This paper (2011) reviews the evidence that indoleamine hallucinogens act not only on the 5-HT2 receptor group but on a variety of receptors to produce their behavioral effects.
Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors.
Hallucinogens are pharmacological agents that produce marked alterations of perception, mood and cognition and have been used in ritual and medicinal contexts for millennia. Classical serotonergic hallucinogens fall into two structural classes: indoleamines (for example LSD, psilocin, DMT and 5-MeO-DMT) and phenylalkylamines (for example mescaline, DOM, DOI). Despite structural differences, the two classes produce very similar subjective effects in humans and show cross-tolerance, which historically suggested a common receptor mechanism. Earlier research converged on the 5-HT2A receptor as the primary mediator of the characteristic effects of serotonergic hallucinogens, but many indoleamines are relatively non-selective and bind to a broader set of monoamine receptors, raising the possibility that non-5-HT2 receptors contribute meaningfully to their psychopharmacology. Halberstadt and colleagues set out to review and synthesise evidence from human and animal studies that address which receptor interactions mediate the behavioural effects of indoleamine hallucinogens. The review examines pharmacology (binding profiles and functional actions), electrophysiological findings (for example effects on dorsal raphe nucleus firing), and behavioural paradigms commonly used to probe hallucinogen effects in animals (drug discrimination, head twitch response, prepulse inhibition, exploratory/investigatory behaviour, 5-HT syndrome components, and species comparisons). The stated aim is to clarify the relative contributions of 5-HT2A and non-5-HT2 receptor mechanisms to the behavioural and subjective effects of indoleamine hallucinogens.
Papers cited by this study that are also in Blossom
Carter, O., Burr, D. C., Pettigrew, J. D. et al. · Journal of Cognitive Neuroscience (2006)
Carter, O. L., Hasler, F. ;., Pettigrew, J. D. et al. · Psychopharmacology (2007)
Geyer, M. A., Vollenweider, F. X. · Trends in Pharmacological Sciences (2008)
Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A. et al. · Pharmacopsychiatry (2005)
The extracted text presents a narrative review rather than a formal systematic review or meta-analysis; it does not report a reproducible search strategy, databases searched, dates, or explicit inclusion/exclusion criteria. Halberstadt and colleagues synthesise findings from diverse experimental approaches, integrating radioligand binding and affinity data, in vivo electrophysiology, pharmacological blockade experiments, knockout mouse studies, and human clinical and PET studies. Material reviewed includes animal behavioural pharmacology paradigms: drug discrimination (two-lever operant procedures in rats and other species), the head twitch response (HTR) in mice and rats, prepulse inhibition (PPI) of startle, the 5-HT behavioural syndrome and its components (e.g. lower lip retraction), exploratory and investigatory behaviour assessed in the Behavioral Pattern Monitor (BPM), and species- and strain-comparison studies including transgenic (knockout) mice. Clinical human studies discussed comprise controlled challenge and blockade experiments with antagonists (e.g. ketanserin, risperidone), PET imaging of 5-HT2A occupancy ([18F]altanserin), and clinical comparisons of different hallucinogen classes (for example DMT versus S-ketamine). Where available in the extracted text, the review reports quantitative pharmacological measures (e.g. receptor Ki and EC50 values), correlation coefficients relating receptor affinity to behavioural potency, and antagonist potencies in blocking behavioural endpoints. The authors place emphasis on pharmacological specificity studies (antagonist and agonist pretreatments), genetic loss-of-function models (5-HT2A, 5-HT1A, and 5-HT2C knockout mice where reported), and combinations of pharmacological manipulations to dissect multi-receptor contributions to complex drug stimuli.
Chemical and binding profiles: Phenylalkylamine hallucinogens are highly selective for 5-HT2 subtypes (5-HT2A, 5-HT2B, 5-HT2C), often showing very large selectivity over 5-HT1 sites. Indoleamines are relatively non-selective, displaying moderate-to-high affinity at both 5-HT1 and 5-HT2 subtypes and interacting with other monoamine receptors; LSD in particular binds to multiple 5-HT, dopaminergic and adrenergic sites. The extracted text reports specific affinities in places (for example DMT σ1 KD ≈ 14.75 µM; LSD suppresses dorsal raphe nucleus (DRN) firing with an EC50 ≈ 4.6 nM and displays 5-HT1A Ki values in the 3.9–5.1 nM range in rats). Unitary mechanism and clinical blockade: Human and animal data support a unitary component of the hallucinogen effect mediated by 5-HT2A activation. Antagonists selective for 5-HT2 receptors (e.g. ketanserin, pirenperone, M100907/MDL 100,907) block many hallucinogen-induced behaviours. Clinical blockade studies with psilocybin show marked attenuation of most subjective effects by the 5-HT2 antagonist ketanserin (20–50 mg p.o.) and by the mixed D2/5-HT2A antagonist risperidone (0.5–1.0 mg p.o.), whereas the D2 antagonist haloperidol produced little blockade. PET imaging with [18F]altanserin found that subjective intensity correlated with 5-HT2A occupancy in anterior cingulate and medial prefrontal cortices. Nevertheless, some psilocybin effects (e.g. slowing of binocular rivalry, certain cognitive and arousal measures) are not blocked by ketanserin, indicating non-5-HT2A contributions. Presynaptic (raphe) versus postsynaptic evidence: Indoleamines (LSD, psilocin, DMT, 5-MeO-DMT) inhibit DRN firing via somatodendritic 5-HT1A autoreceptors. However, multiple lines of evidence argue against a primary presynaptic mechanism for hallucinogenesis: the time course of DRN inhibition does not match behavioural effects; selective 5-HT1A agonists that also inhibit DRN firing are not hallucinogenic in humans; raphe lesions do not reproduce hallucinogen-like behaviours nor abolish hallucinogen effects. Postsynaptic 5-HT receptor mechanisms, particularly 5-HT2A, are implicated instead. Drug discrimination: The hallucinogen discriminative stimulus is strongly linked to 5-HT2A activation. High correlations are reported between 5-HT2A affinity and stimulus potency for phenylalkylamines (r ≈ 0.90–0.97 in humans; r = 0.938 for a series in rats). Selective 5-HT2A antagonists (e.g. M100907, MDL 11,939) block stimulus control for DOI, DOM, LSD and related compounds. By contrast, multiple antagonist and correlation analyses argue against a primary role for 5-HT2C in the discriminative stimulus (antagonist correlation r = 0.95 for 5-HT2A affinity vs blockade potency, and r = -0.29 for 5-HT2C). Complex stimuli and ancillary receptors: Indoleamines often evoke compound discriminative stimuli involving both 5-HT2A and 5-HT1A receptor-mediated components. Examples include 5-MeO-DMT and DPT which generalise to both DOM (a 5-HT2A cue) and 8-OH-DPAT (a 5-HT1A cue). For LSD specifically, dopaminergic receptors (notably D2-like receptors) contribute to aspects of the discriminative stimulus in a time-dependent manner: short pretreatment intervals yield a 5-HT2A-mediated cue, whereas longer pretreatment times can reveal a D2-like component. Mixed blockade studies show that combined 5-HT2A and DA antagonism more effectively antagonises LSD than either alone. Exploratory/investigatory behaviour (BPM): In rats, both phenylalkylamines and indoleamines produce a characteristic profile in a novel BPM: reduced locomotion, fewer investigatory behaviours and increased thigmotaxis (avoidance of the centre). These effects are novelty-dependent and attenuated in a familiar environment. Phenylalkylamine effects in the BPM are mediated by 5-HT2A receptors (blocked by ritanserin, ketanserin, M100907), whereas indoleamine effects are mechanistically more complex: initial locomotor suppression by LSD and 5-MeO-DMT involves 5-HT1A receptors (blocked by WAY-100635 and propranolol), while later hyperactivity is 5-HT2A-mediated. In mice, phenylalkylamines and indoleamines diverge: phenylalkylamines produce an inverted U-shaped locomotor response mediated by 5-HT2A (increase at lower doses) and 5-HT2C (decrease at higher doses), while indoleamines tend to reduce locomotion and investigatory behaviour via 5-HT1A receptors. Prepulse inhibition (PPI): DOI and LSD decrease PPI in rats via 5-HT2A receptors (blocked by M100907/MDL 11,939). The mechanism for 5-MeO-DMT in rats is complex: its PPI-disruptive effect is sensitive to both 5-HT2 (SER-082) and 5-HT1A (WAY-100635) manipulations but not to M100907. Species differences occur: 5-HT1A agonists decrease PPI in rats but increase PPI in some mouse strains, and likewise certain indoleamines increase PPI in 129/SvEv mice. Human studies report parameter-dependent effects of psilocybin on PPI (increases at some interstimulus intervals, decreases at others); continuous DMT infusion or ayahuasca showed no PPI effect in the extracted reports. Head twitch response (HTR) and other stereotypies: The HTR is tightly linked to 5-HT2A activation: DOI-, LSD- and many hallucinogen-induced HTRs are blocked by selective 5-HT2A antagonists and are absent in 5-HT2A knockout mice, with cortical 5-HT2A expression restoring the response. Indoleamine activity at 5-HT1A receptors can attenuate HTR expression; interactions with 5-HT2C receptors also modulate the HTR, often inhibiting HTR at higher doses. The ear-scratch response (ESR) is induced by phenylalkylamines via 5-HT2A but is not produced by indoleamines; in fact indoleamines can suppress the ESR. Species and strain differences: Several behavioural and pharmacological effects differ between rats and mice and across mouse strains; for example, receptor knockouts and pharmacological antagonists can have opposing effects on PPI in mice versus rats. Such species/strain differences influence interpretation and suggest mice may be particularly sensitive to 5-HT1A-mediated actions of indoleamines. Synthesis: Across paradigms, the weight of evidence identifies 5-HT2A activation as the primary mediator of classic hallucinogen effects, but indoleamine hallucinogens additionally engage 5-HT1A receptors and, for some agents (notably LSD), dopaminergic and other monoaminergic sites. Quantitative correlations and genetic/pharmacological loss-of-function studies support this mixed mechanistic picture.
