PDF(Pubmed)
Abstract：
UNASSIGNED: Frequent cannabis use is associated with a higher risk of developing cannabis use disorder and other adverse consequences. However, rodent models studying the underlying mechanisms of the reinforcing and withdrawal effects of the primary constituent of cannabis, Δ9-tetrahydrocannabinol (THC), have been limited.
UNASSIGNED: This study investigated the effects of daily THC (1 mg/kg, intraperitoneal, 9 days) and spontaneous withdrawal (7 days) on hedonic and aversion-like behaviors in male rats. In parallel, underlying neuroadaptive changes in dopaminergic, opioidergic, and cannabinoid signaling in the nucleus accumbens were evaluated, along with a candidate peptide designed to reverse altered signaling.
UNASSIGNED: Chronic THC administration induced anhedonic- and anxiogenic-like behaviors not attributable to altered locomotor activity. These effects persisted after drug cessation. In the nucleus accumbens, THC treatment and withdrawal catalyzed increased cannabinoid CB1 receptor activity without modifying receptor expression. Dopamine D1-D2 receptor heteromer expression rose steeply with THC, accompanied by increased calcium-linked signaling, activation of BDNF/TrkB (brain-derived neurotrophic factor/tropomyosin receptor kinase B) pathway, dynorphin expression, and kappa opioid receptor signaling. Disruption of the D1-D2 heteromer by an interfering peptide during withdrawal reversed the anxiogenic-like and anhedonic-like behaviors as well as the neurochemical changes.
UNASSIGNED: Chronic THC increases nucleus accumbens dopamine D1-D2 receptor heteromer expression and function, which results in increased dynorphin expression and kappa opioid receptor activation. These changes plausibly reduce dopamine release to trigger anxiogenic- and anhedonic-like behaviors after daily THC administration that persist for at least 7 days after drug cessation. These findings conceivably provide a therapeutic strategy to alleviate negative symptoms associated with cannabis use and withdrawal.
UNASSIGNED: This study investigated the effects of daily THC (1 mg/kg, intraperitoneal, 9 days) and spontaneous withdrawal (7 days) on hedonic and aversion-like behaviors in male rats. In parallel, underlying neuroadaptive changes in dopaminergic, opioidergic, and cannabinoid signaling in the nucleus accumbens were evaluated, along with a candidate peptide designed to reverse altered signaling.
UNASSIGNED: Chronic THC administration induced anhedonic- and anxiogenic-like behaviors not attributable to altered locomotor activity. These effects persisted after drug cessation. In the nucleus accumbens, THC treatment and withdrawal catalyzed increased cannabinoid CB1 receptor activity without modifying receptor expression. Dopamine D1-D2 receptor heteromer expression rose steeply with THC, accompanied by increased calcium-linked signaling, activation of BDNF/TrkB (brain-derived neurotrophic factor/tropomyosin receptor kinase B) pathway, dynorphin expression, and kappa opioid receptor signaling. Disruption of the D1-D2 heteromer by an interfering peptide during withdrawal reversed the anxiogenic-like and anhedonic-like behaviors as well as the neurochemical changes.
UNASSIGNED: Chronic THC increases nucleus accumbens dopamine D1-D2 receptor heteromer expression and function, which results in increased dynorphin expression and kappa opioid receptor activation. These changes plausibly reduce dopamine release to trigger anxiogenic- and anhedonic-like behaviors after daily THC administration that persist for at least 7 days after drug cessation. These findings conceivably provide a therapeutic strategy to alleviate negative symptoms associated with cannabis use and withdrawal.
摘要：
■频繁使用大麻与发生大麻使用障碍和其他不良后果的风险较高有关。然而,啮齿动物模型研究了大麻主要成分的增强和戒断作用的潜在机制，Δ9-四氢大麻酚（THC），是有限的。
■这项研究调查了每日THC（1mg/kg，腹膜内,9天）和自发戒断（7天）对雄性大鼠的享乐和厌恶样行为。并行,多巴胺能的潜在神经适应性变化，opiopideric,和大麻素信号在伏隔核进行了评估，以及设计用于逆转信号改变的候选肽。
■慢性THC给药诱导的快感和焦虑样行为不能归因于运动活动的改变。这些作用在停药后仍然存在。在伏隔核,THC治疗和戒断催化大麻素CB1受体活性增加而不改变受体表达。多巴胺D1-D2受体异聚体表达随THC急剧上升，伴随着钙连接信号的增加，BDNF/TrkB（脑源性神经营养因子/原肌球蛋白受体激酶B）途径的激活，强啡肽表达，和κ阿片受体信号。戒断过程中干扰肽对D1-D2异聚体的破坏逆转了焦虑样和无张力样行为以及神经化学变化。
■慢性THC增加伏隔核多巴胺D1-D2受体异聚体的表达和功能，这导致强啡肽表达增加和κ阿片受体激活。这些变化可能会减少多巴胺的释放，从而在每日THC给药后持续至少7天的情况下引发焦虑和无焦虑样行为。这些发现可以想象为缓解与大麻使用和戒断相关的阴性症状提供了治疗策略。
■这项研究调查了每日THC（1mg/kg，腹膜内,9天）和自发戒断（7天）对雄性大鼠的享乐和厌恶样行为。并行,多巴胺能的潜在神经适应性变化，opiopideric,和大麻素信号在伏隔核进行了评估，以及设计用于逆转信号改变的候选肽。
■慢性THC给药诱导的快感和焦虑样行为不能归因于运动活动的改变。这些作用在停药后仍然存在。在伏隔核,THC治疗和戒断催化大麻素CB1受体活性增加而不改变受体表达。多巴胺D1-D2受体异聚体表达随THC急剧上升，伴随着钙连接信号的增加，BDNF/TrkB（脑源性神经营养因子/原肌球蛋白受体激酶B）途径的激活，强啡肽表达，和κ阿片受体信号。戒断过程中干扰肽对D1-D2异聚体的破坏逆转了焦虑样和无张力样行为以及神经化学变化。
■慢性THC增加伏隔核多巴胺D1-D2受体异聚体的表达和功能，这导致强啡肽表达增加和κ阿片受体激活。这些变化可能会减少多巴胺的释放，从而在每日THC给药后持续至少7天的情况下引发焦虑和无焦虑样行为。这些发现可以想象为缓解与大麻使用和戒断相关的阴性症状提供了治疗策略。
