This review (2008) summarises the published research into hallucinogen-induced stimulus control in phenethylamine- and tryptamine-based hallucinogens, highlighting the receptors involved in their mechanism of action.
Background
Although man’s first encounters with hallucinogens predate written history, it was not until the rise of the sister disciplines of organic chemistry and pharmacology in the nineteenth century that scientific studies became possible. Mescaline was the first to be isolated and its chemical structure determined. Since then, additional drugs have been recovered from their natural sources and synthetic chemists have contributed many more. Given their profound effects upon human behavior and the need for verbal communication to access many of these effects, some see humans as ideal subjects for study of hallucinogens. However, if we are to determine the mechanisms of action of these agents, establish hypotheses testable in human subjects, and explore the mechanistic links between hallucinogens and such apparently disparate topics as idiopathic psychosis, transcendental states, drug abuse, stress disorders, and cognitive dysfunction, studies in animals are essential. Stimulus control by hallucinogens has provided an intuitively attractive approach to the study of these agents in nonverbal species.
Objective
The intent of this review is to provide a brief account of events from the time of the first demonstration of hallucinogen-induced stimulus control to the present. In general, the review is limited to lysergic acid diethylamide (LSD) and the hallucinogenic derivatives of phenethylamine and tryptamine.
Results
The pharmacological basis for stimulus control by LSD and hallucinogenic phenethylamines and tryptamines is serotonergic in nature. The 5-HT2A receptor appears to be the primary site of action with significant modulation by other serotonergic sites including 5-HT2C and 5-HT1A receptors. Interactions with other neurotransmitters, especially glutamate and dopamine, are under active investigation. Most studies to date have been conducted in the rat but transgenic mice offer interesting possibilities.
Conclusions
Hallucinogen-induced stimulus control provides a unique behavioral tool for the prediction of subjective effects in man and for the elucidation of the pharmacological mechanisms of the action of these agents.
Papers cited by this study that are also in Blossom
Fantegrossi, W. E., Murnane, K. S., Reissig, C. J. · Biochemical Pharmacology (2007)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Hoch, P. H., Cattell, J. P., Pennes, H. H. · American Journal of Psychiatry (1952)
Vollenweider, F. X., Gamma, A., Liechti, M. et al. · Neuropsychopharmacology (1998)
Papers in Blossom that reference this study
Winter frames the review by noting that, despite long-standing human use of hallucinogens, systematic scientific study of their mechanisms has relied heavily on animal models because many cardinal effects are subjective and not directly observable in nonverbal species. Stimulus control—training animals to report the interoceptive cue produced by a drug by choosing one response under drug and another under vehicle—has emerged as a practical behavioural approach for modelling hallucinogenic effects in animals and for testing pharmacological hypotheses about mechanism. This review is focused narrowly on lysergic acid diethylamide (LSD) and hallucinogenic derivatives of the phenethylamine and tryptamine classes. Winter sets out to trace the development of hallucinogen-induced stimulus control from its first demonstrations through to contemporary pharmacological interpretations, emphasising receptor-level mechanisms (particularly serotonergic sites) and the utility of drug discrimination to predict subjective effects in man and to dissect underlying neurochemistry.
This paper is a narrative review rather than a systematic review or meta-analysis. Winter relied primarily on the primary literature, restricted the scope to LSD, phenethylamines and tryptamines, and deliberately omitted extensive coverage of other classes such as anticholinergics, cannabinoids, salvinorin and many NMDA antagonists except where they illuminate commonalities. The author did not attempt an encyclopedic listing and avoided book chapters where possible; no formal database search strategy, date range, or explicit inclusion/exclusion criteria are reported in the extracted text. Conceptually, the review organises evidence from animal drug discrimination studies: training procedures (mostly two-lever choice tasks in rats) that operationalise a discriminative stimulus, pharmacological antagonism and generalisation tests across compounds, receptor binding and functional data, and some transgenic and cross-species (mouse, primate) studies. Winter notes reliance on antagonist and agonist pharmacology, selective ligands where available, and behavioural generalisation patterns to infer receptor contributions. The author also flags that many primary studies lacked formal statistical analysis and that interpretation often requires consideration of ligand selectivity and potential off-target effects.
