Cannabinoid CB₁ Receptors Bidirectionally Modulate Depressive-like Behaviors via Cell-Type Specific Regulation of Cholecystokinin Release in the Basolateral Amygdala

Abstract

Depression is a chronic and recurring illness that is highly prevalent neuropsychiatric disorder. Approximately 15-18% people worldwide suffer from the major depression disorders (MDD), significantly contributing to the global burden of diseases in 2021. Depression severely diminishes the quality of life for affected individuals and is a significant risk factor for disability and suicide. Clinically, due to the unclear pathological mechanisms and inconsistent therapeutic effects, depression is considered as a heterogeneous disorder and difficult to treat and recover.

Depressed patients often experience stressful life events, and vulnerable individuals facing these stressors may develop clinical depression symptoms. The amygdala is regarded as a prominent component of the stress-response system, modulation emotional behaviors. Both the acute and chronic stressors could induce the alteration in the basolateral amygdala (BLA) at both structural and molecular levels. Clinically, evidence has also indicated that individuals with depressive disorders exhibit notable changes in the BLA.

The cannabinoid CB₁ receptors (CB₁R) and the neuropeptide cholecystokinin (CCK) have been implicated as playing important roles in the regulation of depressive-like behaviors. In this study, we aimed to elucidate the connection between CB₁R and CCK signaling within the BLA region and its contribution to the modulation of depression-related phenotypes.

To achieve this, we employed a multimodal approach, combining behavioral assays, anatomical analysis, electrophysiology recording, two-photon imaging, and fiber photometry. CB₁R agonist arachidonyl-2-chloroethylamide (ACEA), administrated at a dose of 2 mg/kg, exhibited antidepressant effects in both acute and chronic depression models, while administration of ACEA at doses of 10 mg/kg and 20 mg/kg increased despair-like behavior, showing a dose dependent manner. Our results demonstrated that the release of CCK from CCK-Glutamate neurons in the entorhinal cortex (EC) to BLA pathway (EC^CCK-Glu-BLA) was blocked by the CB₁R agonist ACEA at a concentration of 3 μM and 30 μM. Additionally, ACEA (3 μM) impaired the formation of long-term potentiation (LTP) within the BLA and in the hetero-synaptic connections of auditory cortex (AC)-BLA circuit, an effect dependent on the release of CCK from the ECC^CK-Glu-BLA neurons. Notably, a high proportion of CB₁R were also localized on the terminals of CCK-GABA neurons within the BLA (BLA^CCK-GABA). Unlike EC^CCK-Glu-BLA neurons, administration of ACEA at 3 μM had no significant effect on CCK release from the BLAC^CK-GABA neurons. However, increasing the ACEA concentration to 30 μM resulted in a significant decrease in CCK release from the BLA^CCK-GABA neurons, as well as impaired the long-term depression (LTD) and inhibitory LTP (iLTP) formation within the BLA, which were dependent on CCK release from the BLA^CCK-GABA neurons.

Collectively, these results indicate that different concentrations of the CB₁R agonist ACEA exhibit opposite effects on depressive-like behavior by modulating CCK release from either EC^CCK-Glu-BLA neurons or BLA^CCK-GABA neurons.

Date of Award	23 Dec 2024
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Jufang HE (Supervisor)