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.

The 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 high-quality image (102 K)Download as PowerPoint slide