Historically, stimulus control by hallucinogens was established after early biochemical and behavioural work suggested a role for serotonin; Ira Hirschhorn and colleagues were pivotal in demonstrating that LSD and mescaline could serve as discriminative stimuli in rats. The bulk of experimental work has been conducted in rats using two-lever discrimination procedures, with mice and a small number of primate studies reported less often. Across the literature, a serotonergic mechanism—most notably the 5-HT2A receptor—emerges as the primary mediator of the discriminative stimulus effects of LSD and phenethylamine hallucinogens. Evidence includes antagonist correlation studies and the efficacy of the relatively selective 5-HT2A antagonist M100907 (MDL 100,907) to block stimulus control produced by DOI, LSD, 5-MeO-DMT and DOM. Winter summarises issues of ligand selectivity: earlier antagonists were nonselective and some later agents (e.g. AMI-193) showed high nominal 5-HT2A/2C selectivity but also dopaminergic activity. Reported selectivity estimates for M100907 vary by assay, with initial binding and functional potency ratios reported in the hundreds but subsequent studies giving ranges from about 16 to 186 depending on method. Other serotonin receptor subtypes modulate stimulus effects. The 5-HT2C receptor is implicated as a significant modulatory site in several paradigms, and the 5-HT1A receptor shows complex, sometimes contradictory, roles: in some studies 5-HT1A agonists (for example 8-OH-DPAT) antagonise canonical 5-HT2A-mediated behaviours, while in other discrimination assays 5-HT1A agonists potentiated LSD- or DOM-controlled responding; the 5-HT1A/7 antagonist WAY-100,635 has been used to probe these effects. Beyond serotonin, interactions with glutamatergic and dopaminergic systems are reported. Noncompetitive NMDA antagonists (ketamine, PCP, dizocilpine) can potentiate LSD- and DOM-induced stimulus effects, and group II metabotropic glutamate (mGlu2/3) ligands modulate LSD cues: the mGlu2/3 agonist LY379268 produced intermediate antagonism of LSD-induced stimulus control whereas the antagonist LY341495 potentiated LSD’s cue. Chronic treatment with the phenethylamine DOB attenuated behavioural effects of the mGlu2/3 agonist in one study, suggesting plasticity with repeated exposure. Dopaminergic involvement is more debated: some authors propose a two-phase LSD effect with a later dopaminergic component and implicate D4 or D2 receptors, while human PET and antagonist studies have suggested indirect dopamine system engagement by tryptamines such as psilocybin. The tryptamines show more heterogeneity. Some tryptamines (notably 5-MeO-DMT) have high 5-HT1A affinity and in several drug discrimination paradigms 5-HT1A mechanisms appear important for their stimulus control, although they also display partial 5-HT2A agonism. Psilocybin generally generalises to phenethylamines and LSD in discrimination assays and is substantially antagonised by M100907, but psilocybin itself is only partially antagonised by 5-HT1A blockade, indicating a complex receptor contribution. Species differences are evident but underexplored. Most data derive from rats; mice studies have shown broadly concordant results but with notable differences in antagonist sensitivity and the suggestion of greater 5-HT2C or 5-HT1A involvement in some mouse paradigms. Primate data are sparse and sometimes diverge from rodent findings. Early knockout work shows that serotonin transporter (SERT) null mice are impaired in establishing LSD stimulus control, highlighting the potential of genetic models to probe mechanism. Finally, Winter emphasises the conceptual utility of viewing drugs like LSD as compound stimuli composed of multiple receptor-mediated elements, which helps to account for asymmetrical generalisation patterns and pharmacological interactions.
Winter interprets the accumulated evidence as supporting a central role for the 5-HT2A receptor in mediating the discriminative stimulus properties of LSD and phenethylamine hallucinogens, with significant modulation by 5-HT2C and 5-HT1A receptors. The tryptamines may be mechanistically distinct in part because of their often higher affinity at 5-HT1A receptors and mixed 5-HT1A/5-HT2A activity, yielding a more complex pattern of antagonism and generalisation. The review situates glutamatergic and dopaminergic interactions as important and deserving of further study: mGlu2/3 ligands provide convergent behavioural evidence that glutamate release participates in hallucinogen-induced stimulus control, and some data suggest later dopaminergic components, at least for LSD. Winter stresses the interpretive difficulties introduced by nonselective ligands, variable experimental parameters (training drug, dose, species), and inconsistent use of statistical analysis in primary reports. Practical implications emphasised by Winter include the value of drug discrimination as a behavioural tool for predicting subjective effects in humans and for dissecting mechanistic pharmacology in animals. He calls for more selective pharmacological probes (agonists and antagonists) and the use of transgenic models to clarify receptor-specific contributions. The author recognises limitations in extrapolating from animals to humans, notes the paucity of primate and human discrimination studies for classic hallucinogens, and argues that animal data should be used to generate hypotheses that can be clinically tested rather than as definitive demonstrations of human experience.
