VOL ZZ, NO, i), reee 973 Comparison of Phencyclidine and chemical subtypes include PCP-like com- pounds, dioxalanes, benzomorphans, and un- Related Substances With Various bridged and bridged benz(f)isoquinolines, all Indole, Phenethylamine, and Other of which have been called "phencyclinoids" Psychotomimetics 1,2 and/or "sigma" opioids (for SKF 10,047). Substances with other heterocyclic structures also produce psychotomimetic effects in- Edward F. Domino, M.D.3 cluding 6) cannabinoids like ~9-THC, the ac- tive ingredient in marijuana, 7) ~-carbolines like harmine and harmaline, 8) some of the constituents of nutmeg including myristic in Introduction and elemicin, and 9) catatonic producing Psychotomimetics are logically classified on agents such as bulbocapnine. the basis of chemical structure. They include: l~ Indolealkyla~ines such as tryptamine, Prototypic Chemical Structures of Various dimethyltryptamine (DMT), 5-methoxydi- Substances Showing PCP-Like Activity methyl tryptamine (5-MeODMT), psilocin, etc. 2) Lysergic acid amides (also called As mentioned above, a number of chemi- lysergimides) such as lysergic acid diethyl- cals with different molecular structures have amide-25 (LSD-25) or LSD for short. LSD PCP-like effects. All of these have been test- cont~ins an indol~ structure and is frequently ed in animals. Only some of these have been classlfi,ed as an mdole hallucinogen. How- v~rified to be si!llilar in man. The compounds ever, Its more complex chemical structure WIth prototypIC structures include those warrants a separate classification. Further- shown in Figure 1. An important chemical more, it is much more difficult to synthesize pr,oblem is to establish the absolute configur- and therefore to obtain illicitly. 3) Some of anon of all of these substances to determine the, p~enethylamines, including amphet- the common elements shared with PCP itself. amme-hke compounds (amphetamine, p- T~ ma~e matters, even more complex, PCP methoxyamphetamine, methamphetamine), exists in four different conformations as and mescaline-like compounds [mescaline, 2, shown in Figure 2. 5-dimethoxy-4-methy lamphetamine (DOM), This has prompted Kamenka (1983) to use methylenedioxyamphetamine (MDA)]. 4) In- the term "chameleon" in describing the PCP frequ~ntly abused are. the M-cholinergic an- molecule and its four different conforma- tag(j~lsts such as atropine and 3-quinuclidinyl tions. Which is the active conformation in the benzilate (QNB). The latter is also known as PCP receptor complex? BZ and at one time was proposed as a chemi- cal warfare agent to induce a psychotomimet- ic s~ate.. 5) Still. another class of psycho- Mechanism of Action of Psychotomimetic torrumeuc agents ISthe arylcyclohexylamines Agents such as phencyclidine (PCP). At least five An important book which summarizes some of our knowledge on the neurochemi- 'Supported in part by NIDA grant DA 01531, cal, behavioral, and clinical perspectives of 2Presented as part of the Panel on Mechanisms of Action of ha!lucinogens is t~at edited by Jacobs (1984). Indole and Phenalkylamine Hallucinogens, December 13, With so many diverse chemical classes of 1985, ACNP Meetings, Maui, HI. 3Department of Pharmacology, University of Michigan, Ann psychotomimetics, there is no simple unifying Arbor, M148109-0010, theory as to how ,they act. .Most investigators Address all correspondence concerning this manuscript to: feel th~t ~he m~Jor cherr~.lCalmessengers in Dr, E.~, Domino, Department of Pharmacology, M6414 Medi- the ~ram mcludmg n<:>repmephrine(NE), ?O- cal SCienceBldg, I, Ann Arbor, M148109-0010, pamme (DA), serotonm (5-HT), acetylchohne - - -. - - ----- / 974 PSYCHOPHARMACOLOGY BULLETIN On the other hand, other phenethylamines such as mescaline, DaM, and various in- dolealkylamine and lysergic acid amides, ap- pear to involve the chemical messenger 5- HT. The newer developments in this field Phencvc i Ld Lne (PCI') nexoxedro I relate to the subtypes of 5-HT receptors. CH, Ligand binding assays using in vitro brain fI- :-':,-CH":!-CH ~_,",_l?,"'membrane fractions from animals are now widely used by neuroscientists. LSD-25 binds to both 5-HTI and 5-HT2 receptors as do ol h- f.eN] ~ 110 some nonhallucinogenic ergot analogs like elll lisuride. However, almost all of these two N~Allylnurr.letazocin e (SH 10.0:'7) cve raacc tne classes of hallucinogens seem to interact more on 5-HT2 sites (Peroutka & Snyder, cs- ,",-C/"'- 1983; Shannon et al., 1984). Shannon et al. ' (1984) used radiolabeled 3H-5-HT and 3H_ CH3 ketanserin to label 5-HT1 and 5-HT2 sites, respectively. They found that among the va- I "" rious hallucinogens studied (especially 110 j}--::;::: phenethylamine derivatives which can be fur- flrid<>."d BE'n:df)isnquin,,;ine9 Bcnz I f ) i5v'1uinolIJw~ ther subclassified as phenisopropylamines) that radioactive binding was more stereo- FIGURE 1. Chemical structures of various com- selective to 5-HT 2than 5-HT 1 sites. Further- pounds that have phencyclidine-like activity. more, the 5-HT2 binding affinities (called K, values) of those hallucinogens correlated with rat