Comparative effects of LSD and lisuride: clues to specific hallucinogenic drug actions

This review compares the effects of LSD and its nonhallucinogenic congener lisuride hydrogen maleate (LHM) on various biochemical, behavioral and electrophysiological indices of neuronal function. The underlying rationale is that any differences between the effects of LSD and LHM might be relevant to neuronal actions which are unique and specific to hallucinogenic drugs and thereby provide clues to the neurobiological substrates of hallucinogenesis. In biochemical studies, LHM appears to be very similar to LSD with respect to its actions on monoaminergic (5-HT, DA, NE) systems. The major difference between the two ergots appears quantitative in nature since LHM is more potent than LSD, especially on DA neurochemistry. Needed at the present time are additional comparative studies of LSD and LHM with respect to other biochemical measures, for example on the release of 5-HT and DA and comparisons at more molecular levels such as subcellular compartmentation. Also necessary are more intensive regional analyses on specific subpopulations of 5-HT and DA systems (mesolimbic, mesostriatal and mesocortical). Behavioral studies are relatively uniform in their characterization of the greater DA-ergic activity of LHM as compared to LSD. In particular, the drug discrimination (DD) procedure has indicated a more specific interaction of LSD with 5-HT neuronal systems as compared to LHM and has successfully differentiated the relative roles of 5-HT and DA systems in the behavioral effects of LSD and LHM. Electrophysiological studies have been consistent with both biochemical and behavioral findings with respect to the much greater effect of LHM on DA receptors. In fact, the effects of LSD on DA-containing neurons are both weak and heterogeneous, again indicating a need for more detailed analyses of specific DA projection systems. The greater potency of LHM than LSD on 5-HT containing dorsal raphe neurons has lessened the attractiveness of the once popular theory that hallucinogenic efficacy is related to diminution of impulse flow in 5-HT systems but has also spawned greater interest in the possible role of postsynaptic 5-HT receptors in hallucinogenic drug action. Thus far, the most interesting finding is the ability of LSD and other hallucinogens, but not LHM, to potentiate an excitomodulatory effect of 5-HT in the facial motor nucleus. If such a phenomenon occurs more generally in the CNS, the importance of this finding will be greatly enhanced. Preliminary data is presented which suggests that LSD may also induce such an effect in a limbic forebrain structure, the nucleus accumbens.(ABSTRACT TRUNCATED AT 400 WORDS)