Sherrill Luke K, Gulley Joshua M
Department of Psychology, University of Illinois, Urbana-Champaign, United States.
Department of Psychology, University of Illinois, Urbana-Champaign, United States; Neuroscience Program, University of Illinois, Urbana-Champaign, United States; Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, United States.
Brain Res. 2018 Sep 1;1694:111-120. doi: 10.1016/j.brainres.2018.05.028. Epub 2018 May 21.
Repeated exposure to psychostimulants during adolescence produces long-lasting changes in behavior that may be mediated by disrupted development of the mesocorticolimbic dopamine system. Here, we tested this hypothesis by assessing the effects of amphetamine (AMPH) and dopamine receptor-selective drugs on behavior and neuron activity in the prelimbic region of the medial prefrontal cortex (PFC). Adolescent male, Sprague-Dawley rats were given saline or 3 mg/kg AMPH between postnatal day (P) 27 and P45. In Experiment 1, locomotor behavior was assessed during adulthood following challenges with a dopamine D (SKF 82958) or D (quinpirole) receptor-selective agonist. In Experiment 2, pre-exposed rats were challenged during adulthood with AMPH and a D (SKF 83566) or D (eticlopride) receptor-selective antagonist. In Experiment 3, the activity of putative pyramidal cells in the prelimbic cortex was recorded as rats behaved in an open-field arena before and after challenge injections with AMPH and one of the antagonists. We found that compared to controls, adolescent pre-exposed rats were more sensitive to the stimulant effects of AMPH and the dopamine receptor agonists, as well as to the ability of the antagonists to reverse AMPH-induced stereotypy. Prelimbic neurons from AMPH pre-exposed rats were also more likely to respond to an AMPH challenge in adulthood, primarily by reducing their activity, and the antagonists reversed these effects. Our results suggest that exposure to AMPH during adolescence leads to enduring adaptations in the mesocorticolimbic dopamine system that likely mediate heightened response to the drug during adulthood.
青春期反复接触精神兴奋剂会导致行为产生持久变化，这可能是由中脑皮质边缘多巴胺系统发育受阻介导的。在此，我们通过评估苯丙胺（AMPH）和多巴胺受体选择性药物对内侧前额叶皮质（PFC）前边缘区域的行为和神经元活动的影响来验证这一假设。在出生后第（P）27天至P45天期间，给青春期雄性Sprague-Dawley大鼠注射生理盐水或3mg/kg的AMPH。在实验1中，成年后用多巴胺D（SKF 82958）或D（喹吡罗）受体选择性激动剂激发后评估运动行为。在实验2中，成年后用AMPH和D（SKF 83566）或D（依替必利）受体选择性拮抗剂对预先接触过的大鼠进行激发。在实验3中，在开放场环境中，在给大鼠注射AMPH和其中一种拮抗剂进行激发前后，记录前边缘皮质中假定锥体细胞的活动。我们发现，与对照组相比，青春期预先接触过的大鼠对AMPH和多巴胺受体激动剂的刺激作用以及拮抗剂逆转AMPH诱导的刻板行为的能力更敏感。预先接触过AMPH的大鼠的前边缘神经元在成年后也更有可能对AMPH激发产生反应主要是通过降低其活动，并且拮抗剂可逆转这些作用。我们的结果表明，青春期接触AMPH会导致中脑皮质边缘多巴胺系统产生持久适应性变化，这可能介导成年期对该药物的反应增强。