Halberstadt and colleagues interpret the assembled evidence as supporting a primary mechanistic role for 5-HT2A receptor activation in the behavioural effects of both phenylalkylamine and indoleamine hallucinogens, while emphasising that indoleamines exert additional actions at other monoamine receptors that modulate their overall behavioural profile. They note strong convergent findings: antagonist blockade of HTR, drug discrimination and exploratory/investigatory changes by 5-HT2A antagonists; significant correlations between 5-HT2A affinity and behavioural potency; and human clinical blockade and PET data linking 5-HT2A occupancy to subjective intensity. At the same time, the authors stress that indoleamines are pharmacologically promiscuous and that 5-HT1A receptor activation by these compounds contributes to several distinctive effects (inhibitory effects on DRN firing, components of the 5-HT behavioural syndrome, 5-HT1A-like discriminative stimulus elements, and attenuation of some 5-HT2A-mediated responses). For LSD, dopaminergic interactions appear to add further complexity, including a delayed dopaminergic discriminative component and late behavioural phases in some paradigms. The authors place importance on species and strain differences: mice and rats can show divergent receptor contributions in PPI and BPM paradigms, and genetic knockout data reveal receptor-specific roles. They also argue that 5-HT2C receptor activation generally attenuates hallucinogen-evoked behaviours rather than mediating them, citing pharmacological and clinical evidence (for example lorcaserin trials without hallucinogenic effects). Key limitations acknowledged in the extracted text include the complexity of ligand binding profiles (parallel structure–affinity relationships between 5-HT2A and 5-HT2C can confound interpretation), strain-dependent differences in receptor function (for example mRNA editing of 5-HT2C), and the difficulty of attributing biphasic behavioural effects to pharmacokinetic versus pharmacodynamic causes. The review also recognises that antagonist and knockout studies can produce discrepant outcomes across species and strains, and that some clinical effects of psilocybin are not blocked by 5-HT2A antagonists, indicating incomplete mechanistic resolution. The authors call for further research to clarify unresolved issues: direct clinical comparisons of phenylalkylamine versus indoleamine hallucinogens, investigations into the basis of biphasic behavioural profiles, detailed studies of temporal phases of drug action (including potential active metabolites), and greater use of cross-species and genetic approaches to parse receptor contributions. They suggest that mice may be a useful model to probe 5-HT1A-mediated effects of indoleamines, while emphasising the need to interpret rodent data in light of species and strain variability.
Hallucinogens are a class of pharmacological agents that increase the intensity and lability of affective responses and produce profound distortions of perceptual processes encompassing the visual, auditory and tactile modalities. These compounds, in the form of botanical preparations, have been used by humans for thousands of years to induce states of mysticism and inebriation. Notable examples include the peyote cactus (Lophophora williamsii), which contains mescaline; teonanácatl mushrooms containing psilocin and psilocybin; and ayahuasca, a decoction prepared from the bark of βcarboline-containing Banisteriopsis species in combination with plants containing N,Ndimethyltryptamine (DMT). Hallucinogen use has remained relatively stable over the past decades, but these drugs are becoming more widely available with increased access to psychoactive natural products and the extant knowledge base on the use and preparation of these compounds introduced through the internet. For example, the sacramental use of ayahuasca originated in South America, but in recent years the use of this hallucinogen has spread to Europe and North America. Research into the profound effects of hallucinogens on perception has shaped our neurobiological understanding of consciousness and informed our understanding of neuropsychiatric disorders. For example, the notion that psychotic states seen in schizophrenia may involve serotonin (5-HT) dysfunction arose in part from the observed psychedelic effects of (+)-lysergic acid diethylamide (LSD) and other classical serotonergic hallucinogens.
As shown in Figure, classical hallucinogens belong to two classes of chemicals: (1) indoleamines, including the ergoline LSD and indolealkylamines such as DMT, 5-methoxy-DMT (5-MeO-DMT), psilocin, and 4-phosphoryloxy-DMT (psilocybin); (2) phenylalkylamines, such as the phenethylamines mescaline and 2,5-dimethoxy-4bromophenethylamine (2C-B), and the phenylisopropylamines 2,5-dimethoxy-4iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), and 2,5dimethoxy-4-bromoamphetamine (DOB). Recently, highly potent rigid analogs of hallucinogenic phenylalkylamines have been synthesized in which the alkoxy ring substituents are incorporated into furanyl and/or pyranyl rings (e.g.,difuran-4-yl)-2-aminopropane ("Bromo-Dragonfly";, or the ethylamine side chain is conformationally constrained by incorporation into a cycloalkane ring (e.g., TCB-2;. Radioligand binding studies have shown that phenylalkylamine hallucinogens are highly selective for 5-HT 2 sites (5-HT 2A , 5-HT 2B , and 5-HT 2C receptors), and some of these compounds display over 1000-fold selectivity for agonist-labeled 5-HT 2 receptors versus 5-HT 1 sites. By contrast, indolealkylamines are relatively nonselective for 5-HT receptors, displaying moderate to high affinity for 5-HT 1 and 5-HT 2 subtypes. Tablesandshow the binding profiles of psilocin and DMT, respectively, for 5-HT receptors. It has been reported that DMT is a σ 1 receptor agonist with moderate affinity (K D = 14.75 µM;; however, it is not clear whether this interaction contributes to the effects of DMT because the affinity of the drug for 5-HT 1A and 5-HT 2A receptors is ~2-orders of magnitude greater than for σ 1 binding sites (see Table). Further, other σ 1 receptor agonists (e.g., cocaine) are not hallucinogenic, making it unlikely that σ 1 activation by DMT plays a primary role in mediating its hallucinogenic effects. Certain indolealkylamines, including DMT, N,N-dipropyltryptamine (DPT), 5-MeO-DMT, and 5methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) block 5-HT uptake at micromolar concentrationsand serve as substrates for the 5-HT transporter. As shown in Table, LSD binds to a number of 5-HT receptors with high (nanomolar) affinity, and also interacts with dopaminergic and adrenergic receptors.
