Gorberg Victoria, Harpaz Tamar, Shamir Emilya Natali, Karminsky Orit Diana, Fride Ester, Pertwee Roger G, Greig Iain R, McCaffery Peter, Anavi-Goffer Sharon
Institute of Medical Sciences, University of Aberdeen, Aberdeen AB24 2ZD, UK.
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Int J Mol Sci. 2025 Jun 24;26(13):6052. doi: 10.3390/ijms26136052.
Cannabinoid receptor 1 (CB) signalling is critical for weight gain and for milk intake in newborn pups. This is important as in humans, low birth weight increases the risk for attention-deficit hyperactivity disorder (ADHD). Moreover, some children with ADHD also have Tourette syndrome (TS). However, it remains unclear if insufficient CB receptor signalling may promote ADHD/TS-like behaviours. Here, ADHD/TS-like behaviours were studied from postnatal to adulthood by exposing postnatal wild-type CB and Cannabinoid receptor 2 (CB) knockout mouse pups to SR141716A (rimonabant), a CB receptor antagonist/inverse agonist. Postnatal disruption of the cannabinoid system by SR141716A induced vocal-like tics and learning deficits in male mice, accompanied by excessive vocalisation, hyperactivity, motor-like tics and/or high-risk behaviour in adults. In CB knockouts, rearing and risky behaviours increased in females. In CB knockouts, vocal-like tics did not develop, and males were hyperactive with learning deficits. Importantly, females were hyperactive but showed no vocal-like tics. The appearance of vocal-like tics depends on disrupted CB receptor signalling and on functional CB receptors after birth. Inhibition of CB receptor signalling together with CB receptor stimulation underlie ADHD/TS-like behaviours in males. This study suggests that the ADHD/TS phenotype may be a single clinical entity resulting from incorrect cannabinoid signalling after birth.
大麻素受体1（CB1）信号传导对于新生幼崽的体重增加和乳汁摄入至关重要。这一点很重要，因为在人类中，低出生体重会增加患注意力缺陷多动障碍（ADHD）的风险。此外，一些患有ADHD的儿童还患有抽动秽语综合征（TS）。然而，尚不清楚CB受体信号不足是否会促进类似ADHD/TS的行为。在此，通过将出生后的野生型CB和大麻素受体2（CB2）基因敲除小鼠幼崽暴露于CB受体拮抗剂/反向激动剂SR141716A（利莫那班），研究了从出生后到成年期类似ADHD/TS的行为。SR141716A对大麻素系统的出生后破坏在雄性小鼠中诱导出类似发声的抽搐和学习缺陷，并伴有成年期过度发声、多动、类似运动的抽搐和/或高风险行为。在CB基因敲除小鼠中，雌性的饲养和风险行为增加。在CB基因敲除小鼠中，类似发声的抽搐未出现，雄性表现为多动且有学习缺陷。重要的是，雌性多动但未出现类似发声的抽搐。类似发声的抽搐的出现取决于出生后CB受体信号的破坏和功能性CB受体。CB受体信号的抑制与CB受体刺激共同构成了雄性类似ADHD/TS的行为基础。这项研究表明，ADHD/TS表型可能是出生后大麻素信号错误导致的单一临床实体。