Hallucinogens, most often in the form of crude botanical extracts, have been known to man for thousands of years. However, scientific investigation of these drugs awaited the rise, in the nineteenth century, of organic chemistry and experimental pharmacology. Indeed, it was not untilisolation of mescaline in 1896 from the cactus, Lophophora williamsii, and the determination of its chemical structurebythat a welldefined substance could be said to produce hallucinations. In view of the remarkable alterations in thought and perception produced by hallucinogens and because of the essentially subjective nature of a major portion of the effects of these drugs, it is not surprising that selfexperimentation played a prominent role in the initial investigation of drugs such as mescaline), 3,4-methylenedioxy-alpha-methylphenylethylamine, lysergic acid diethylamide (LSD; Hofmann 1959), N,N-dimethyltryptamine (DMT;, and psilocybin. No account of the selfadministration of psychoactive drugs would be complete without reference to Ann, whose personal experiences with an extensive series of tryptamines and phenethylamines are compiled in two volumes. However, even in those instances when adequate experimental designs have been employed in clinical studies (e.g.,;, ethical considerations have placed significant constraints on the type of experiments undertaken. Thus, in seeking what the late Leo Hollister called the Holy Grail of pharmacology, the mechanism of action of drugs, investigators have often turned to infrahuman species. In so doing, certain ethical and legal problems are avoided and a wider range of experimental manipulation becomes permissible but, then, there arise questions of interpretation and extrapolation. It is generally assumed that the biological events that precede and accompany chemically induced hallucinations in man have some counterpart in lower species. Early infrahuman studies of hallucinogens employed what Peter Dews, the founder of behavioral pharmacology, referred to as "isolated bits of dying tissue." These usually took the form of a section of smooth muscle situated in a tissue bath so that contraction and relaxation might be quantified (e.g.,. While studies such as these provided valuable insights into the possible mechanisms of the action of hallucinogens, including a role for serotonin, it was natural to seek behavioral correlates of human hallucinogenesis in animals. In a typical series of experiments, a profile of hallucinogenic activity was drawn using, it sometimes seemed, whatever behavior was at hand. The dependent variables ranged from neuropharmacological indicesto nonconditioned behaviorto operant behavior. Consensus as to the predictive ability of these approaches was achieved seldom if ever. It was propitious therefore that Ira Hirschhorn, as a part of his Ph.D. thesis research, successfully trained both LSD and mescaline as discriminative stimuli in the rat. The technique of hallucinogen-induced stimulus control was then transferred, first by Hirschhorn's colleague, Martin Schechter, and then by Hirschhorn himself, to the laboratory of John Rosecrans where it flourishedOn a purely intuitive basis, the study of the stimulus properties of hallucinogens is more attractive than, for example, analysis of LSD-impaired rope-climbing ability.
A dictionary definition of hallucination seems simple enough: a perception of objects with no reality. That apparent simplicity belies the range of potentially hallucinogenic chemicals and the complexity of human responses to those agents. In deference to that range and to that complexity, this review is restricted to the stimulus effects of LSD, tryptamines, and phenethylamines. Only passing mention will be made of anticholinergics, cannabinoids, exotic agents such as salvinorin, and all those other drugs which properly lay claim to the title hallucinogen. It is true that some attention will be paid to the noncompetitive N-methyl-D-aspartate (NMDA) antagonists as represented by phencyclidine (PCP) but only with respect to their possible commonalities with the objects of this review. I have made no attempt to be encyclopedic in my coverage but would direct the interested reader to the comprehensive list of stimulus control studies provided by the Drug Discrimination Bibliographic Database, to earlier reviews of hallucinogen-induced stimulus control, and to the more general recent reviews of hallucinogens byand by. I have relied upon the primary literature and have attempted to avoid references to book chapters as these are often difficult to acquire. In general, I have uncritically accepted the conclusions expressed in the papers cited but too often, in my opinion, those conclusions would have been strengthened by statistical analysis. Tests of significance may merely confirm the obvious but in many instances they will rid us of illusions born of random variation. Throughout this review, I will follow the convention, adopted from animal psychophysics, that the stimulus effects of a trained drug generalize to a specified degree to a tested drug, not vice versa. Finally, I will attempt no further definition of hallucinogen beyond saying that if a chemical mimics in human subjects the subjective effects of LSD or a tryptamine such as psilocybin or a phenethylamine such as mescaline, then it is a hallucinogen.
