cocaine-induced locomotion. Mice reinstated cocaine-CPP when given a cocaine prime, and CP94253 pretreatment attenuated cocaine reinstatement.The findings suggest that stress from repeated saline injections and/or co-housing with cocaine-injected mice may cross-sensitize with cocaine effects on locomotion and that CP94253 attenuates these effects, as well as reinstatement of cocaine-CPP. This study supports the idea that 5-HTR agonists may be useful anti-cocaine medications.
5-羟色胺受体（5-HTRs）可调节可卡因的行为效应。在此，我们研究了5-HTR激动剂5-丙氧基-3-(1,2,3,6-四氢-4-吡啶基)-1H-吡咯并[3,2-b]吡啶（CP94253）对雄性小鼠自发活动及可卡因诱导的活动的影响，以及对经每日重复注射生理盐水或可卡因（15毫克/千克，腹腔注射）20天的小鼠进行可卡因激发的条件性位置偏爱（CPP）恢复的影响。在自发活动实验中，在最后一次注射后的第1天和第20天进行测试。在CPP实验中，小鼠在接受每日最后一次注射时进行条件化程序，每日最后一次注射在CPP程序期间或之后≥2小时进行。CPP程序时间表包括基线偏爱测试（慢性给药方案的第12 - 13天）、条件化（第14 - 19天，每天2次30分钟的时段，间隔5小时）、CPP测试（第21天）、消退（第22 - 34天；不注射）、CPP消退测试（第35天）和恢复测试（第36天）。未消退的小鼠在第42天恢复测试前接受额外的消退时段。在测试日，小鼠预先接受生理盐水或CP94253（10毫克/千克，腹腔注射）处理。30分钟后开始测试，即在小鼠用生理盐水或可卡因激发后立即进行（自发活动测试用5毫克/千克；恢复测试用15毫克/千克）。我们发现，在最后一次注射后1天进行测试时，CP94253增加了接受重复注射生理盐水或可卡因的小鼠的自发活动，但在重复注射停药20天后对自发活动没有影响。令人惊讶的是，无论小鼠接受的是重复生理盐水注射还是可卡因注射，可卡因诱导的活动均出现敏感化。在停药20天后，CP94253减弱了敏感化活动的表达。在未注射过药物的天真小鼠中进行的对照实验表明，CP94253对自发活动或可卡因诱导的活动没有影响。给予可卡因激发时，小鼠恢复了可卡因-CPP，而CP94253预处理减弱了可卡因的恢复。这些发现表明，重复注射生理盐水和/或与注射可卡因的小鼠共同饲养所产生的应激可能与可卡因对活动的影响产生交叉敏感化，并且CP94253减弱了这些影响以及可卡因-CPP的恢复。本研究支持5-HTR激动剂可能是有用的抗可卡因药物这一观点。
