Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo.

It is generally assumed that cannabinoids induce transient modulations of dopamine transmission through indirect regulation of its release. However, we previously described a direct cannabinoid-mediated control of tyrosine hydroxylase (TH) expression, in vitro. We herein report on the influence of cannabinoid agonists on the expression of this key enzyme in catecholamine synthesis as well as on the modification of dopamine content in adult rats. As expected for cannabinoid agonists, the exposure to either Δ(9)-THC, HU 210 or CP 55,940 induced both catalepsy and hypolocomotion. Supporting a possible long-lasting control on dopaminergic activity, we noticed a significant HU 210-mediated increase in TH expression in the striatum that was concomitant with an increase in striatal dopamine content. Surprisingly, while a similar trend was reported with Δ(9)-THC, CP 55,940 completely failed to modulate TH expression or dopamine content. Nevertheless, the access of CP 55,940 to brain structures was validated by determinations of drug concentrations in the tissue and by ex vivo binding experiments. Furthermore, confirming the central activity of CP 55,940, the analysis of dopamine metabolites revealed a reduction in striatal DOPAC concentrations. Consistent with the involvement of the CB(1) cannabinoid receptor in these different responses, both HU 210- and CP 55,940-mediated effects were prevented by SR 141716A. Therefore, the present data suggest that both HU 210 and CP 55,940 cause a delayed/persistent regulation of the dopamine neurotransmission system. Nevertheless, these commonly used cannabinoid agonists endowed with similar pharmacodynamic properties clearly triggered distinct biochemical responses highlighting the existence of functional selectivity in vivo.