LSD affects a large number of the G protein coupled receptors, including all dopamine receptor subtypes, all adrenoreceptor subtypes as well as many others. LSD binds to most serotonin receptor subtypes except for 5-HT3 and 5-HT4. However, most of these receptors are affected at too low affinity to be activated by the brain concentration of approximate 10–20 nM. Recreational doses of LSD can affect 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5B, and 5-HT6 receptors. The psychotropic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors as specific 5-HT2A agonist drugs are psychotropics and largely 5-HT2A specific antagonists block the psychotropic activity of LSD. Exactly how this produces the drug's effects is unknown, but it is thought that it works by increasing glutamate release and hence excitation in the cortex, specifically in layers IV and V. In the later stages, LSD might act through DARPP-32 - related pathways that are likely the same for multiple drugs including cocaine, amphetamine, nicotine, caffeine, PCP, ethanol and morphine. A particularly compelling look at the actions of LSD was performed by Barry Jacobs recording from electrodes implanted into cat Raphe nuclei. Behaviorally relevant doses of LSD result in a complete blockade of action potential activity in the dorsal raphe, effectively shutting off the principal endogenous source of serotonin to the telencephalon.