Despite differences in their chemical structure, the classical hallucinogens LSD, psilocybin, mescaline, and DOM produce extremely similar experiences in humans. By contrast, the subjective effects of hallucinogens are readily distinguished from the effects of drugs in other pharmacological classes, including anticholinergics, stimulants, entactogens, and NMDA antagonists. Tolerance rapidly develops to the effects of hallucinogens, and indoleamine and phenylalkylamine hallucinogens produce cross-tolerance. The similarity of their psychopharmacological effects and their ability to produce cross-tolerance indicate that indoleamine and phenylalkylamine hallucinogens act through a common receptor mechanism. It is generally accepted, based on evidence reviewed below, that the unitary mechanism responsible for the effects of serotonergic hallucinogens is activation of the 5-HT 2A receptor. Given the high affinity and selectivity of DOB and other phenylisopropylamine hallucinogens for 5-HT 2 subtypes, it follows that a member of the 5-HT 2 receptor family is likely to be responsible for mediating the effects of these compounds. Nevertheless, although the unitary pharmacological effects of hallucinogens are mediated by the 5-HT 2A receptor, this does not preclude the possibility that the interaction of indoleamines with non-5-HT 2 receptors does have psychopharmacological and behavioral consequences. This article will review the evidence showing that both 5-HT 2 and non-5-HT 2 receptors contribute to the behavioral effects of indoleamine hallucinogens.
Although neglected for several decades, clinical testing of hallucinogens has resumed in recent years. The majority of this clinical work has focused on psilocybin, although mescalineand DMThave also been studied. Most of the studies listed above were designed to characterize the subjective and physiological effects of hallucinogens. Studies have also examined whether psilocybin is effective at reducing symptoms in patients with obsessive-compulsive disorder (OCD), and anxiety in terminal cancer patients. Other groups have revisited the hypothesis that hallucinogens can be used to model the symptoms of psychosis in normal subjects. Gouzoulis-Mayfrank and colleaguesconducted a double-blind crossover study comparing the subjective effects of DMT with those of the noncompetitive NMDA antagonist S-ketamine. This study is notable because it demonstrated that DMT produced effects that primarily resembled the positive symptoms of schizophrenia, whereas the effect of S-ketamine resembled the negative and cognitive symptoms of schizophrenia. In addition to confirming that serotonergic and glutamatergic hallucinogens evoke distinguisible psychological effects, these findings clearly demonstrate that both drug classes can be used to model different aspects of schizophrenia. Vollenweider and colleagues have conducted a series of studies examining the contribution of 5-HT and dopamine (DA) receptors to the subjective and behavioral effects of psilocybin in human volunteers. These studies have demonstrated that most of the subjective effects of psilocybin are blocked by the 5-HT 2 antagonist ketanserin (20-50 mg, p.o.;. Similar findings were reported for the mixed D 2 /5-HT 2A antagonist risperidone (0.5-1.0 mg, p.o.), whereas the DA D 2 antagonist haloperidol (0.021 mg, i.v.) produced very little blockade of psilocybin effects. Taken together, these findings confirm that the hallucinogenic effects of psilocybin are mediated primarily by the 5-HT 2A receptor. This conclusion is supported by the results of a recent PET study with the 5-HT 2A ligand [ 18 F]altanserin, which demonstrated that the intensity of psilocybin-induced subjective effects is directly correlated with 5-HT 2A occupation in the anterior cingulate and medial prefrontal cortices. Importantly, however, ketanserin does not block some of the effects of psilocybin, including slowing of binocular rivalry, impairment of multiple object tracking, and reduction of measures of arousal and vigilance. Although the 5-HT 2A receptor is responsible for most of the effects of psilocybin, it is clear that interactions with non-5-HT 2A receptors also contribute to the effects of the drug. The mechanism for the subjective effects of DMT has also been investigated clinically. Blockade studies with low doses of the nonselective 5-HT 2 antagonist cyproheptadine produced inconclusive results, and the sedative effects of cyproheptadine precluded testing higher doses. By contrast, Strassman has reported that the mixed 5-HT 1A/1B /β-adrenergic antagonist pindolol markedly potentiates the subjective effects of DMT. Since DMT has only low affinity for β-adrenergic receptors, this finding indicates that interactions with 5-HT 1A receptors serve to attenuate the action of DMT at the 5-HT 2A receptor. It is likely that the effects of other indoleamines at the 5-HT 2A receptor are also modulated by their 5-HT 1A agonist activity.
It was recognized as early as 1954 that the profound intoxicating effects of LSD are likely to result from interactions with serotonin (5-hydroxytryptamine, 5-HT) in the brain. Although it was soon widely accepted that the hallucinogenic effects of LSD result from effects on central serotonergic systems, it took several more years for researchers to find evidence that directly supported this contention. In 1968, Aghajanian and colleagues found that intravenous LSD (10-20 µg/kg) completely inhibits the firing of serotonergic neurons in the dorsal (DRN) and median (MRN) raphe nuclei in rats. It was subsequently demonstrated that psilocin, DMT, and 5-MeO-DMT induced similar raphe-depressant effects in rats and cats. The microiontophoretic application of these agents directly to raphe cells allowed workers to determine that the depressant effects of indoleamines upon raphe firing are mediated by somatodendritic 5-HT autoreceptors. There is extensive evidence that LSD and other indoleamine hallucinogens inhibit the firing of serotonergic DRN neurons by activating 5-HT 1A receptors. Like the indoleamine hallucinogens, 5-HT 1A receptor-selective agonists (e.g., 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), ipsapirone, gepirone, and buspirone) inhibit DRN firing. It has also been shown that 5-HT 1A antagonists block the inhibition of DRN neuronal activity induced by LSD. As noted earlier, hallucinogenic indoleamines, including LSD, psilocin, DMT, 5-MeO-DMT, N,N-diethyltryptamine (DET), and N,N-dipropyltryptamine (DPT), bind to the 5-HT 1A receptor with moderate to high affinity, and are potent agonists at 5-HT 1A receptors negatively coupled to adenylate cyclase. LSD is estimated to suppress DRN firing in rats with an EC 50 of 4.6 nM, consistent with the reported affinity of LSD for the rat 5-HT 1A receptor, with K i values ranging from 3.9 to 5.1 nM. Anatomical studies have confirmed that 5-HT 1A receptors are primarily expressed in the DRN and MRN as somatodendritic autoreceptors. Indeed, following the destruction of 5-HT-containing nerve cells by intracerebral injection of the selective serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), the density of [ 3 H]8-OH-DPAT-labeled 5-HT 1A binding sites in the DRN is greatly reduced. In addition to their depressant effects upon raphe activity, LSD, psilocin, DMT, and 5-MeO-DMT inhibit cells downstream from the raphe nuclei by stimulating postsynaptic 5-HT 1A receptors. These agents are approximately 4 to 5 times more potent at presynaptic than postsynaptic sites (de Montigny and, and thus they tend to preferentially inhibit DRN cells while leaving downstream neurons relatively unaffected. The preferential action of indoleamine hallucinogens on somatodendritic 5-HT 1A autoreceptors contrasts with the effect of 5-HT, which inhibits cells in the DRN and in DRN target regions with similar potencies (de Montigny and. The ability of indoleamine hallucinogens to selectively inhibit DRN cells probably results from the marked (>50%) 5-HT 1A receptor reserve present on the cell bodies of serotonergic raphe cellsbut not on postsynaptic membranes. It has been shown that 5-HT 1A receptors in the DRN and hippocampus couple preferentially to Gi 3 and Go, respectively, and this difference in G-protein coupling may also contribute to the different efficacies of indoleamine hallucinogens at presynaptic versus postsynaptic sites. The evidence outlined above led to the hypothesis that by selectively depressing the activity of neurons in the DRN and thereby decreasing 5-HT release, hallucinogens remove the tonic inhibition of downstream neurons mediated by 5-HT. It was theorized that LSD and related agents induce hallucinogenic effects indirectly by disinhibiting brain regions targeted by DRN efferents. The observation bythat LSD, at an intravenous dose of 20 µg/kg, accelerates the firing of cells targeted by inhibitory DRN projections provided additional support for the "presynaptic hypothesis" of hallucinogen action. Further research identified several problems with this hypothesis: 1. Trulson and coworkers observed dissociations between the behavioral and raphe inhibitory effects of hallucinogens. The depression of DRN neuronal firing induced by LSD in cats is transient and does not correspond to the time course of LSDinduced behavioral effects. Further, low doses of LSD and psilocin produce significant behavioral alterations but have negligible effects on DRN unit activity.
