Scheggi Simona, Braccagni Giulia, De Montis Maria Graziella, Gambarana Carla
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Behav Pharmacol. 2020 Apr;31(2&3):283-292. doi: 10.1097/FBP.0000000000000545.
Morphine sensitization is associated with increased locomotion and stereotypies in rats. This persistent condition has been proposed as a model of manic-like symptoms. Modifications in reward threshold are considered a central feature of mania and have been related to changes in mesocorticolimbic dopaminergic transmission. Thus, to further characterize this model, we investigated reward responses in morphine-sensitized male rats and the mechanisms underlying the behavioral phenotype. In particular, we examined the possible involvement of hyperpolarization-activated cyclic nucleotide-gated channels as they play a critical role in regulating the excitability of dopaminergic neurons. Rats were trained to self-administer sucrose to study whether morphine sensitization affected motivated behavior. Next, the dopaminergic response to sucrose was examined in the nucleus accumbens shell by in vivo microdialysis. To investigate the possible mechanisms underlying the increased dopaminergic transmission in morphine-sensitized rats, HCN2 channel expression levels in mesocorticolimbic regions were analyzed by immunoblotting. Sensitized rats showed an enhanced motivation to work for sucrose that was accompanied by an increased dopaminergic response to sucrose consumption in the nucleus accumbens shell. Moreover, HCN2 expression levels were increased in the ventral tegmental area, suggesting that their increased expression may underpin the enhanced motivation for sucrose reward and nucleus accumbens shell dopaminergic response in sensitized rats. The modified behavioral and dopaminergic reward response observed in sensitized rats supports the suggestion that the condition of morphine sensitization can be regarded as a model of manic symptoms.
吗啡致敏与大鼠运动增加和刻板行为有关。这种持续性状况已被提出作为躁狂样症状的模型。奖励阈值的改变被认为是躁狂症的一个核心特征，并且与中脑皮质边缘多巴胺能传递的变化有关。因此，为了进一步表征这个模型，我们研究了吗啡致敏雄性大鼠的奖励反应以及行为表型背后的机制。特别地，我们研究了超极化激活的环核苷酸门控通道可能的参与情况，因为它们在调节多巴胺能神经元的兴奋性中起关键作用。训练大鼠自行摄入蔗糖，以研究吗啡致敏是否影响动机行为。接下来，通过体内微透析检测伏隔核壳对蔗糖的多巴胺能反应。为了研究吗啡致敏大鼠多巴胺能传递增加背后的可能机制，通过免疫印迹分析中脑皮质边缘区域的HCN2通道表达水平。致敏大鼠表现出为获取蔗糖而工作的动机增强，同时伏隔核壳对蔗糖消耗的多巴胺能反应增加。此外，腹侧被盖区的HCN2表达水平升高，表明其表达增加可能是致敏大鼠对蔗糖奖励的动机增强和伏隔核壳多巴胺能反应增强的基础。在致敏大鼠中观察到的行为和多巴胺能奖励反应的改变支持了这样一种观点，即吗啡致敏状态可被视为躁狂症状的模型。