behavioral discriminative data (effective (ACh), and some excitatory amino acids like dose 50 percent or ED50s). In turn, these glutamate, in particular, N-methylaspartate correlated with the potencies of some of (NMA), are involved. The two catechol- these compounds as hallucinogens in man. amines, DA and NE, along with the trace About 20 years ago, it was discovered that brain amines phenethylamine and phenetha- animals, when properly trained, discriminate nolamine, appear to be most implicated with the effects of drugs. Ho et al. (1978), Col- stimulant-induced psychoses such as those paert and Rosecrans (1978), and Colpaert produced by amphetamine, methampheta- and Slangen (1982) organized symposia that mine, etc. have summarized much of our knowledge in this field. A given class of drugs such as LSD has discrete stimulus properties that can be A B distinguished from another unrelated class p~ N (~9-THC, etc). Furthermore, animals such as rats can be trained to distinguish morphine ffN Ph from 0.9 percent NaCl placebo from LSD-25, --"" d etc. Appel et al. (1982) and Appel and Rose- crans (1984) have reviewed the behavioral pharmacology of hallucinogens in animals on H+~~ H+~~ HN+ respondent (pavlovian) conditioning and op- Ph erant (instrumental) conditioning. They -==- Ph point out that the most highly specific oper- d~ ~ d ant paradigm to distinguish hallucinogens is drug discrimination. They reviewed the evi- A+ 8+ dence for a common 5-HT2 and/or halluci- nogen receptor mode of action for a variety FIGURE 2. PCP exists in four different conforma- of compounds. Rech and Commissaris (1982) tions. VOL. n. NO. J, 1see 975 additionally have provided evidence that a amine, indicating different mechanisms un- particular spectrum of activity at 5-HT2 rela- derlie the effects of acute and chronic admin- tive to 5-HT I receptor sites is characteristic istration of both drugs. of a large variety of hallucinogens. Perhaps the most important new develop- Jacobs (1984) summarized the evidence ment in the mechanisms of action of PCP that hallucinogens such as DMT, DaM, LSD- involves its effects on excitatory amino acid 25, mescaline, and psilocybin act on post- neurotransmitter systems. It has long been synaptic 5-HT receptors. All of these com- known that PCP in receptor, binding assays pounds elicit a so-called "5-HT behavioral acts on the muscarinic cholinergic receptor, syndrome" in rats which consists of head on the delta subunit of the ion channel of the weaving, tremor, rigidity, Straub tail, splayed nicotinic receptor, and on various Ca + + and hindlegs, and forepaw treading. Tolerance K + ion channels (see Domino, 1981; Ka- and cross-tolerance to these effects are ob- menka et al., 1983). Lodge et al. (1982, 1983) served which correlate with decreases (down- and Anis et al. (1983) were the first to show regulation) of 5-HT binding sites. Jacobs that arylcyclohexylamines including keta- (1984) has provided evidence that the behav- mine, PCP, tiletamine, and etoxadrol selec- ioral effects of such 5-HT acting halluci- tively reduced excitation of mammalian neu- nogens can be dissociated from their presyn- rons by NMA, but not by quisqualate and aptic actions on 5-HT neurons. kainate. Subsequently, Snell and Johnson Can the actions of LSD-25 and related in- (1985, 1986) reported that several substances dole and phenethylamine hallucinogens on with PCP-like behavioral effects inhibited the the 5-HT system be related to the actions of release of two chemical messengers, ACh and arylcyclohexylamines such as PCP or to psy- DA, evoked by MA from rat striatal slices chomotor stimulants like amphetamine? in vitro. They also showed that these effects Probably not, but there are some interesting were similar to the classic NMA antagonist, relationships and contrasts. Most 2-amino-5-phosphonovalerate, except that psychotomimetics, when given chronically, the latter produced a parallel shift to the induce tolerance. On the other hand, in ro- right in the concentration effect curve, while dents chronic amphetamine effects are PCP produced a non-parallel shift to the potentiated. In other words, chronic use pro- right, suggesting a noncompetitive interac- duces super sensitivity. Nabeshima and his tion between PCP and NMA. Koek et al. colleagues in Japan (1985) have shown that (1986) have used a behavioral analysis in ani- PCP given chronically to rats produces a mals regarding PCP and its interaction with mixed picture. The PCP-induced "5-HT like NMA. They suggest that this might be im- syndrome" is attenuated with chronic PCP portant in the mechanisms of anesthesia in- administration and shows cross-tolerance to duced by arylcyclohexylamines and related 5-MeODMT, while DA mediated behavioral substances. effects such as sniffing, rearing, or licking are enhanced in chronic PCP treated rats given Conclusions PCP or DA agonists such as apomorphine and methamphetamine. Thus, tolerance is PCP-like compounds appear to possess a observed in the 5-HT mediated but not the unique wide spectrum of pharmacological ef- DA mediated effects of PCP.