Although humans and laboratory animals develop tolerance to the effects of LSD and other hallucinogens after chronic administration, DRN neurons fail to develop a tolerance to the inhibitory effects of those drugs. By contrast, 5-HT 2A receptors are downregulated by treatment with LSD, psilocybin, DOI, DOB, and DOM. 3. Antagonists at postsynaptic 5-HT receptors, including mainserin, ketanserin, and metergoline, attenuate many of the behavioral effects of LSD but fail to block the effect of that drug upon DRN activity.
Phenylalkylamine hallucinogens such as mescaline, DOI, and DOM have inconsistent effects upon raphe firing, and bind to 5-HT 1A sites with negligible affinity. Furthermore, DOM is completely inactive as a 5-HT 1A receptor agonist.
Despite that fact that the LSD congener lisuride has high-affinity for the 5-HT 1A receptorand inhibits the firing of DRN neurons when administered to rats at intravenous doses of 1 to 5 µg/kg, it is not a hallucinogenic drug in humans.
Even though they completely suppress the firing of serotonergic neurons in the raphe nuclei, selective 5-HT 1A receptor agonists are not hallucinogenic when administered to humans. Indeed, buspirone and ipsapirone are used clinically as anxiolytic agents. As was found with the indoleamine hallucinogens, 8-OH-DPAT and gepirone act preferentially on presynaptic 5-HT 1A sites. Hence, the ability of hallucinogenic indoleamines to selectively activate presynaptic 5-HT 1A receptors per se is not responsible for their psychoactive effects.
If the effects of hallucinogens are mediated by inhibition of raphe neurons, then destruction of the raphe nuclei should evoke behavioral alterations identical to those produced by hallucinogens. Likewise, hallucinogens should have only minimal effects on behavior when administered to animals with raphe lesions because the anatomical locus where these agents act is not intact. However, lesioning the midbrain raphe nuclei of laboratory animals does not produce hallucinogen-like behavioral effectsnor does it diminish the effectiveness of mescaline or other hallucinogens. All of the aforementioned evidence contradicts the hypothesis that inhibition of the raphe nuclei plays a primarily mechanistic role in the effects of hallucinogenic agents. The ability to evoke a cessation of serotonergic cell firing is clearly an epiphenomenon unrelated to the production of hallucinogenic activity. Importantly, some of the evidence against the presynaptic hypothesis indicated that postsynaptic 5-HT receptor mechanisms are likely involved in mediating the effects of this class of agents. Hence, the presynaptic hypothesis of hallucinogen action is untenable and has correctly been abandoned in favor of a postsynaptic mechanism.
The phenomenon of drug-induced stimulus control has been applied successfully to the study of hallucinogens, and these methodologies have proven especially useful when applied to the mechanistic analysis of these compounds. Hirschhorn and Winter first demonstrated in 1971 that rats can be trained to discriminate mescaline and LSD from saline using standard two-lever operant procedures, and it was subsequently shown that many classical hallucinogenic drugs (e.g., LSD, mescaline, DOM, DOB, DOI, psilocybin, 5-MeO-DMT, and DPT) are capable of serving as discriminative stimuli in the drug discrimination paradigm. The interoceptive stimulus cues evoked by a variety of hallucinogenic agents in laboratory animals appear to be uniform in nature, as cross-generalization occurs between all of these drugs. Most drug discrimination studies with hallucinogens have employed rats, although pigeons, mice, and rhesus monkeyshave also been used. The drug discrimination assay displays pronounced pharmacological specificity, and members of other drug classes, including opiates, sedatives, stimulants, NMDA antagonists (e.g., phencyclidine and ketamine), salvinorin A, cannabinoids, and anticholinergics, consistently fail to evoke hallucinogen-like stimulus effects. There is also evidence demonstrating that hallucinogens and 5-HT 1A receptor-selective agonists produce distinct interoceptive cues).
The hallucinogen discriminative stimulus is blocked to varying degrees by a variety of non-selective 5-HT antagonists, including methysergide, metergoline, mianserin, methiothepin, and cyproheptadine. The high-affinity, selective 5-HT 2 receptor antagonists pirenperone and ketanserin are also potent and highly efficacious antagonists of the discriminative stimulus properties of DOM and LSD, and of DOM-stimulus generalization to LSD, mescaline, and 5-MeO-DMT. Based on these findings, Glennon and colleaguesproposed that the stimulus effects of hallucinogenic drugs are mediated by the 5-HT 2A receptor. It was soon demonstrated that a significant correlation (r = 0.938) exists between the 5-HT 2A affinities of various phenylalkylamine hallucinogens and their ED 50 values obtained from stimulus generalization studies using 1.0 mg/kg DOM as the training drug (see Fig.); also observed was a significant correlation (r = 0.90-0.97) between the 5-HT 2A receptor affinities and the potencies of these drugs in humans. Taken together, these findings strongly indicate that the stimulus effects of hallucinogens are mediated by the 5-HT 2A receptor. The existence of the 5-HT 2C receptor was first proposed by Pazos and associates in 1984, and these and other workers were able to label 5-HT 2C sites in porcine and rat choroid plexus membranes with radioligands such as [ 3 H]5-HT, [ 3 H]mesulergine, and [ 125 I]2-iodo-LSD. Soon after the discovery of 5-HT 2C sites, it was recognized that LSD binds to 5-HT 2C sites with nanomolar affinity. Subsequent work demonstrated that phenylalkylamine and indolealkylamine hallucinogens bind to 5-HT 2C receptors with moderately high-affinity. Binding studies using agonist radioligands have shown that hallucinogens are relatively nonselective for 5-HT 2A and 5-HT 2C receptors. The observation that hallucinogens interact with 5-HT 2C receptors confounded the hypothesis that activation of 5-HT 2A receptors is the primary mechanism for the effects of serotonergic hallucinogens. This hypothesis was proposed prior to the discovery of 5-HT 2C sites, and was partially based on evidence demonstrating that ketanserin and pirenperone block the behavioral effects of hallucinogens in several animal paradigms. However, ketanserin and pirenperone exhibit less than a 100-fold difference in affinity for 5-HT 2A receptors versus 5-HT 2C receptors, and therefore display only moderate selectivity for the 5-HT 2A receptor. It was also reported that there is a significant correlation (r = 0.78) between the affinities of various phenylalkylamine hallucinogens for 5-HT 2C receptors and their psychoactive potency in humans. However, 5-HT 2A and 5-HT 2C receptors display parallel structure-affinity relationships for ligand binding, so it is not clear whether this correlation is due to the involvement of 5-HT 2C receptors in the effects of hallucinogens or whether it merely reflects the relationship between 5-HT 2A and 5-HT 2C binding affinities. Because the potency of hallucinogens strongly correlates with their 5-HT 2A receptor affinity, and given that the 5-HT 2A and 5-HT 2C affinities of hallucinogens are correlated, it might be expected that a correlation between hallucinogen potency and 5-HT 2C affinity would exist even if the 5-HT 2C receptor played absolutely no role in the effects of these compounds. The potent action of hallucinogens at 5-HT 2C receptors has led to speculation that 5-HT 2C receptor occupation may play an important mechanistic role in the action of hallucinogenic drugs. In order to determine whether the 5-HT 2C receptor is involved in mediating the discriminative stimulus effects of hallucinogens, attempts have been made to block the effects of hallucinogens with 5-HT 2 subtype-selective antagonists. Before 1993, the most selective agent known was the butyrophenone neuroleptic spiperone, an antagonist at dopaminergic D 2 /D 4 and serotonergic 5-HT 1A receptors that displays 500-to 1000-fold higher affinity for 5-HT 2A than for 5-HT 2C binding sites. Unfortunately, most (but not all) of the antagonist blockade studies with spiperone produced inconclusive results because the compound can severely disrupt responding when administered in combination with LSD or DOM. It has been reported, however, that the ether analog of spiperone (AMI-193), a 5-HT 2A receptor antagonist with 2,150-fold selectivity versus 5-HT 2C sites, blocks DOM-induced stimulus control in rats at very low doses (ED 50 = 0.003 mg/kg) without altering the response rate. More recently, it has been demonstrated that stimulus control in animals trained with DOI, DOM, LSD, and 2C-T-7is blocked by the highly selective 5-HT 2A antagonist M100907 (formerly MDL 100,907). The LSD cue is also blocked by MDL 11,939, a 5-HT 2A antagonist with high selectivity versus the 5-HT 2C receptor (Marona-Lewicka and. The apparent lack of 5-HT 2C involvement in the stimulus effects of hallucinogens is supported by the fact that even high doses of the mixed 5-HT 2C/2B antagonists SB 200,646A and SB 206,553 fail to alter DOI-and LSD-induced responding in rats. It has also reported that the selective 5-HT 2C antagonist SB 242,084 does not block the psilocybin discriminative stimulus. Furthermore, an antagonist correlation analysis studyfound that the rank order of potencies for blockade of LSD-like stimulus effects by 5-HT 2 antagonists parallels their binding affinities for the 5-HT 2A receptor (r = 0.95) but not for the 5-HT 2C receptor (r = -0.29). In sum, it appears that the hallucinogen discriminative stimulus is mediated by the 5-HT 2A receptor and not by the 5-HT 2C receptor.