LSD and the tryptamines are often lumped together as "indoleamine hallucinogens". It is true that one can trace within the elegant structure of LSD (Fig.) the indole nucleus common to the tryptamines. However, it is equally true that one can find phenethylamine. More important, based on evidence both biochemical and behavioral, LSD and the tryptamines are sufficiently different to justify separate categories. To this end, I here classify LSD as an ergoline) to distinguish it from the tryptamines. Figureillustrates tryptamine, an endogenous neurochemical, as well as its hallucinogenic relatives, DMT, 5-methoxy-DMT (5-MeO-DMT), and psilocybin together with its presumed active derivative, psilocin (4hydroxy-DMT). The hallucinogenic efficacy of bufotenine (5-hydroxy-DMT) has been a matter of contention for some time. The phenethylamine hallucinogens (Fig.) are simple ring-substituted derivatives either of the endogenous neurochemicals, phenethylamine or amphetamine (alpha-methylphenethylamine). Mescaline is representative of the former neurochemical, 2,5-dimethoxy-4methylamphetamine (DOM) of the latter neurochemical. However, whatever classification scheme is adopted, it is impossible to discuss these groups in isolation because of the overlap between them both experimentally and mechanistically. This is not to say that intriguing differences between the groups do not continue to emerge.
Serotonin Soon after the discovery of LSD by Hofmann in 1943 and the identification of serotonin as 5hydroxytryptamine, it was recognized (a) that LSD might act via a serotonergic mechanismand (b) that the clinical syndromes produced by mescaline and DOM are quite similar to those following LSD and DMT. That LSD, tryptamines, and phenethylamine hallucinogens might have a common mechanism was suggested by a number of observations. In human subjectsas well as in animals, cross-tolerance develops between LSD and mescaline. Furthermore, it was known that serotonergic antagonists block some of the nonbehavioral effects of phenethylamine hallucinogens in animals. With respect to the stimulus effects of phenethylamine hallucinogens, antagonism of mescaline-induced stimulus control by the nonselective serotonergic antagonists was reported independently byand by. This observation was then extended to include other antagonists of serotonin and other hallucinogens including LSD, DOM, and DMT. It thus appeared appropriate to apply the term "serotonergic hallucinogen" to these structurally disparate drugs. Two factors complicated this simple picture; the second of these was yet to appear but the first was evident at the time. The antagonists then available, drugs such as cinanserin, methysergide, cyproheptadine, mianserin, and pizotyline (BC-105), were nonselective with respect to other neurotransmitter systems and, indeed, some had behaviorally evident partial agonist effects in LSD-trained rats. Even the wonderfully efficacious LSD antagonist, pirenperone, was soon shown to have activity as a dopamine D 2 receptor antagonist. The factor yet to be discovered was the complexity of the serotonergic family of drug receptors. The original classification byof serotonin receptors as either M or D, those blocked by morphine and by dibenzyline, respectively, was based on studies in smooth muscle and is now largely forgotten. In contrast, the two subtypes designated 5-HT 1 and 5-HT 2 byremain with us today but in a refined and expanded state that now includes 14 serotonin receptors categorized into seven families (5-HT 1-7 ;.implicated the 5-HT 2 receptor in hallucinogenesis based upon a high degree of correlation between affinities for the 5-HT 2 receptor and both potency in substituting for DOM-induced stimulus control as well as hallucinogenic potency in man. However, the subsequent discovery of the 5-HT 2C receptor) with a high level of structural and functional similarities to the 5-HT 2A receptor as well as the demonstration that indoleamine and phenethylamine hallucinogens are partial agonists at the 5-HT 2C receptor) demanded consideration of this serotonin receptor subtype.employed antagonist correlation analysis to address the question of the relative roles of the 5-HT 2A and the 5-HT 2C receptors in stimulus control mediated by LSD and DOM. A series of ten serotonergic antagonists nonselective for the 5-HT 2A and the 5-HT 2C receptors but with differing selectivity ratios for those receptors was used to block LSD-induced stimulus control and the generalization of LSD to DOM. The conclusion from this study was that stimulus control by LSD and the generalization of LSD to DOM are mediated by 5-HT 2A receptors. More direct evidence was provided by the antagonism of DOM-induced stimulus control by a newly discovered antagonist, AMI-193, having 2,000-fold selectivity for the 5-HT 2A receptor as compared with the 5-HT 2C receptor). However, like pirenperone before it, AMI-193 was found to have functionally significant activity as a dopamine D 2 antagonist. The current consensus is that differentiation of stimulus effects mediated by 5-HT 2A and 5-HT 2C receptors, respectively, is best accomplished with