Berezovskaia Anna, Thomsen Morgan, Fink-Jensen Anders, Wörtwein Gitta
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Mental Health Services in the Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark.
Copenhagen Center for Translational Research, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
Front Mol Neurosci. 2024 Dec 16;17:1451010. doi: 10.3389/fnmol.2024.1451010. eCollection 2024.
Acetylcholine modulates the activity of the direct and indirect pathways within the striatum through interaction with muscarinic M and M receptors. M receptors are uniquely positioned to regulate plasticity within the direct pathway and play a substantial role in reward and addiction-related behaviors. However, the role of M receptors on cholinergic neurons has been less explored. This study aims to fill this gap by addressing the role of M receptors on cholinergic neurons in these behaviors.
To investigate the significance of M-dependent inhibitory signaling in cholinergic neurons we created mutant mice that lack M receptors on cholinergic neurons. Cholinergic neuron-specific depletion was confirmed using hybridization. We aimed to untangle the possible contribution of M autoreceptors to the effects of the global M knockout by examining aspects of basal locomotion and dose-dependent reactivity to the psychostimulant and rewarding properties of cocaine, haloperidol-induced catalepsy, and examined both the anti-cataleptic and locomotion-inducing effects of the non-selective anticholinergic drug scopolamine.
Basal phenotype assessment revealed no developmental deficits in knockout mice. Cocaine stimulated locomotion in both genotypes, with no differences observed at lower doses. However, at the highest cocaine dose tested, male knockout mice displayed significantly less activity compared to wild type littermates ( = 0.0084). Behavioral sensitization to cocaine was similar between knockout and wild type mice. Conditioned place preference tests indicated no differences in the rewarding effects of cocaine between genotypes. In food-reinforced operant tasks knockout and wild type mice successfully acquired the tasks with comparable performance results. M receptor depletion did not affect haloperidol-induced catalepsy and scopolamine reversal of catalepsy but attenuated scopolamine-induced locomotion in females ( = 0.04). Our results show that M receptor depletion attenuated the locomotor response to high doses of cocaine in males and scopolamine in females, suggesting sex-specific regulation of cholinergic activity.
Depletion of M receptors on cholinergic neurons does not significantly impact basal behavior or cocaine-induced hyperactivity but may modulate the response to high doses of cocaine in male mice and the response to scopolamine in female mice. Overall, our findings suggest that M-dependent autoregulation plays a minor but delicate role in modulating specific behavioral responses to pharmacological challenges, possibly in a sex-dependent manner.
乙酰胆碱通过与毒蕈碱型M1和M4受体相互作用来调节纹状体内直接和间接通路的活性。M4受体在调节直接通路的可塑性方面具有独特地位，并且在奖赏及成瘾相关行为中发挥重要作用。然而，M4受体在胆碱能神经元上的作用尚未得到充分研究。本研究旨在通过探讨M4受体在胆碱能神经元对这些行为的作用来填补这一空白。
为了研究胆碱能神经元中M4依赖性抑制信号的重要性，我们构建了胆碱能神经元上缺乏M4受体的突变小鼠。使用杂交技术确认了胆碱能神经元特异性缺失。我们旨在通过检查基础运动方面以及对精神兴奋剂可卡因的剂量依赖性反应性、奖赏特性、氟哌啶醇诱导的僵住症，并研究非选择性抗胆碱能药物东莨菪碱的抗僵住症和诱导运动作用，来理清M4自身受体对整体M4基因敲除效应的可能贡献。
基础表型评估显示基因敲除小鼠无发育缺陷。可卡因在两种基因型中均刺激运动，在较低剂量下未观察到差异。然而，在测试的最高可卡因剂量下，雄性基因敲除小鼠与野生型同窝小鼠相比活动明显减少（P = 0.0084）。基因敲除小鼠和野生型小鼠对可卡因的行为敏化相似。条件性位置偏爱测试表明不同基因型之间可卡因的奖赏效应无差异。在食物强化的操作性任务中，基因敲除小鼠和野生型小鼠均成功完成任务，表现结果相当。M4受体缺失不影响氟哌啶醇诱导的僵住症以及东莨菪碱对僵住症的逆转，但减弱了东莨菪碱在雌性小鼠中诱导的运动（P = 0.04）。我们的结果表明，M4受体缺失减弱了雄性小鼠对高剂量可卡因以及雌性小鼠对东莨菪碱的运动反应，提示胆碱能活性存在性别特异性调节。
胆碱能神经元上M4受体的缺失不会显著影响基础行为或可卡因诱导的多动，但可能调节雄性小鼠对高剂量可卡因的反应以及雌性小鼠对东莨菪碱的反应。总体而言，我们的研究结果表明，M4依赖性自身调节在调节对药理学挑战的特定行为反应中起次要但微妙的作用，可能以性别依赖的方式。