Effects of LSD-Numerous studies, cited above, demonstrate that the interoceptive state governing hallucinogen discrimination in animals is mediated primarily by 5-HT 2A receptor interactions. Although the phenylalkylamines and the indoleamines act via a common 5-HT 2A mechanism, the former agents have high affinity only for 5-HT 2 receptors and therefore produce a discriminative stimulus which is less complex and more selective than that of the indoleamines. For example, Fiorella and colleaguesexamined the correlation between the 5-HT 2A affinity of ten 5-HT antagonists and their median effective dose (ID 50 values) for blocking the LSD stimulus and found that 5-HT 2A receptor affinity alone could only account for 56% of the variance in the LSD-antagonist potencies of the compounds; however, interactions with the 5-HT 2C receptor did not account for the remaining variability in antagonist potency. In contrast to the above findings, variance in the potency for inhibiting R-(-)-DOM substitution in LSD-trained animals was almost completely accounted for by 5-HT 2A affinity. These data support the notion that LSD evokes a compound stimulus, whereas the phenylalkylamine cue displays greater selectivity with respect to the 5-HT 2A receptor. Moreover, there is considerable evidence that higher doses of antagonists are consistently required to block the LSD discriminative stimulus than are required to block phenylalkylamine-induced stimulus control. Indeed, while cinanserin potently antagonizes DOM and mescaline, it is much less effective against LSD-and 5-MeO-DMT-appropriate responding. Such findings are indicative of the complex nature of the LSD cue. LSD evokes a compound stimulus; although the most salient component of the LSD stimulus is transduced through the 5-HT 2A receptor, it appears that ancillary interactions with other monoamine receptors are responsible for secondary non-essential components of the LSD stimulus complex (Marona-Lewicka and. The secondary elements of the LSD cue have been attributed to occupation of 5-HT 1A receptors (Marona-Lewicka andand DA D 2 receptors. As with any drug possessing complex stimulus properties, the nature of the LSD discriminative stimulus will vary depending upon the training and testing conditions. There is considerable evidence that the 5-HT 1A subtype contributes to the discriminative effects of LSD. It has been reported that LSD, at a dose of 0.48 µmol/kg, elicits intermediate levels of drug-lever selection in rats trained with 1.2 µmol/kg 8-OH-DPAT. Unfortunately, trials with larger doses of LSD were precluded because the partial generalization was accompanied by severe disruption of behavior. When ipsapirone was tested in LSD-discriminating rats it occasioned a maximum of 71% drug-lever responding (i.e., partial substitution;. 8-OH-DPAT has also been shown to produce partial substitution in rats and mice trained to discriminate LSD. Interestingly, data from drug discrimination studies with yohimbine reveal that this drug can fully substitute for LSD in rats, though this finding has been disputed by Winter. Although normally classified as a α 2 -adrenoceptor antagonist, yohimbine actually displays comparable affinities for α 2adrenoceptors and 5-HT 1A sites. Cross-substitution has been observed to occur between yohimbine, 8-OH-DPAT, and ipsapirone, indicating that the yohimbine discriminative stimulus is mediated primarily by the 5-HT 1A receptor. Given these facts, the observation by Marona-Lewicka and Nichols (1995) that yohimbine but not the selective α 2 -adrenoceptor antagonist RS 2026-197 substitutes for LSD indicates that there is a 5-HT 1A -mediated stimulus component common to both yohimbine and LSD. LSD binds to DA D 1 , D 2 , D 3 , D 4 , and D 5 receptors with high affinity, and acts as a partial agonist at DA D 1 and D 2 receptorsand as a full agonist at DA D 4 receptors. There is some evidence that interactions with DA receptors contribute to the LSD cue. For example, rats trained with 0.25 mg/kg of the DA D 1 /D 2 agonist apomorphine respond to LSD with partial generalization. However, although the apomorphine cue is antagonized by the D 2 antagonist haloperidol but not the 5-HT antagonist pizotifen, substitution of LSD for apomorphine could be blocked by pizotifen but not haloperidol, implicating serotonergic mechanisms rather than dopaminergic mechanisms in the substitution. The mixed 5-HT 2A /D 2 antagonist risperidone blocks the LSD cue with much greater potency than the 5-HT 2 antagonist ritanserin. Specifically, risperidone blocks LSD discrimination with 414 times the potency of ritanserin, a finding that is surprising because risperidone has only slightly higher affinity for the 5-HT 2A receptor than ritanserin. Although 0.63 mg/kg ritanserin produces full occupation of 5-HT 2A sites, it fails to attenuate the LSD stimulus; ritanserin must be administered at 40 mg/ kg to completely antagonize the LSD cue, and at that dose ritanserin produces significant occupation of catecholamine receptors. By contrast, risperidone and ritanserin display nearly identical potencies as antagonists of the DOM cue. These findings indicate that both 5-HT 2A and DA D 2 receptor interactions contribute to the interoceptive state governing LSD discrimination, whereas only the 5-HT 2A receptor is involved in DOM discrimination. Supporting this conclusion is the fact that the potency of ritanserin as an antagonist of LSD stimulus control is markedly potentiated when administered in combination with low doses of haloperidol. Stimulus antagonism studies have shown that DA antagonists alone have no effect on the discriminability of LSD. Therefore, it appears that the LSD cue is most effectively and potently antagonized by concurrent blockade of 5-HT 2A and DA sites. In this regard, risperidone is similar in potency to the combination of ritanserin and haloperidol. Recent reports indicate that that the dopaminergic component of the LSD discriminative stimulus is time-dependent. Drug discrimination studies using LSD as the training drug have typically used 15-30 min pretreatment times, and have shown consistently that 5-HT 2A antagonists block LSD-induced stimulus control. However, when rats are trained to discriminate LSD with a longer 90 min pretreatment time, the resulting stimulus cue evoked by LSD is mediated by D 2 -like receptors and not by 5-HT 2A receptors (Marona-Lewicka and. These findings demonstrate that the stimulus effects of LSD occur in two temporal phases, the first phase involving 5-HT 2A receptors and the second involving DA receptors. It is not clear whether the delayed dopaminergic cue is a direct effect of LSD or is produced by a LSD metabolite with selective DA agonist activity.