M100907 (MDL 100,907), a drug initially reported byto have a potency ratio of 102 for binding affinity at 5-HT 2A /5-HT 2C receptors, a selectivity ratio of 1,283 for antagonism of 5-HT-stimulated inositol phosphate accumulation in NIH 3T3 fibroblast cells expressing 5-HT 2A or 5-HT 2C receptors, and a potency ratio Subsequent studies employing a variety of receptor sources and competing ligands have yielded selectivity ratios ranging from 16) to 186. Despite the relatively low selectivity value found byusing cloned human 5-HT 2A and 5-HT 2C receptors and radiolabeled 2,5-dimethoxy-4-iodoamphetamine (DOI), M100907 was the most selective of 22 antagonists tested. The efficacy of M100907 as an antagonist of hallucinogen-induced stimulus control in the rat was first demonstrated byfor DOI and has now been extended to include, among others, LSD, 5-MeO-DMT, and DOM. An interesting complication was added bywho observed that M100907 can establish stimulus control in the rat and suggested that the effect is mediated by antagonism of 5-HT 2A receptors with possible involvement of alpha 1 adrenoceptors and other yet to be identified mechanisms. Despite the considerable evidence pointing to the 5-HT 2A receptor as the primary site mediating the stimulus effects of LSD and the phenethylamine hallucinogens, other serotonergic receptor subtypes almost certainly play at least a modulatory role). Prominent among these are the 5-HT 1A receptor as well as the aforementioned 5-HT 2C receptor. With respect to the latter receptor,observed that potentiation of the stimulus effects of LSD caused by serotonin depletion) was accompanied by the upregulation of the 5-HT 2C receptor. In addition, potentiation of the stimulus effects in rats of DOM and LSD by NMDA antagonists appears to involve a significant 5-HT 2C -receptor-mediated component. Although not directly related to hallucinogenesis, it is of interest that Cunningham and her colleagueshave presented data in support of a modulatory role for the 5-HT 2C receptor in the discriminative stimulus effects of cocaine. Evidence implicating activity at the 5-HT 1A receptor as a mediator of stimulus control by the tryptaminergic hallucinogen, 5-MeO-DMT, will be discussed in somewhat greater detail below. With respect to the 5-HT 1A receptor as a modulating factor in stimulus control by hallucinogens, the data are both extensive and contradictory. In a study of membrane excitability of pyramidal neurons in rat cortex, it was found that the 5-HT 1A agonist, 8-OH-DPAT, and the 5-HT 2A/C agonist, (-)-2,5-dimethoxy-4-bromo-amphetamine (DOB), have opposite effects thus suggesting the hypothesis that activation of 5-HT 1A and 5-HT 2 receptors have opposing effects. Behavioral data in support of these results include antagonism by 5-HT 1A agonists of DOI-induced head twitch) and wet dog shakesin the rat, effects widely accepted as indicative of agonist activity at 5-HT 2A receptors. In a study of stimulus control in the rat by the 5-HT 1A agonist, flesinoxan, it likewise was concluded that 5-HT 1A receptor activation has an inhibitory effect on activation of 5-HT 2A receptors. Against this background, it is difficult to reconcile the observation that DOM-induced stimulus control is potentiated by 8-OH-DPAT. Furthermore, LSD-induced stimulus control was found byto be potentiated by 8-OH-DPAT as well as by the 5-HT 1A receptor agonists, buspirone, gepirone, and ipsapirone. The potentiating effects of these agents were completely antagonized by the 5-HT 1A/7 receptor-selective antagonist, WAY-100,635. It is clear that further studies will be needed to resolve apparent inconsistencies. Dopamine Despite the abundant evidence of a primary role for serotonergic mechanisms in the actions of indoleamine and phenethylamine hallucinogens and the emerging evidence for glutamatergic factors, note must also be taken of dopamine and possible serotonergic-dopaminergicglutamatergic interactions. On the basis of drug discrimination data in the rat, Marona-Lewicka andhave proposed that stimulus control by LSD occurs in two phases, the first mediated by serotonin and a second later phase mediated by dopamine, and that this dopaminergic component is not shared by phenethylamine or tryptamine hallucinogens. The same group) subsequently suggested a primary role for the dopamine D 4 receptor. It should be noted however that, in a study in human subjects, the dopamine D 2 antagonist, haloperidol, significantly altered some of the subjective effects of psilocybin). Furthermore, psilocybin reduced [ 11 C]raclopride binding potential as measured by positron emission tomography). In the latter study, the authors concluded that this effect must be indirect in nature, citing a 1975 report that psilocin has only negligible affinity for dopamine receptors). However, in light of the provocative data presented by the Nichols group, our present knowledge of multiple dopamine receptor subtypes, the continued discovery of more selective dopaminergic ligands, and renewed interest in hallucinogens as tools for the understanding of psychosis, this issue clearly is worthy of further investigation.
