Department of Psychological Sciences, Kansas State University, 492 Bluemont Hall, 1114 Mid-Campus Drive North, Manhattan, KS 66506-5302, USA.
Department of Psychological Sciences, Kansas State University, 492 Bluemont Hall, 1114 Mid-Campus Drive North, Manhattan, KS 66506-5302, USA.
Behav Brain Res. 2025 Jan 5;476:115261. doi: 10.1016/j.bbr.2024.115261. Epub 2024 Sep 21.
There are no approved therapeutics for psychostimulant use and recurrence of psychostimulant use. However, in preclinical rodent models environmental enrichment can decrease psychostimulant self-administration of low unit doses and cue-induced amphetamine seeking. We have previously demonstrated that glutamate-dependent therapeutics are able to alter amphetamine seeking to amphetamine-associated cues only in enriched rats. In the current experiment, we will determine if enrichment can attenuate responding and cue-induced amphetamine seeking during extended access to a high dose of intravenous amphetamine. We will also determine if N-acetylcysteine (NAC), a glutamate dependent therapeutic, can attenuate amphetamine seeking in differentially reared rats. Female and male Sprague-Dawley rats were reared in enriched, isolated, or standard conditions from postnatal day 21-51. Rats were trained to self-administer intravenous amphetamine (0.1 mg/kg/infusion) during twelve 6-hour sessions. During the abstinence period, NAC (100 mg/kg) or saline was administered daily. Following a cue-induced amphetamine-seeking test, astrocyte densities within regions of the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb) were quantified using immunohistochemistry. Environmental enrichment decreased responding for amphetamine and during the cue-induced amphetamine-seeking test. NAC did not attenuate cue-induced amphetamine seeking or alter astrocyte density. Across all groups, female rats self-administered less amphetamine but responded more during cue-induced amphetamine seeking than male rats. While amphetamine increased astrocyte densities within the ACb and mPFC, it did not alter mPFC astrocyte densities in female rats. The results suggest that enrichment can attenuate responding during extended access to a high dose of amphetamine and the associated cues. Sex alters amphetamine-induced changes to astrocyte densities in a regionally specific matter.
目前尚无批准的治疗药物可用于治疗精神兴奋剂的使用和复发。然而，在临床前啮齿动物模型中，环境丰富可以减少低单位剂量的精神兴奋剂自我给药和线索诱导的安非他命寻求。我们之前的研究表明，谷氨酸依赖性治疗药物仅在丰富的大鼠中能够改变对安非他命相关线索的安非他命寻求。在当前的实验中，我们将确定环境丰富是否可以在延长接触高剂量静脉注射安非他命时减轻反应和线索诱导的安非他命寻求。我们还将确定 N-乙酰半胱氨酸（NAC），一种谷氨酸依赖性治疗药物，是否可以减轻在不同条件下饲养的大鼠的安非他命寻求。雌性和雄性 Sprague-Dawley 大鼠从出生后第 21-51 天在丰富、隔离或标准条件下饲养。大鼠接受训练以在十二次 6 小时的会议期间自我管理静脉注射安非他命（0.1mg/kg/剂量）。在禁欲期，每天给予 NAC（100mg/kg）或生理盐水。在线索诱导的安非他命寻求测试后，使用免疫组织化学定量测量内侧前额叶皮层（mPFC）和伏隔核（ACb）区域内的星形胶质细胞密度。环境丰富减少了安非他命的反应，并且在线索诱导的安非他命寻求测试中减少了反应。NAC 并未减轻线索诱导的安非他命寻求，也未改变星形胶质细胞密度。在所有组中，雌性大鼠自我管理的安非他命较少，但在线索诱导的安非他命寻求中比雄性大鼠的反应更多。虽然安非他命增加了 ACb 和 mPFC 内的星形胶质细胞密度，但它没有改变雌性大鼠 mPFC 内的星形胶质细胞密度。结果表明，环境丰富可以减轻长时间接触高剂量安非他命和相关线索时的反应。性别以区域特异性的方式改变安非他命诱导的星形胶质细胞密度变化。