LSD, certain hallucinogenic indolealkylamines produce stimulus effects that are both DOMand 8-OH-DPAT-like. For instance, the hallucinogen 5-methoxy-N,N-dipropyltryptamine (5-MeO-DPT), which displays nearly identical affinities for 5-HT 1A receptors (K i = 4.0 nM) and agonist-labeled 5-HT 2A receptors (K i = 7.1 nM), produces complete generalization in animals trained with DOM and in animals trained with 8-OH-DPAT. The 5-MeO-DMT discriminative stimulus also involves 5-HT 1A -and 5-HT 2A -mediated components. Generalization occurs between DOM, LSD, and 5-MeO-DMT regardless of which is used as the training drug.proposed that the ability of 5-MeO-DMT to substitute for DOM involves 5-HT 2A receptors whereas the ability of 5-MeO-DMT to substitute for LSD involves both 5-HT 1A and 5-HT 2A receptors. Not only do the discriminative stimulus properties of 5-MeO-DMT vary depending upon conditions of training and testing, however, but may also depend upon the dose of 5-MeO-DMT. Nevertheless, there is evidence that 5-MeO-DMT-induced stimulus control primarily involves 5-HT 1A receptors, with 5-HT 2A receptors playing only a secondary role. This conclusion is consistent with the fact that the behavioral response to the drug in rats and mice is predominantly 5-HT 1A -mediated. The 5-MeO-DMT discriminative stimulus completely generalizes to 8-OH-DPAT and ipsapirone, and the ability of these and other agents to substitute for 5-MeO-DMT is correlated with their 5-HT 1A , but not 5-HT 2A , affinities. Both WAY 100635 and pindolol antagonize the 5-MeO-DMT cue and its generalization to 8-OH-DPAT and ipsapirone. By contrast, the 5-HT 2 antagonists pirenperone, ketanserin, and ritanserin are much less effective antagonists. Several studies have shown that 5-MeO-DMT evokes intermediate levels of 8-OH-DPAT-like responding followed by considerable behavioral disruption at higher doses. After pretreatment with ketanserin, however, 5-MeO-DMT engenders complete substitution in 8-OH-DPAT-trained animals. As such, it would appear that the 5-HT 2A agonist activity of 5-MeO-DMT is responsible for the behavioral disruption. There is other evidence that 5-HT 2A receptor activation can disrupt 5-HT 1A -mediated stimulus control: response rates are severely depressed when animals trained to discriminate 8-OH-DPAT are given DOM in combination with the training drug. Interestingly, administration of 5-MeO-DMT to animals trained with ipsapirone results in full drug-appropriate responding. This observation raises the question of why 5-MeO-DMT disrupts responding in 8-OH-DPATtrained animals but not in ipsapirone-trained animals. Given that ipsapirone is a less efficacious 5-HT 1A agonist than is 8-OH-DPAT, the most plausible explanation is that whereas low, non-disruptive doses of 5-MeO-DMT can fully mimic ipsapirone, 5-MeO-DMT fails to fully mimic 8-OH-DPAT because the doses required to evoke full substitution also induce significant 5-HT 2A receptor activation, leading to behavioral disruption. There is also evidence that the hallucinogen DPT produces a discriminative stimulus that is mediated by interactions with both 5-HT 2A and 5-HT 1A receptors. DPT produces complete generalization in rats trained with DOMand partial generalization in animals trained with LSD, effects that are fully blocked by M100907. However, in animals trained to discriminate 1.5 mg/kg DPT, pretreatment with a combination of WAY-100,635 and M100,907 was much more effective at antagonizing stimulus control than was either antagonist given alone, indicating that DPT elicits a compound stimulus involving both 5-HT 1A receptor-and 5-HT 2A receptor-mediated components. Likewise, although psilocybin-induced stimulus control is mediated primarily by the 5-HT 2A receptor, with the 5-HT 1A receptor playing no apparent role, the ability of DPT to evoke partial generalization in animals trained with psilocybin appears to involve interactions with both 5-HT 1A and 5-HT 2A receptors.
Administration of 8-OH-DPAT to rats produces a 5-HT behavioral syndrome that includes flat body posture, reciprocal forepaw treading, hindlimb abduction, and lateral head weaving. The behavioral effects of 8-OH-DPAT are very similar to those produced by treatment with a 5-HT precursor in combination with a monoamine oxidase (MAO) inhibitor (Grahame-. Indoleamine hallucinogens, including 5-MeO-DMT, LSD, and DPT, can also induce components of this behavioral syndrome. By contrast, phenylalkylamine hallucinogens do not reliably produce the 5-HT behavioral syndrome. The ability of 8-OH-DPAT and 5-MeO-DMT to induce the 5-HT behavioral syndrome is blocked by WAY-100635 and pindolol, and therefore the syndrome is likely mediated by 5-HT 1A receptors. It appears that these 5-HT 1A receptors are located postsynaptically because destruction of central serotonergic projections with 5,7-DHT does not prevent 5-MeO-DMT and LSD from inducing the behavioral syndrome. Compared to the doses of LSD and 5-MeO-DMT that inhibit DRN firing, relatively high doses of those indoleamines are required to induce the 5-HT behavioral syndrome. For example, although 75 µg/kg (IP) LSD completely inhibits the firing of serotonergic DRN neurons in rats (Gallagher and, much higher doses of LSD (400-1000 µg/kg) are required to induce hindlimb abduction, head weaving, and forepaw treading. This discrepancy probably reflects the fact that for 5-HT 1A receptors there is a large receptor reserve present in the DRN but not in postsynaptic regions. Indeed, although the 5-HT 1A partial agonists buspirone, ipsapirone, and gepirone inhibit the firing of DRN neurons (and thus behave as full agonists presynaptically), they block the ability of 8-OH-DPAT and 5-MeO-DMT to induce the behavioral syndrome. The 5-HT 1A agonists 8-OH-DPAT, buspirone, ipsapirone, flesinoxan, and lisuride induce lower lip retraction (LLR) in rats. WAY-100,635 blocks LLR induced by 8-OH-DPAT, demonstrating that this behavioral response involves activation of 5-HT 1A receptors. Microinjection of 8-OH-DPAT directly into the MRN induces LLR, indicating that 5-HT 1A receptors expressed by MRN neurons are responsible for mediating this behavior. Interestingly, 5-MeO-DMT and DPT induce LLR only in animals that have been pretreated with a 5-HT 2A antagonist. It has also been shown that DOI and the 5-HT 2C agonist mchlorophenylpiperazine (mCPP) can attenuate lower lip retraction induced by 8-OH-DPAT, indicating that 5-HT 2A and/or 5-HT 2C receptors act to attenuate the behavioral effects of 5-HT 1A receptor activation. These findings indicate that the activity of 5-MeO-DMT and DPT at 5-HT 2 receptors acts to functionally antagonize LLR induced by 5-HT 1A receptor activation.
Tests of drug effects on locomotor activity have been used frequently to assess psychoactive agents for stimulant or depressant activity. However, studies examining the effects of hallucinogens on behavior in an open field produce inconsistent results and fail to distinguish the effects of hallucinogens from those of other drug classes. Given the complex nature of hallucinogen effects, it is not surprising that the locomotor paradigm produces inconclusive results because it does not provide a qualitative assessment of behavior and fails to assess whether changes in sensitivity to environmental stimuli contribute to the behavioral effect. The Behavioral Pattern Monitor (BPM) is a combination of activity and holeboard chambers that provides quantitative and qualitative measures of unconditioned locomotor and investigatory activity in rats, and can be used to assess for changes in the response of animals to environmental stimuli. Statistical assessment of the geometrical and dynamical structure of motor behavior in the BPM has proven very useful in characterizing drug effects in rats. Using the BPM it is possible to differentiate statistically the effects of various stimulants at doses that produce comparable increases in locomotion but marked differences in qualitative aspects of behavior involving spatiotemporal patterns of locomotion and investigatory responses directed at specific environmental stimuli).
