Do cannabinoids reduce brain power?

Abstract

Extracts from the Cannabis plants, cannabinoids, bind to the same receptors as do endogenous cannabinoids. Although usually found on nerve terminals where their activation inhibits transmitter release, cannabinoid receptors are reported by Bernard et al. to exist on mitochondria, where their activation by endocannabinoids regulates energy metabolism.

Figure 1

Model of pmCB1s and mtCB1s in presynaptic nerve terminals. Stimulation is represented by solid arrows and inhibition by dotted lines. Postsynaptic depolarization induces Ca²⁺ influx and the subsequent activation of DGLα results in 2-AG synthesis and release. 2-AG is degraded by MAGL in mitochondria and other presynaptic intracellular compartments. Weak DSI produces only enough 2-AG for pmCB1 activation; strong DSI generates enough to also activate mtCB1s. Stimulation of pmCB1 reduces transmitter release mainly by inhibiting presynaptic, voltage-gated Ca²⁺ channels (not shown). Stimulation of mtCB1 inhibits the cAMP-PKA pathway and thereby inhibits the activity of complex I in the electron transport chain. The resulting reduction of mitochondrial respiration triggers further inhibition of transmitter release through an unknown mechanism. Complex I can also be inhibited by rotenone. Membrane permeant agonists such as HU210 or antagonists such as AM251 gain access to both pmCB1s and mtCB1s. However, hemopressin, a membrane-impermeant CB1 antagonist, prevents eCB effects only partially because it inhibits only pmCB1s. Similarly, the membrane-impermeant CB1 agonist HU-biot activates only pmCB1s and so cannot completely occlude eCB-mediated effects if mtCB1s are involved.