In vivo evidence for functional selectivity at the CB1 cannabinoid receptor
(2009) Gordon Research Conferences on Cannabinoid function in the CNS — Location: Biddeford, ME, US (2.August.2009)
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- Abstract
- While cannabinoids are generally expected to modulate synaptic communication through depolarisation-induced suppressions of inhibition or excitation (DSI/DSE), we previously reported a CB1 cannabinoid receptor-mediated complex regulation of tyrosine hydroxylase (TH) gene expression in neuroblastoma cells (Bosier et al., J Neurochem, 2007). Hence, one could suggest that beside rapid and transient DSI/DSE-dependent modifications of catecholamine circuits, the cannabinoid system may also direct critical neuronal functions through delayed and long-lasting controls of catecholamine brain levels. Arguing against a direct control of TH expression by the cannabinoid receptor, studies have reported on the lack of CB1 receptor and TH colocalisation (Herkenham et al., Brain Res, 1991). Nevertheless, in favour of this mechanism, more recent studies have demonstrated the expression of the CB1 receptor on dopaminergic and noradrenergic neurons (Patel and Hillard, Brain Res, 2003; Lau and Schloss, Eur J Pharmacol, 2008; Oropeza et al., Brain Res, 2007). Therefore, we now further investigated the influence of cannabinoid agonists on the expression of TH in vivo as well as on the modification of dopamine content. In addition, in our previous study the two typical cannabinoid agonists HU210 and CP55,940 were shown to decrease and increase TH transcription respectively, highlighting the concept of functional selectivity. Thus, the present study also intends to evidence the existence of functional selectivity in vivo. As expected for cannabinoid agonists, the exposure to either HU210 (10-100µg/kg, i.p.) or CP55,940 (10-100µg/kg, i.p.) induced a marked reduction of locomotion in rats. Of note, time course responses revealed prolonged effects, as hypolocomotion persisted for at least 24h after HU210 treatment. Furthermore, consistent with the previously published data, both agonists also strongly induced catalepsy. Along this line, TH protein level, dopamine and dopamine metabolite contents were quantified in the striatum of control or treated rats. 24h after the injection of HU210 (100µg/kg), we noticed a significant increase in the level of TH protein expressed in the striatum. According to this, the total dopamine content was increased in striatal homogenates, while no change was observed in dopamine metabolites. Contrasting with this, CP55,940 elicited no change in either TH protein level or in total dopamine concentration in the striatum. Nevertheless, the analysis of dopamine metabolites revealed a CP55,940-mediated decrease in DOPAC content, confirming that this compound properly penetrates the brain. Finally, consistent with the involvement of the CB1 receptor, both the HU210- and the CP55,940-mediated responses were totally prevented in the presence of the CB1 selective antagonist SR141716A. Together, the present data indicate that commonly used cannabinoid agonists could induce distinct patterns of functional responses in rats, even though they display similar pharmacodynamic properties. More particularly, these results suggest that both HU210 and CP55,940 could support a delayed/persistent regulation of the neurotransmission associated with the dopamine system. Nevertheless, dissimilarities in the experimental responses are clearly evidenced, supporting the existence of functional selectivity in vivo.
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Bosier, B., & et al. (2009). In vivo evidence for functional selectivity at the CB1 cannabinoid receptor. Gordon Research Conferences on Cannabinoid function in the CNS, Biddeford, ME, US. https://hdl.handle.net/2078.5/225911