Cannabinoids modulate ultrasound-induced aversive responses in rats

Rationale: Mechanisms and brain substrates mediating cannabinoid-induced modulation of behaviour towards aversive stimuli are poorly understood. Objectives: To investigate the effects of systemic and intradorsal periaqueductal grey (PAG) administration of the cannabinoid receptor agonist HU210 on behaviour and plasma corticosterone levels in rats exposed to ultrasound and determine the contribution of CB₁ receptors. Methods: In experiment 1, rats received vehicle or CB₁ receptor antagonist SR141716A (3 mg/kg, IP) 30 min prior to a second injection of vehicle or HU210 (5, 20 or 80 μg/kg, IP). In experiment 2, rats received intra-dorsal PAG vehicle or SR141716A (30 μg/rat) 10 min prior to intra-dorsal PAG vehicle or HU210 (5 μg/rat). Following injections, rats were exposed to an aversive 20 kHz ultrasonic tone for 3 min. Behaviour, including hyperlocomotor activity and freezing, was monitored during and post-ultrasound. Plasma corticosterone levels 10 min post-ultrasound were measured. Results: Ultrasound induced explosive running and freezing behaviour. Systemic administration of HU210 attenuated the expression of ultrasound-induced hyperlocomotor activity and increased freezing. The HU210-induced attenuation of hyperlocomotor activity was blocked by SR141716A. Intra-PAG administration of HU210 reduced the expression of ultrasound-induced hyperlocomotor activity, an effect not blocked by SR141716A. Systemic and intra-PAG administration of HU210 increased plasma corticosterone levels, an effect not blocked by SR141716A. Conclusions: The cannabinoid receptor agonist HU210 modulates behaviour towards an aversive ultrasound stimulus in rats, an effect accompanied by increased HPA axis activity. These effects may be mediated, at least in part, by the dorsal PAG but cannot be explained solely by an action at CB₁ receptors.