村松 慎一

BACKGROUND: Adverse psychiatric symptoms caused by cannabis are a significant concern, and Δ9-tetrahydrocannabinol (THC) has been identified as a key contributor to these symptoms. THC binds to cannabinoid type 1 receptors (CB1Rs), which are abundant in the brain and associated with cognition. The prefrontal cortex (PFC) is crucial for cognitive functions. However, the functions of CB1Rs in the PFC in cognition processes remain unclear. Here, we injected arachidonylcyclopropylamide (ACPA), a CB1Rs agonist, into the PFC of male C57BL/6J mice via the cannula and conducted cognitive tests, including the novel object recognition test and object location test (OLT). RESULTS: These tests assessed memory in three stages: acquisition, consolidation, and retrieval. ACPA was administered immediately before each stage, and its intra-PFC administration specifically impaired memory acquisition in the OLT. In addition, in vivo microdialysis revealed that ACPA reduced extracellular GABA levels within the PFC. Next, we produced an adeno-associated virus with a glutamic acid decarboxylase promoter and an hM3Dq-encording chemogenic activator to activate GABAergic neurons in the PFC. Subsequently, deschloroclozapine (DCZ), an hM3Dq agonist, restored the memory acquisition impaired by ACPA. CONCLUSION: Our findings suggest that CB1Rs in the PFC are involved in memory acquisition through the regulation of GABA release, offering new insights into how cannabis use lead to cognitive impairment.

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Goreisan (GRS), first described in <jats:italic>Shang Han Lun</jats:italic> and <jats:italic>Jin Gui Yao Lue</jats:italic> during the Han dynasty, is indicated for thirst and oliguria.</jats:p></jats:sec><jats:sec><jats:title>Key Findings</jats:title><jats:p>The use of Goreisan (GRS) to treat headaches has increased in Japan. The Kampo physicians Keisetsu Otsuka and Doumei Yakazu applied GRS for trigeminal neuralgia or headache, and Hajime Haimoto revealed that GRS was effective for the treatment of headaches that develop before it starts raining. The Clinical Practice Guidelines for Headache 2013 and 2021 described GRS as a treatment option. GRS may also be effective for symptoms such as edema, dizziness, vomiting, diarrhea, and fever. GRS is recently applied for the treatment of chronic subdural hematoma (CSDH), disdialysis syndrome, and medication‐overuse headaches. Eight random controlled trials and a propensity‐matched analysis of GRS have been conducted, mainly in the field of neurosurgery. In a study of patients with CSDH in a national inpatient database, GRS treatment was associated with significantly lower reoperation rates and total hospitalization costs compared to control groups. GRS has also been reported to suppress the recurrence of CSDH through a decrease in aquaporin (AQP)1 expression. Concerning the adverse effects of GRS, its Kampo extract granules for ethical use are considered to have few side effects, which is likely because GRS does not contain <jats:italic>Scutellariae radix</jats:italic> or <jats:italic>Glycyrrhizae radix</jats:italic>, which can cause interstitial pneumonia, liver dysfunction, or pseudoaldosteronism. Regarding GRS basic research, a close relationship between the pharmacological actions of GRS and a modulatory effect on the functions and expression of aquaporins (AQPs) has been elucidated. For example, GRS increases the output of urine by inhibiting AQPs, especially AQP4‐mediated water transport. GRS also suppresses increases in the brain's water content by inhibiting AQPs, which may lead to the prevention of brain edema formation. Further, GRS can inhibit the AQP4‐mediated enhancement of inflammatory responses. GRS is also useful for treating diarrhea from infectious gastroenteritis, and an antidiarrhea effect of GRS in mice via an inhibition of the decrease in AQP3 has been reported. GRS thus has a wide range of pharmacological actions that are closely related to the regulation of AQP function and expression. GRS is a unique medicine that differs from the diuretics used in Western medicine.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Owing to its clinical efficacy and safety, GRS will be prescribed much more frequently in the future for the treatment of various symptoms and diseases that are accompanied by a water imbalance in the body.</jats:p></jats:sec>