rats-When phenylalkylamine (mescaline, DOM, DOI, and DOET) and indolealkylamine (psilocin, DMT, 5-MeO-DMT, and 5-methoxy-α-methyltryptamine) hallucinogens are tested in rats in a novel BPM environment they produce a characteristic behavioral profile: (1) there is reduced locomotor activity; (2) the frequency of investigatory behaviors (rearings and holepokes) is diminished; and (3) avoidance of the center of the BPM chamber is increased. Figureillustrates the behavioral profile of psilocin in the BPM. The effects of hallucinogens are not observed when animals are tested in a familiar environment, and thus likely reflect potentiation of the neophobia displayed by rats in a novel environment. It has been theorized that the diminution of the behavioral effects of hallucinogens in a familiar test environment occurs because hallucinogen-treated animals are more willing to explore the BPM chambers once the stimuli associated with the test environment become less threatening due to habituation. LSD has similar effects on investigatory behavior and center entries, but it has biphasic effects on locomotor behavior with activity initially suppressed and then increasing over time. Mescaline and DOM can also produce biphasic effects on locomotor activity, but this occurs only after relatively high doses are administered (100 mg/kg and ≥5 mg/kg, respectively;. The effects of hallucinogens on investigatory and exploratory behavior in the BPM are distinct from those produced by other drug classes, including lisuride (Adam and, 5-HT releasers such as 3,4methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), 5-HT 1 agonists, psychostimulantsPretreatment with the 5-HT 2 antagonists ritanserin and ketanserin blocks the effects of DOI, DOM, and mescaline in the BPM. The effects of DOI are blocked by M100907 but not by the selective 5-HT 2C/2B antagonist SER-082, and are therefore likely mediated by the 5-HT 2A receptor and not by the 5-HT 2C receptor. The action of the indoleamines in the BPM is more complex mechanistically. The initial suppression of locomotor activity induced by LSD is blocked by the mixed 5-HT 1 /β-adrenergic antagonist propranololand the selective 5-HT 1A antagonist WAY-100635, whereas ritanserinand M100907block LSDinduced hyperactivity . Thus, both 5-HT 1A and 5-HT 2A receptors appear to contribute to the behavioral effects of LSD in the BPM, and this finding is supported by the fact that chronic treatment with either 8-OH-DPAT or DOI produces cross-tolerance with LSD in this behavioral paradigm. The effects of low doses of 5-MeO-DMT are antagonized by WAY-100635 but not by M100907, and thus are likely mediated by 5-HT 1A receptors. However, when 5-MeO-DMT is administered in combination with a behaviorally inactive dose of a MAO A inhibitor such as harmaline, clorgyline, or pargyline, it produces LSD-like delayed hyperactivity that is blocked by the 5-HT 2A -selective antagonist MDL 11,939 and is sensitive to the novelty of the testing environment. Thus, both 5-HT 1A and 5-HT 2A receptors mediate the effects of LSD and 5-MeO-DMT in the BPM.
The original BPM was designed for rats, but we have also tested hallucinogens in a mouse version of the BPM. In mice, DOI, mescaline, DOM, DOET, and DOPR reduce investigatory behavior and produce effects on locomotor activity that follow an inverted U-shaped dose-response function, with low and moderate doses increasing activity and higher doses decreasing activity. The increase in locomotor activity induced by 1.0 mg/kg DOI or 25 mg/kg mescaline is absent in 5-HT 2A receptor knockout mice, suggesting the involvement of 5-HT 2A receptors. Conversely, the reduction in locomotor activity produced by 10 mg/kg DOI is potentiated in 5-HT 2A knockout mice and attenuated by SER-082, indicating that the decrease in activity is mediated by the 5-HT 2C receptor. This conclusion is supported by the fact that selective 5-HT 2C agonists decrease locomotor activity in mice. By contrast to the phenylalkylamine hallucinogens, psilocin, DMT, 5-MeO-DMT, and LSD produce decreases in locomotor activity, investigatory behavior, and time spent in the center of the mouse BPM chambers. The effects of psilocin and 5-MeO-DMT are blocked by WAY-100635 but are not altered by the selective 5-HT 2C antagonist SB 242,084 or by 5-HT 2A receptor gene deletion. Thus, the effects of indoleamines in the mouse BPM are mediated by 5-HT 1A receptors, whereas the effects of the phenylalkylamines are mediated by 5-HT 2A and 5-HT 2C receptors. Figurecompares the effects of DOM and 5-MeO-DMT on locomotor activity in the mouse BPM. These studies demonstrate that phenylalkylamine and indoleamine hallucinogens produce disparate effects on exploratory and investigatory behavior in mice, behavioral differences that are not readily apparent when these agents are studied in rats.
Prepulse inhibition (PPI) describes the phenomenon where the startle response is attenuated when preceded by a weak prestimulus. PPI has been used as an operational measure of sensorimotor gating and has been found to be deficient in patients with a variety of psychiatric illnesses, including schizophrenia. LSD, DOI, DOB, mescaline, and 5-MeO-DMT disrupt PPI in rats. The decrease in PPI induced by DOI and LSD is blocked by the highly selective 5-HT 2A antagonists M100907 and MDL 11,939 but not by the 5-HT 2C antagonist SB 242,084, the 5-HT 2C/2B antagonist SER-082, or the 5-HT 1A antagonist (+)WAY-100135, demonstrating the involvement of 5-HT 2A receptors. In comparison with DOI and LSD, the mechanism for the effect of 5-MeO-DMT on PPI in rats is more complex: the effect of 5-MeO-DMT is attenuated by pretreatment with either SER-082 or WAY-100,635, but not by M100907. The nonhallucinogenic LSD congener lisuride also disrupts PPI in rats, and thus can be considered to be a LSD false-positive. However, LSD and lisuride disrupt PPI in rats via distinct mechanisms, and the effect of lisuride is blocked by the selective DA D 2 /D 3 antagonist raclopride but is unaffected by pretreatment with MDL 11,939. This finding indicates that the 5-HT 2A agonist activity of lisuride does not contribute to the effects of the drug on PPI. The effects of DOI on PPI in rats appear to be mediated specifically by actions in the ventral pallidum, since bilateral infusion of DOI directly into the ventral pallidum but not into the nucleus accumbens produces disruption of PPI. It is likely that the effects of DOI on PPI are mediated by activation of 5-HT 2A receptors in the ventral pallidum because local infusion of M100907 attenuated the effects of systemic DOI on PPI. However, the possibility remains that dopamine receptors in the ventral pallidum or in other brain regions may play a downstream role in the PPI-disruptive effects of DOI because haloperidol and raclopride can also block the effect of systemic DOI on PPI. It is not currently clear whether the ventral pallidum plays a role in mediating the ability of LSD and 5-MeO-DMT to disrupt PPI in rats. Activation of 5-HT 1A receptors has opposing effects on sensorimotor gating in rats and mice. In rats, selective 5-HT 1A agonists such as 8-OH-DPAT, buspirone, gepirone, and ipsapirone decrease PPI. Conversely, in 129/SV and Balb/c mice, treatment with 8-OH-DPAT increases PPI. The ability of 8-OH-DPAT to increase PPI is blocked by the 5-HT 1A antagonist WAY-100,635 and is absent in 5-HT 1A knockout mice. Interestingly, we have found that 5-MeO-DMT and psilocin produce dose-dependent increases in PPI in 129/SvEv mice; Fig.). The ability of 5-MeO-DMT to increase PPI was partially attenuated by pretreatment with 1.0 mg/kg WAY-100,635, indicating that 5-HT 1A receptors are involved in mediating this effect (Fig.). Clinical studies have demonstrated that psilocybin can alter PPI in human volunteers.reported that psilocybin increases PPI in humans when an interstimulus interval (ISI) of 100 ms was used for the prepulse trials. However,found that psilocybin increases PPI at long ISIs (120-2000 ms) but reduces PPI when shorter ISIs of 30 ms are used. Thus, the effects of psilocybin on PPI are dependent on the testing parameters. The receptor mechanism(s) responsible for the effects of psilocybin on PPI in humans have not yet been investigated. In contrast to the effect of psilocybin, administration of DMT by continuous i.v. infusionor orally as a component of ayahuascahas no effect on PPI in human subjects.
