Hallucinogen binding to dopamine/neuroleptic receptors


Although previous work has established that the hallucinogenic drugs have a high affinity for 5-hydroxy- tryptamine and (+)-lysergic acid diethylamide receptor sites (Bennett & Snyder, 1976; Fillion, Fillion & others, 1976; Lovell & Freedman, 1976), it is known that the hallucinogen actions are blocked by neuroleptic drugs (Snyder, Faillace & Hollister, 1967; Lloyd, 1970) which are thought to act by dopamine receptor blockade (AndCn, Roos & Werdinius, 1964; van Rossum, 1967; AndCn, 1968). In order to examine the suggestion (Pieri, Pieri & Haefely, 1974; Von Hungen, Roberts & Hill, 1974; Stone, 1974) that hallucinogenic drugs can act directly on brain dopamine receptors, we tested the effect of various hallucinogens on the binding of [3H]haloperidol and [3H]apomorphine to brain tissue. It is known that these two ligands bind to sites closely related to, if not identical with, the dopamine receptor (Seeman, Wong & Lee, 1974; Seeman, Chau-Wong & others, 1975; Burt, Creese & Snyder, 1976; Seeman, Lee & others, 1976a, b). The experiments were done on crude homogenates of calf caudate, using procedures previously described (Seeman & others, 1976a, b). The final concentration in the incubation tube was 3.3 nM for [3H]haloperidol and 1-5 nM for [3H]apomorphine. The stereoselective com- ponent of binding was defined as that amount of [3H] haloperidol or [3H]apomorphine bound in the presence of (-)-butaclamol (inactive neuroleptic) minus that bound in the presence of (+)-butaclamol (active neuroleptic); 100 IIM butaclamol was used for [3H]haloperidol, and 1 PM butaclamol was used for [3H]apomorphine. The results (Table 1) indicate that N,N-dimethyl tryptamine (DMT), N,N-diethyltryptamine (DET) bufotenin and ibogaine were all rather active on the neuroleptic receptor ([3H]haloperidol) in the nM region; methysergide and 2,5-dimethoxy-4-methylamphetarnin (STP) were active in the 30-50 nM range, while mescaline and LSD blocked in the 100-500 nM region. The trypta- mine derivatives which were potent in blocking the binding of [3H]haloperidol were generally much weaker in blocking the binding of [3H]apomorphine. In contrast (+)-LSD has a very low IC50 against [3H]ap~morphine binding (6 nM) but was less active against [3H]halopefl- do1 binding (500 nM). The low IC50 for ($)-LSD on [3H]ap~morphine binding (6 nM) does suggest that there is a direct action of (+)-LSD on dopamine receptors. The crude relation in Fig. 1 further suggests that the tryptamine derivatives may reciprocally affect both the antagonist as well as the agonist state of the dopamine receptor, if such a two-state hypothesis is correct (Bennett & Snyder 1976).



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