In considering hallucinogens as psychotomimetics, clear distinctions have been drawn between noncompetitive antagonists at the NMDA subtype of glutamate receptor and serotonergic hallucinogens. The respective subjective effects of glutamatergics and serotonergics in human subjects are quite different) and their presumed mechanisms are distinct. Recently, however, there has been an increasing recognition that these systems do not operate in isolation but, instead, that there are complex and ever changing interactions between them. Illustrative of such interactions is the observation of potentiation of the stimulus effects in rats of DOM and LSD by ketamine, dizocilpine, and PCP). An explanation for such interactions is provided by the hypothesis that glutamate release represents a final common pathway for the actions both of serotonergic and of glutamatergic hallucinogens. Though the mechanisms of these interactions are largely unknown, there is evidence that the NMDA antagonists do not act directly upon 5-HT 2A receptorsand that the 5-HT 2C receptor may play a significant role. Direct testing of the hypothesis that glutamate release is correlated with behavioral effects of both serotonergics and glutamatergics has been greatly aided by the discovery of a family of ligands for group II (mGlu2/3) metabotropic glutamate receptors. These agents, exemplified by the antagonist LY341495 and the agonist LY379268, are able to increase and to decrease, respectively, glutamate release in vivo. It was observed in rats trained with LSD as a discriminative stimulus that LY379268 produced significant, albeit intermediate, antagonism of LSD-induced stimulus control and that LY341495 resulted in potentiation of the stimulus effects of LSD). These results provide significant behavioral support for the hypothesis ofthat hallucinogenesis is glutamatergically mediated. It remains to be seen whether the interactions observed between LSD and the metabotropic glutamatergic ligands generalize to the tryptamine and phenethylamine hallucinogens. Were these matters not already sufficiently complex,have reported that chronic treatment in a drug discrimination study with the phenethylamine hallucinogen, DOB, attenuates the behavioral effects of the mGlu2/3 receptor agonist, LY379268. This finding has implications for all investigations of the stimulus effects of drugs and, perhaps, may explain differences noted when results from discrimination studies are compared with dependent variables requiring only acute treatment. With respect to possible links between glutamate, hallucinogens, and psychosis, it is most interesting that an agonist at mGlu2/3 receptors has been found to be efficacious in the treatment of schizophrenia. Tryptamine hallucinogens 5-methoxy-N,N-dimethyltrypamine Against the background provided above implicating the 5-HT 2A receptor as the primary site of action of LSD and the phenethylamine hallucinogens and the 5-HT 2C receptor as a significant modulatory site, the tryptamine hallucinogens are puzzling. In terms of stimulus generalization, there is no absence in the literature of reports that the tryptamine hallucinogens mimic LSD and the phenethylamines and vice versa. Nonetheless, there have been repeated intimations that the pattern of antagonism of the tryptamines may differ from that of LSD. Later suggestions focus on the 5-HT 1A receptor. In a particularly interesting study,reported that ring fluorination of hallucinogenic tryptamines reduced the degree of mimicry of the stimulus effects of LSD by these drugs while at the same time diminishing their affinity for the 5-HT 1A receptor. The tryptamines, ranging from classic agents such as DMT) to a series of ring-and amine-substituted agents such as DPT), 2,5-dimethoxy-4-n-propylthiophenethylamine, and 5-methoxy-N,N-diisopropyltryptamine, are unquestionably hallucinogenic) yet binding data regularly indicate that their highest affinity is for 5-HT 1A receptors. Indeed, a study byconcluded that stimulus control by 5-MeO-DMT in the rat is mediated by 5-HT 1A receptors. This conclusion was fully supported by a subsequent investigation) that employed WAY-100,635, an agent not yet discovered at the time of the work by Spencer et al. The latter study suggested as well that 5-MeO-DMT differs from LSD and DOM with respect to the serotonergic element which mediates stimulus control in the rat but that it shares with those drugs a functionally significant interaction with 5-HT 2 receptors. In support of this hypothesis, 5-MeO-DMT as well as the closely related analog, DMT, displays partial agonist activity at the 5-HT 2A receptor expressed in PC12-5-HT 2A cells. Left unanswered at this time is the question of whether activity at the 5-HT 1A receptor plays a functionally significant role in hallucinogenesis by the tryptamines. Psilocybin In reports of drug-induced stimulus control, psilocybin has been found to substitute fully for racemic DOMand mescaline) thus suggesting a 5-HT 2 -mediated effect because phenethylamines such as DOM) and, presumably, mescaline have negligible affinity for 5-HT 1A receptors. Furthermore,observed that the subjective effects in normal subjects of psilocybin are blocked by ketanserin, an antagonist with low nanomolar affinity for 