Valenti Ornella, Rekawek Katarzyna Anna, Wieser Sophie, Bulut Hilal, Scholze Petra, Boehm Stefan
Division of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Molecular Biotechnology, Fachhochschule (FH) Campus Wien, Vienna, Austria.
Front Pharmacol. 2025 Apr 23;16:1534101. doi: 10.3389/fphar.2025.1534101. eCollection 2025.
The psychostimulant actions of amphetamine (AMPH) have been correlated with its ability to orchestrate ventral tegmental area (VTA) dopamine (DA) neuron activity states and, thus, DA release in output regions: in rats, a single exposure is sufficient to reduce the fraction of spontaneously active DA neurons, i.e., DA neuron population activity, whereas AMPH abstinence after repeated exposure leads to an increase. Here, this switch in DA neuron activity was resolved in detail in mice, and its sensitivity towards activation of group II metabotropic glutamate receptor (mGluR2 and mGluR3) was investigated.
All experiments were conducted on C57BL/6J male mice. After repeated AMPH administration (2 mg/kg), the amine was withdrawn for up to 15 days and VTA DA neuron activity was assessed. The involvement VTA afferent regions with respect to AMPH actions was analyzed either by local instillation of drugs or through inactivation by tetrodotoxin. Selective agonists or allosteric modulators of mGluR2 and mGluR3 were used to explore whether group II mGluR might interfere with VTA disturbances caused by the amine.
After repeated AMPH exposure, VTA DA neuron activity remained reduced for 4 days and then rose to a hyperdopaminergic state within 15 days. The initial hypodopaminergia was coordinated by an amygdala (AMG) - nucleus accumbens (NAc) -VTA pathway, whereas the hyperactivity relied on ventral hippocampus (vHPC). Hypodopaminergic VTA activity was recovered towards physiological levels by activation of mGluR2, but not mGluR3, and this remission was contingent on glutamatergic transmission within NAc and propagation via the ventral pallidum. Results of a light-dark transition task confirmed anxiolytic efficaciousness of mGluR2 activation. The hyperdopaminergic VTA activity, in contrast, was normalized by selective activation of mGluR3, but not mGluR2, within vHPC. AMPH re-exposure after abstinence turned VTA activity down, but this suppression involved alternative circuits and could no longer be rescued by mGluR activation.
Thus, abstinence from repeated AMPH intake drives VTA activity from hypo-into hyperdopaminergic states, and both can be readjusted towards physiological levels via different members of group II mGluRs.
苯丙胺（AMPH）的精神兴奋作用与其协调腹侧被盖区（VTA）多巴胺（DA）神经元活动状态以及由此导致的DA在输出区域释放的能力相关：在大鼠中，单次暴露足以降低自发活动的DA神经元比例，即DA神经元群体活动，而重复暴露后的AMPH戒断则导致该比例增加。在此，详细解析了小鼠DA神经元活动的这种转变，并研究了其对II型代谢型谷氨酸受体（mGluR2和mGluR3）激活的敏感性。
所有实验均在C57BL/6J雄性小鼠上进行。重复给予AMPH（2mg/kg）后，撤去该胺类药物长达15天，并评估VTA DA神经元活动。通过局部滴注药物或通过河豚毒素失活来分析VTA传入区域与AMPH作用的关系。使用mGluR2和mGluR3的选择性激动剂或变构调节剂来探究II型mGluR是否可能干扰该胺类药物引起的VTA紊乱。
重复暴露于AMPH后，VTA DA神经元活动在4天内持续降低，然后在15天内升至高多巴胺能状态。最初的低多巴胺能状态由杏仁核（AMG）-伏隔核（NAc）-VTA通路协调，而高活性则依赖于腹侧海马（vHPC）。通过激活mGluR2而非mGluR3可使低多巴胺能的VTA活动恢复到生理水平，并且这种缓解取决于NAc内的谷氨酸能传递以及通过腹侧苍白球的传播。明暗转换任务的结果证实了mGluR2激活的抗焦虑效力。相比之下，通过在vHPC内选择性激活mGluR3而非mGluR2可使高多巴胺能的VTA活动恢复正常。戒断后再次暴露于AMPH会使VTA活动降低，但这种抑制涉及其他回路，并且不再能通过mGluR激活来挽救。
因此，重复摄入AMPH后的戒断会使VTA活动从低多巴胺能状态转变为高多巴胺能状态，并且两者均可通过II型mGluR的不同成员重新调整至生理水平。
