Hubbard Elizabeth, Derdeyn Pieter, Galinato Vivienne Mae, Wu Andrew, Bartas Katrina, Mahler Stephen V, Beier Kevin T
Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Program in Mathematical, Computational, and Systems Biology, University of California, Irvine, CA, USA.
Neuropsychopharmacology. 2025 Apr;50(5):818-827. doi: 10.1038/s41386-024-02033-8. Epub 2024 Dec 10.
Use of one addictive drug typically influences the behavioral response to other drugs, either administered at the same time or a subsequent time point. The nature of the drugs being used, as well as the timing and dosing, also influence how these drugs interact. Here, we tested the effects of adolescent THC exposure on the development of morphine-induced behavioral adaptations following repeated morphine exposure during adulthood. We found that adolescent THC administration paradoxically prevented the development of anxiety-related behaviors that emerge during a forced abstinence period following morphine administration but facilitated reinstatement of morphine CPP. Following forced abstinence, we then mapped the whole-brain response to a moderate dose of morphine and found that adolescent THC administration led to an overall increase in brain-wide neuronal activity and increased the functional connectivity between frontal cortical regions and the ventral tegmental area. Last, we show using rabies virus-based circuit mapping that adolescent THC exposure triggers a long-lasting elevation in connectivity from the frontal cortex regions onto ventral tegmental dopamine cells. Our study adds to the rich literature on the interaction between drugs, including THC and opioids, and provides potential neural substates by which adolescent THC exposure influences responses to morphine later in life.
使用一种成瘾性药物通常会影响对其他药物的行为反应，这些药物可以在同一时间或随后的时间点给药。所使用药物的性质以及给药时间和剂量，也会影响这些药物之间的相互作用。在这里，我们测试了青少年接触四氢大麻酚（THC）对成年期反复接触吗啡后吗啡诱导的行为适应发展的影响。我们发现，青少年给予THC产生了自相矛盾的结果，它阻止了在给予吗啡后的强制戒断期出现的焦虑相关行为的发展，但促进了吗啡条件性位置偏爱（CPP）的恢复。在强制戒断后，我们接着绘制了对中等剂量吗啡的全脑反应，发现青少年给予THC导致全脑神经元活动总体增加，并增加了额叶皮质区域与腹侧被盖区之间的功能连接。最后，我们使用基于狂犬病病毒的回路映射显示，青少年接触THC会引发从额叶皮质区域到腹侧被盖区多巴胺能细胞的连接性长期升高。我们的研究为包括THC和阿片类药物在内的药物之间相互作用的丰富文献增添了内容，并提供了潜在的神经基质状态，通过这些状态，青少年接触THC会影响其在以后生活中对吗啡的反应。
