Characterization of environmental chemical action at the CB1 receptor of mammalian brain and investigation of synaptosomal exocytosis as a means to assess functional effects of CB1 receptor modulators

This investigation first examined various environmental chemicals and natural products (including pesticides, mitochondrial function-disrupting chemicals, benzophenanthridines alkaloids and tributyltins) for their capacity to bind to mouse brain cannabinoid-1 (CB1) receptors and modify the functional coupling of the CB1 receptor to its G protein. Many of these compounds inhibited binding of [3H]CP-55,940 and CB1 receptor agonist-stimulated [35S]GTPγS binding to the G protein at micromolar concentrations. While benzophenanthridines exhibited inverse agonist-like profiles, the majority of the other compounds acted as antagonists. Some environmental chemicals may have potential to interfere with endocannabinoid-mediated synaptic signaling in vivo and behavioral/physiological outcomes. This research also explored the effects of CB1 receptor agonists and an antagonist/inverse agonist (AM251) on exocytosis (as measured with acridine orange) in a purified synaptosomal fraction from mouse brain. Cannabinoid agonists inhibited KCl-induced exocytosis. Paradoxically, AM251 was also inhibitory and failed to relieve CB1 receptor agonist-dependent inhibition of exocytosis.