Neurobiology of antidepressant action: Cellular and molecular aspects pertinent to the antidepressant effects of dissociative anesthetics and psychedelics. Mark Rasenick (Physiology & Biophysics, U. Illinois College of Medicine, Chicago, IL ) PL3
All antidepressants examined thus far, including "atypical" compounds such as HDAC6 inhibitors and dissociative anesthetics like ketamine, increase cAMP by translocating the G protein Gsa from cholesterol-rich lipid rafts to non-raft membrane regions, where they activate adenylyl cyclase. This antidepressant-induced, sustained increase in cAMP leads to activation of several genes, including the neurotrophic factor, BDNF (brain-derived neurotrophic factor). Recent studies reveal that Gsa becomes depalmitoylated (loses its lipid modification) and dissociates from membrane tubulin (the protein anchoring Gsa in lipid rafts and implicated by Hameroff and others as a molecular basis for consciousness) after antidepressants concentrate, slowly, in lipid rafts. In this session, we describe the actions of ketamine, psilocybin and LSD in both cellular and rodent model systems and reveal the similarities and differences of these drugs to the actions of traditional monoamine-centric antidepressants. We show that, all of these compounds translocate the G protein, Gsa from cholesterol-rich lipid raft regions, where it is constrained from activating adenylyl cyclase and producing the second messenger, cAMP. However, the onset of therapeutic action, as well as the sustainability of antidepressant effect, varies widely among the compounds. Furthermore, while the putative targets of these drugs (NMDA receptors for ketamine and serotonin 2A receptors for LSD and psilocybin) are not coupled to the activation of adenlylyl cyclase and increased cAMP, the drugs do increase cAMP, and achieve this along a significantly faster timescale than traditional antidepressants.