Changes in rat brain cannabinoid binding sites after acute or chronic exposure to their endogenous agonist, anandamide, or to δ9-tetrahydrocannabinol

Abstract

A brain constituent, the N-amide derivative of arachidonic acid, termed anandamide, has been recently proposed as a possible endogenous ligand for the cannabinoid receptor. The present study has been designed to examine whether the acute or chronic exposure to anandamide affected the binding of cannabinoid receptors in specific brain areas as occurred with the exogenous cannabinoid agonist, Δ 9-tetrahydrocannabinol (THC). To this end, we measured the maximum binding capacity ( B max) and the affinity ( K d) of cannabinoid receptors, by using [ 3H]CP-55,940 binding assays, in membranes obtained from several brain areas of male rats acutely or chronically treated with anandamide or THC. Results were as follows. The acute administration of either anandamide or THC increased the B max of cannabinoid receptors in the cerebellum and, particularly, in the hippocampus. This effect was also observed after 5 days of a daily exposure to either anandamide or THC. However, whereas the increase in the B max after the acute treatment seems to be caused by changes in the receptor affinity (high K d), the increase after the chronic exposure may be attributed to an increase in the density of receptors. On the contrary, the [ 3H]CP-55,940 binding to cannabinoid receptors in the striatum, the limbic forebrain, the mesencephalon, and the medial basal hypothalamus was not altered after the acute exposure to anandamide or THC. However, the chronic exposure to THC significantly decreased the B max of these receptors in the striatum and nonsignificantly in the mesencephalon. This effect was not elicited after the chronic exposure to anandamide and was not accompanied by changes in the K d. In summary, the response of cannabinoid receptors to the exposure to cannabinoid agonists varied depending on the brain region. Thus, there were brain areas, such as the hippocampus and the cerebellum, where [ 3H]CP-55,940 binding increased after the acute or chronic exposure to either anandamide or THC. Cannabinoid receptors were unaffected in other regions, such as the limbic forebrain and the medial basal hypothalamus, or downregulated in the striatum and slightly in the mesencephalon, but only after a chronic exposure to THC.