5-HT 2A receptorsand only micromolar affinity for 5-HT 1A receptors. Receptor binding data provided no clue in thatobserved K I values for psilocin of 49, 25, and 10 nM for 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors, respectively. Nonetheless, given the close structural similarity of 5-MeO-DMT and both psilocybin and psilocin (Fig.), it was expected that psilocybin-induced stimulus control in the rat would have a salient element mediated by agonist activity at the 5-HT 1A receptor. That expectation was not realized). Instead, it was found that, while the full generalization of psilocybin to LSD and DOM is completely blocked by M100907, psilocybin itself is only partially antagonized. Most remarkable, psilocybin-induced stimulus control was diminished not at all by WAY-100,635. It appears that there remains much to be learned regarding the tryptamine family of hallucinogens and, in particular, the functional effects of ligands at 5-HT 1A receptors. Our fascination with these drugs is further heightened by the continued interest in the human pharmacology of DMT) and a possible role for bufotenine as an endogenous psychotogen (RJ Strassman, personal communication). That the 5-HT 1A receptor might provide a link between the serotonergic and glutamatergic systems is suggested by the emergence of aripiprazole, an atypical antipsychotic with agonist activity at 5-HT 1A receptors); PCP-induced deficits in social interaction and recognition memory in rats are ameliorated by aripiprazole and these effects of aripiprazole are antagonized by).
The majority of studies of stimulus control by hallucinogens have been done in the rat, most often employing a two-lever choice procedure. This uniformity has the virtue of making much of the literature directly comparable. On the other hand, possible species differences are obscured. Unfortunately, there is little to be said about possible differences between the rat and primates, whether monkey or man, for the simple reason that few studies have been conducted in the latter species. Indeed, I am aware of only two investigations which employed infrahuman primates.trained four monkeys (Cercopithecus aethiops) with LSD andestablished DOM as a discriminative stimulus in four rhesus monkeys. Given this paucity, one cannot draw broad conclusions but it is of interest that while the data offor DOM are consistent with findings in the rat, e.g., complete antagonism by M100907, Nielsen observed a maximum of 55% antagonism of LSD by pirenperone and no blockade by pizotyline, results clearly at odds with the rat literature. In the only study in which rats and monkeys were compared directly,observed approximately 50% generalization of PCP to LSD in rats but no consistent evidence of generalization in the four monkeys tested. Turning to human subjects, the stimulus effects of a number of psychoactive drugs have been well characterized (for reviews, see) but, to my knowledge, there have been no reports of the training or cross testing of LSD or any of the tryptamine-phenethylamine hallucinogens. It should be noted that methylenedioxymethamphetamine (MDMA, Ecstasy), a drug sometimes said to be hallucinogenic, has been examined in human subjects trained to simultaneously discriminate d-amphetamine, metachlorophenylpiperazine, and placebo. MDMA shared some effects with both reference drugs and all three increased scores on the hallucinogen rating scalebut none of the participants reported hallucinations nor were hallucinations observed bydespite some references to this paper to the contrary. While the consensus is that MDMA is not hallucinogenic, drug discrimination studies in animals indicate a number of interesting generalizations, almost always partial in nature, to hallucinogens and vice versa. The complexities of the animal data are well represented by the elegant work of Baker and her colleagues) using both two-and three-choice tasks. Beginning with the training of mice with amphetamine by, this species has been used infrequently relative to the rat. Nevertheless, a number or other drugs have been examined including hallucinogens of the noncompetitive NMDA antagonist type, PCP) and dizocilpine (MK-801; Geter-Douglas and Witkin 1999). In the first report of stimulus control by a hallucinogen of the indole-phenethylamine type,employed racemic DOI. This was followed soon after by reports of the training of LSD. Broadly speaking, the results were compatible with earlier studies in the rat. DOI generalized fully to LSD and to DOB and DOI-induced stimulus control was fully antagonized by M100907. In LSD-trained mice, full generalization was observed to DOBand to DOM). An unexpected finding in both studies of LSD was the absence of complete blockade of the stimulus effects of LSD by the selective 5-HT 2A selective antagonist, M100907, results clearly at odds with those in the rat. On the basis of partial antagonism by selective 5-HT 2C receptor antagonists,suggested a significant role for this receptor whileinvoked the 5-HT 1A receptor in attempting to explain rate suppression following M100907 and the combination of the antagonist with LSD, effects not observed in the rat. With the advent of techniques to genetically modify mice, this species provides the advantage