Abstract
19th biennial IPEG Meeting: Nijmegen, The Netherlands. 26-30 October 2016. Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce convulsive seizures which were EEG-confirmed. However, due to the wide distribution of CB1 receptors throughout the CNS, it is highly unlikely that chronic blocking of the CB1 receptor is only manifested in seizures. CB1 agonists have been described to alter the EEG frequency spectrum. No such data are available for CB antagonists. In a regulatory repeat-dose toxicity study "muscle spasms" were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 h. Subsequently, random segments of the interictal EEG were selected, totaling 20 min per animal. These segments were assigned to subsets of 'active state' or 'passive state', based on Passive Infrared (PIR) motion detection. Spectral information was calculated using a Fast Fourier Transformation analysis. 25 % of SLV326 treated animals showed, EEG-confirmed, spontaneously occurring generalized convulsive seizures, whereas all controls were seizure-free. The behavioral signs of the seizures were typical for a limbic origin. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. However, the treatment did not affect the amount of locomotor activity itself. Apart from confirming our previous finding that long-term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats, this study shows that SLV326 alters the frequency spectrum of the EEG, but only when rats are highly active. It is therefore likely that the EEG effects caused by SLV326 are linked to higher order behavior that might be present during locomotion. Theta rhythm is shown to be a marker of complex behavior, and gamma rhythm is typically associated with cognitive functions. Therefore, these observations suggest that CB antagonists might have effects on complex behavior and cognition.
