Lack of interaction of endocannabinoids and 5-HT₃ neurotransmission in associative fear circuits of the amygdala: Evidence from electrophysiological and behavioural experiments

Both the serotonergic and the endocannabinoid system play a major role in mediating fear and anxiety. In the basolateral amygdala (BLA) it has been shown that the cannabinoid receptor 1 (CB1) is highly co-expressed with 5-HT ₃ receptors on GABAergic interneurons suggesting that 5-HT ₃ receptor activity modulates CB1-mediated effects on inhibitory synaptic transmission. In the present study, we investigated the possible interactions of CB1 and 5-HT₃-mediated neuronal processes in the BLA using electrophysiological and behavioural approaches. Whole-cell patch-clamp recordings were performed in coronal brain slices of mice. Electric stimuli were delivered to the lateral amygdala to evoke GABA_A receptor-mediated inhibitory postsynaptic currents (GABA_A-eIPSCs) in the BLA. The induction of LTDi, a CB1-mediated depression of inhibitory synaptic transmission, was neither affected by the 5-HT₃ antagonists ondansetron (OND; 20 μM) and tropisetron (Trop; 50 nM) nor by the 5-HT ₃ agonists SR57227A (10 μM). In auditory fear conditioning tests, mice treated with SR57227A (3.0 mg/kg i.p.) showed sustained freezing, whereas treatment with Trop (1.0 mg/kg i.p.) decreased the expression of conditioned fear. These effects were overruled by the CB1 antagonist rimonabant (RIM; 3.0 mg/kg), which caused increased freezing with or without co-treatment with Trop. In summary, these experiments do not support a functional interaction between CB1 and 5-HT₃ receptors at the level of GABA neurotransmission in the BLA nor in terms of fear regulation.