that a particular gene can be deleted to produce knockout (KO) mice. Although KO mice have been employed in investigations of the stimulus effects of nicotine, cocaine, and ethanol); until recently, there have been no studies of hallucinogens reported. In 2007, Krall et al. described an investigation in which the stimulus effects of LSD were examined in mice lacking the serotonin transporter (SERT;. Previous work had shown that the changes in SERT KO mice due to gene deletion are restricted almost exclusively to the serotonergic system including reduction in 5-HT 1A and 5-HT 2A receptors.observed that C57BL/6 mice homozygous for the null mutation (SERT -/-) were impaired in their ability to establish stimulus control with LSD as compared with littermate controls (SERT +/+ ). Obvious experiments yet to be reported include the assessment of the stimulus effects of hallucinogens in mice in which 5-HT 2A , 5-HT 2C , and 5-HT 1A receptors, respectively, have been knocked out. Compound stimuli Selective agonists and antagonists are among the most powerful tools for analyzing the stimulus effects of hallucinogens. Progress in establishing mechanisms of action of psychoactive drugs has been and continues to be dependent upon the discovery of ever more selective ligands. We are fortunate at this time to have available the 5-HT 2A receptor antagonist, M100907, and the 5-HT 1A/7 receptor antagonist, WAY-100,635. Many of the apparent contradictions found in the drug discrimination literature may be reconciled if we assume that a drug may function as a compound stimulus with each element mediated by a distinct pharmacological receptor. For example, according to the Berry-Ator hypothesis of specificity in drug discrimination, asymmetrical generalizations are explained in terms of differential salience of individual elements of the compound stimulus depending upon experimental factors including the training drug, the dose of that drug, etc.. Given the fact that LSD binds with high affinity to a variety of receptors, it is a prime candidate to function as a compound stimulus. Figureillustrates the use of M100907 and WAY-100,635 to rationalize the effects of 8-OH-DPAT in rats trained with LSD as a discriminative stimulus. It is seen that the generalization of LSD to 8-OH-DPAT is intermediate in nature and that this intermediate generalization is completely antagonized by WAY-100,635. In contrast, stimulus control by LSD is influenced not at all by WAY-100,635. The conclusion to be drawn is that LSD does indeed induce a compound stimulus which includes elements mediated by both 5-HT 2A and 5-HT 1A receptors. The former element is witnessed by the complete antagonism of LSD-induced stimulus control by M100907). The latter element is evident only when generalization of LSD to a 5-HT 1A receptor agonist is tested. A final note: we must remain aware of the sometimes-ephemeral nature of the title selective when applied to a drug. For example, with respect to WAY-100,635, agonist activity at the dopamine D 4 receptor has been reported. Nonetheless,express confidence in the selectivity of WAY-100,635 for the 5-HT 1A receptor as compared with the dopamine D 4 receptor. As noted above, various estimates have been provided for the selectivity ratio of M100907 for the 5-HT 2A and 5-HT 2C receptors, respectively. We can only hope that synthetic chemists will eventually provide uniquely selective agonists and antagonists at every receptor of interest to those who study stimulus control by hallucinogens. Epilog During the 30-year life of the Society for Stimulus Properties of Drugs, study of stimulus control by hallucinogens in animals has come a long way from the time when an anonymous reviewer described resultssubmitted to the Journal of Pharmacology and Experimental Therapeutics as having "a scent of the occult." Today, preclinical analysis of the stimulus effects of potentially psychoactive drugs has gained near universal acceptance. More important, in my opinion, are stimulus control studies that seek the still elusive mechanisms of action of hallucinogens. There remain of course those who question the relevance to the human condition of studies of hallucinogens in animals. Might hallucination be a uniquely human experience and, even if not, how are we to demonstrate, in the absence of verbal communication, the validity of an animal model of complex human behavior? My answer to those critics is that if we can agree that all translations of data from nonhuman species to predictions for man involve, to use Weinberg's term (1972), a transscientific residue, then our task in studying the stimulus effects in animals of hallucinogens and other drugs whose actions in man include a prominent subjective component is to make predictions for man which are amenable to clinical verification. In the wise words of Lawrence Berra, "it's tough to make predictions, especially about the future." Nonetheless, if the rebirth of human studies of hallucinogens is at hand, we may envisage a time when close relationships exist between those who study hallucinogens in man and in animals, a time when hypotheses based on animal data are quickly confirmed, or rejected, in the clinical laboratory.
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