Martinez Maricela X, Alizo Vera Vanessa, Ruiz Christina M, Floresco Stan B, Mahler Stephen V
Department of Neurobiology and Behavior, University of California, 1132 McGaugh Hall, Irvine, CA, 92697, USA.
Department of Psychology, University of British Columbia, Vancouver, British Columbia, V6T 1Z4, Canada.
Psychopharmacology (Berl). 2025 Feb;242(2):309-326. doi: 10.1007/s00213-024-06676-9. Epub 2024 Aug 27.
Adolescent cannabis use is linked to later-life changes in cognition, learning, and memory. Rodent experimental studies suggest Δ-tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence.
We determined how 14 daily THC injections (5 mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition.
In adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks-strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impact probabilistic discounting.
AdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats.
These studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine neurons or their projections to mPFC.
青少年使用大麻与后期生活中的认知、学习和记忆变化有关。啮齿动物实验研究表明，Δ-四氢大麻酚（THC）会影响这些过程背后的神经回路发育，尤其是在青春期成熟的前额叶皮质。
我们确定了青春期连续14天注射THC（5毫克/千克）如何持续影响内侧前额叶皮质（mPFC）中依赖多巴胺的认知。
在青春期接受THC治疗（AdoTHC）的成年朗·埃文斯大鼠中，我们量化了两项基于mPFC多巴胺依赖奖励的任务——策略转换和概率折扣——的表现。我们还确定了用苯丙胺（0、0.25、0.5毫克/千克）急性增强多巴胺，或对腹侧被盖区（VTA）多巴胺神经元及其向mPFC的投射进行特定化学遗传刺激如何影响概率折扣。
AdoTHC对线索引导的工具性奖励寻求的习得有性别依赖性影响，但对两性的转换或概率折扣影响最小。在概率折扣过程中，当我们用苯丙胺急性刺激多巴胺回路时，我们发现对不太可能的奖励选项的折扣减少，AdoTHC大鼠比对照组对这些影响更敏感。相比之下，对VTA多巴胺神经元的急性化学遗传刺激或其向mPFC投射的通路特异性化学遗传刺激均未影响对照大鼠的概率折扣，尽管对该皮质多巴胺投射的刺激略微扰乱了AdoTHC大鼠的选择。
这些研究证实了AdoTHC暴露对认知过程的显著特异性影响。它们还表明，AdoTHC的一些持续性影响可能以独立于VTA多巴胺神经元或其向mPFC投射的方式改变苯丙胺诱导的认知变化。
