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

•CB1 is highly co-expressed with 5-HT3 receptors on GABAergic interneurons in the BLA.•It has been proposed that 5-HT3 receptors interact with CB1-mediated effects.•CB1-mediated depression of IPSC was not affected by modulation of 5-HT3 activity.•The CB1 receptor antagonist rimonabant increases freezing, independently of 5-HT3 antagonism.•Our experiments do not support a functional interaction between CB1 and 5-HT3 receptors.

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-HT3 receptors on GABAergic interneurons suggesting that 5-HT3 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 GABAA receptor-mediated inhibitory postsynaptic currents (GABAA-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-HT3 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.

Graphical abstractThe effects of endocannabinoid release on inhibitory synaptic transmission does not interfere with 5-HT3 receptors by tropisetron (A). 5-HT3 receptors control the expression of conditioned fear, however the fear alleviating consequences of Trop (1 mg/kg) failed to ameliorate the fear-promoting effects of the CB1 receptor antagonist/inverse agonist rimonabant (RIM; B).Figure optionsDownload full-size imageDownload high-quality image (102 K)Download as PowerPoint slide