Addiction Research Group.
Department of Anatomy and Cell Biology, and.
J Neurosci. 2019 Oct 30;39(44):8762-8777. doi: 10.1523/JNEUROSCI.0708-19.2019. Epub 2019 Sep 30.
Evidence suggests that the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) differentially regulate salience attribution and psychiatric risk. The ventral hippocampus (vHipp) relays emotional salience via control of dopamine (DA) neuronal activity states, which are dysregulated in psychosis and schizophrenia. Using electrophysiology in male Sprague Dawley rats, we demonstrate that intra-vHipp THC strongly increases ventral tegmental area (VTA) DA neuronal frequency and bursting rates, decreases GABA frequency, and amplifies VTA beta, gamma and ε oscillatory magnitudes via modulation of local extracellular signal-regulated kinase phosphorylation (pERK1-2). Remarkably, whereas intra-vHipp THC also potentiates salience attribution in morphine place-preference and fear conditioning assays, CBD coadministration reverses these changes by downregulating pERK1-2 signaling, as pharmacological reactivation of pERK1-2 blocked the inhibitory properties of CBD. These results identify vHipp pERK1-2 signaling as a critical neural nexus point mediating THC-induced affective disturbances and suggest a potential mechanism by which CBD may counteract the psychotomimetic and psychotropic side effects of THC. Strains of marijuana with high levels of delta-9-tetrahydrocannabinol (THC) and low levels of cannabidiol (CBD) have been shown to underlie neuropsychiatric risks associated with high-potency cannabis use. However, the mechanisms by which CBD mitigates the side effects of THC have not been identified. We demonstrate that THC induces cognitive and affective abnormalities resembling neuropsychiatric symptoms directly in the hippocampus, while dysregulating dopamine activity states and amplifying oscillatory frequencies in the ventral tegmental area via modulation of the extracellular signal-regulated kinase (ERK) signaling pathway. In contrast, CBD coadministration blocked THC-induced ERK phosphorylation, and prevented THC-induced behavioral and neural abnormalities. These findings identify a novel molecular mechanism that may account for how CBD functionally mitigates the neuropsychiatric side effects of THC.
有证据表明，植物大麻素 Δ-9-四氢大麻酚（THC）和大麻二酚（CBD）可差异化调节突显归因和精神风险。腹侧海马体（vHipp）通过控制多巴胺（DA）神经元活动状态来传递情绪突显，而这种状态在精神病和精神分裂症中失调。我们使用雄性 Sprague Dawley 大鼠的电生理学方法证明，vHipp 内的 THC 强烈增加腹侧被盖区（VTA）DA 神经元的频率和爆发率，降低 GABA 频率，并通过调制局部细胞外信号调节激酶磷酸化（pERK1-2）来放大 VTA 的β、γ和ε振荡幅度。值得注意的是，尽管 vHipp 内的 THC 也增强了吗啡位置偏好和恐惧条件反射试验中的突显归因，但 CBD 共给药通过下调 pERK1-2 信号来逆转这些变化，因为 pERK1-2 的药理学再激活阻断了 CBD 的抑制特性。这些结果确定了 vHipp pERK1-2 信号作为介导 THC 诱导的情感障碍的关键神经连接点，并提出了 CBD 可能抵消 THC 的致幻和精神作用的潜在机制。具有高水平 δ-9-四氢大麻酚（THC）和低水平大麻二酚（CBD）的大麻菌株已被证明与高效力大麻使用相关的神经精神风险有关。然而，CBD 减轻 THC 副作用的机制尚未确定。我们证明，THC 直接在海马体中诱导类似于神经精神症状的认知和情感异常，同时通过调节细胞外信号调节激酶（ERK）信号通路来调节多巴胺活动状态和放大腹侧被盖区的振荡频率。相比之下，CBD 共给药阻断了 THC 诱导的 ERK 磷酸化，并防止了 THC 诱导的行为和神经异常。这些发现确定了一种新的分子机制，可能解释了 CBD 如何在功能上减轻 THC 的神经精神副作用。
