Interaction of LSD and other hallucinogens with dopamine-sensitive adenylate cyclase in primate brain: regional differences.

The influence of D-lysergic acid diethylamide (LSD) and mescaline on adenylate cyclase activity was studied in homogenates of Cebus and rhesus monkey anterior limbic cortex (ALC), frontal cortex (FC), caudate nucleus and retina. Previous studies have shown these tissues to contain dopamine-stimulated adenylate cyclase (AC). In addition, we are now reporting the presence of a dopamine-sensitive adenylate cyclase in the auditory cortex. AC of ALC and auditory cortex was stimulated by LSD and mescaline, whereas activity of FC, caudate nucleus and retina was not stimulated by the same agents. In contrast to regional specificity for stimulation, LSD was capable of antagonizing dopamine-stimulated activity in all brain regions examined. LSD and mescaline produced similar maximal stimulation (about 70%) of AC of ALC homogenates, but the EC50 for LSD (0.43 micrometer) was about one-tenth that for mescaline (4.5 micrometer). Similar relative potencies were also observed for the auditory cortex enzyme. Although much weaker than LSD, methamphetamine also produced a dose-dependent stimulation of ALC AC. Both agonist and antagonist effects of the hallucinogens appear to involve interaction with dopamine receptors; LSD- or methamphetamine-stimulated activity in ALC was blocked by haloperidol and fluphenazine, which are dopamine antagonists, but not by phentolamine, an alpha-receptor blocker. Antagonism of dopamine by LSD in both ALC and FC was found to be competitive and mescaline was an effective but weaker antagonist than was LSD. In addition, neither histamine--nor Gpp(NH)p--stimulated activity of FC was inhibited by LSD. It is proposed that the occurrence of dopamine agonistic action of hallucinogens in only certain regions of primate brain may provide a basis for at least some of the behavioral effects of LSD, mescaline and methamphetamine in primates.