Corne and Pickering reported in 1967 that a variety of hallucinogens, including LSD, psilocybin, psilocin, DMT, and mescaline, produce a head twitch response (HTR) in mice consisting of a paroxysmal rotational movement of the head. This behavior had been observed previously to occur after systemic administration of the 5-HT precursor 5-hydroxytryptophan. It was subsequently demonstrated that LSD, 5-MeO-DMT, DOM, and mescaline also induce the HTR when administered to rats. In rats, the HTR often involves not only the head but also the neck and trunk of the animal, and thus the behavior has also been referred to as the wet-dog shake in that species. Evidence linking the HTR to the 5-HT 2A receptor emerged almost immediately after 5-HT 2A binding sites were first detected by radioligand binding studies. Specifically, Leysen reported in 1982 that there is a significant correlation (r = 0.88) between the 5-HT 2A affinity of a series of 19 5-HT antagonists and their potency for blocking mescaline-induced HTR in rats. It was later shown that the ability of 5-HT antagonists to block the HTR induced by DOI is also significantly correlated (r = 0.83) with 5-HT 2A affinity. Studies have also demonstrated that the HTR evoked by DOI in rats is blocked by the selective 5-HT 2A antagonist M100907 but not by the selective 5-HT 2C antagonist SB 242,084 or the mixed 5-HT 2C/2B antagonist SB 200,646A. Likewise, HTR induced by DPT, 5-MeO-DIPT, and TCB-2 in mice is blocked by. It has also been reported that 5-HT 2A knockout mice do not display the HTR in response to administration of LSD, DOI, DOM, DOB, mescaline, psilocin, 1-methylpsilocin, DMT, or 5-MeO-DMT, conclusively linking the HTR to 5-HT 2A activation. Further, genetic restoration of the 5-HT 2A receptor to the cortex of 5-HT 2A knockout mice restores the ability of LSD to induce the HTRExpression of 5-HT 2A receptor-induced HTR can be modified by activity at a variety of receptors, including 5-HT 1A . Selective 5-HT 1A agonists, including 8-OH-DPAT, attenuate the HTR induced by DOI in mice and rats. Furthermore, although 5-MeO-DMT induces the HTR, pretreatment with 5-MeO-DMT dose-dependently reduces DOI-induced HTR in mice. This finding raises the possibility that activation of the 5-HT 1A receptor by 5-MeO-DMT and other indoleamines may attenuate their ability to induce the HTR. Experiments with LSD, however, demonstrate that the response to the drug is not altered by deletion of the 5-HT 1A receptor gene. Given the especially potent 5-HT 1A agonist activity of 5-MeO-DMT, additional studies are needed to determine whether the 5-MeO-DMT dose-response for HTR is altered in 5-HT 1A knockout mice. Finally, it is important to note that some discrepancies exist regarding the interaction between 5-HT 1A receptors and 5-HT 2A -induced HTR; indeed, whereas WAY-100,635 can potentiate DOI-induced HTR in rats, it has also been reported that WAY-100,635 can antagonize DPT-induced HTR in mice. It is not clear whether this discrepancy reflects species differences or is indicative of pharmacological differences between phenylalkylamines and indoleamines. This issue is further complicated by the fact that 5-HT 1A antagonists such as WAY-100635 and S-(-)-UH-301 can themselves provoke HTR in mice through a mechanism that purportedly involves elevation of 5-HT release and subsequent 5-HT 2A receptor activation. There is also evidence that the 5-HT 2C receptor can regulate the HTR induced by 5-HT 2A receptor activation. The 5-HT 2 agonist Ro 60-0175, which is ~30-fold selective for 5-HT 2C receptors vs 5-HT 2A receptors, does not induce the HTR in rats unless administered in combination with SB 242,084. This finding indicates that the ability of Ro 60-0175 to induce the HTR via 5-HT 2A receptor activation is suppressed by its interaction with the 5-HT 2C receptor. Ro 60-0175 has also been shown to inhibit the HTR induced by DOI in mice. Fantegrossi and colleagues have reported that the HTR induced by DOI, 2C-T-7, DPT, and 5-MeO-DIPT in NIH Swiss and Swiss-Webster mice typically follows an inverted U-shaped dose-response function. The descending limb of the DOI response is shifted to the right by SB 242,084, indicating that the 5-HT 2C receptor is responsible for the inhibition of HTR that occurs at higher doses. By contrast, it has been reported that 5-HT 2C knockout mice display a significant reduction in DOI-induced HTR. Although compensatory developmental adaptations in 5-HT 2C knockout mice may have contributed to these contradictory findings, the same investigators found that pretreatment with SB 242,084 reduced the magnitude of the HTR to DOI in C57BL/6J and DBA/2J mice. It is not clear why those two groups obtained such discrepant results with DOI in animals pretreated with SB 242,084, but the fact that the studies used different strains of mice may have been a contributing factor. It has been reported that there are strain differences in 5-HT 2C receptor mRNA editing. Editing of 5-HT 2C receptor mRNA can dramatically alter G-protein coupling, and thus differences in 5-HT 2C editing could potentially alter how 5-HT 2A and 5-HT 2C receptors interact in different strains of mice.
Deegan and Cook first reported in 1958 that administration of mescaline produces stereotypic hindlimb scratching of the head and ears in mice but not in other species. Later work showed that DOM, DOI, DOET, and the 4-ethoxy analog of mescaline (escaline) also induce the ear-scratch response (ESR). It appears that the ESR is mediated by 5-HT 2A receptors, because the effect of DOI is blocked by ketanserin and spiperone. It should be noted that the ESR is not induced by indoleamine hallucinogens. In fact, LSD and 5-MeO-DMT actually block the ESR induced by mescaline, DOM, and DOI. Based on the finding that the DOI-induced ESR is also inhibited by the 5-HT 1A/1B agonist RU 24969 but not by the 5-HT 1A agonist 8-OH-DPAT), it appears that blockade of the ESR by the indoleamine hallucinogens involves interactions between 5-HT 2A and 5-HT 1B receptors. This hypothesis needs to be evaluated by testing indoleamine hallucinogens in 5-HT 1B knockout mice or in mice pretreated with a selective 5-HT 1B antagonist.
Despite the structural differences between indoleamine and phenylalkylamine hallucinogens, these agents evoke a nearly identical spectrum of behavioral effects in rats and provoke similar mental and subjective states in humans. As summarized in this review, it is clear that activation of the 5-HT 2A receptor plays a primary mechanistic role in mediating the behavioral effects of the indoleamine and phenylalkylamine classes of serotonergic hallucinogens. Indeed, there is a wide consensus that administration of 5-HT 2A antagonists blocks the effects of hallucinogens on HTR, drug discrimination, exploratory and investigatory behavior, and sensorimotor gating in rats. Most importantly, clinical investigations have shown that 5-HT 2A antagonists block most, although certainly not all, of the subjective and behavioral effects of psilocybin. Recent experiments have also demonstrated 5-HT 2A involvement in the discriminative stimulus effects of hallucinogens in non-human primates. Lastly, there tends to be a strong correlation between the behavioral potencies of hallucinogens in animals and humans and 5-HT 2A binding affinity. Thus, over the last two decades, most research focusing on the mechanism of action for the unitary pharmacological effects of serotonergic hallucinogens has concentrated primarily on effects mediated by 5-HT 2A receptors. It is currently accepted that extremely potent phenylisopropylamine ("amphetamine") hallucinogens such as DOB and DOI are highly selective for 5-HT 2 sites, and it thus follows quite logically that the behavioral effects of those compounds are likely to be exclusively 5-HT 2 -mediated. By contrast, the indoleamine hallucinogens are not 5-HT 2 selective and bind to a much larger set of monoamine receptors. Although the two classes of hallucinogens produce similar effects, it is likely that the ancillary receptor interactions of indoleamine hallucinogens modulate their overall effects on perception, cognition, and behavior. Consistent with the complexity of the binding profiles of indoleamine hallucinogens, there is evidence that the behavioral profiles of these compounds are more complex than those of their phenylalkylamine counterparts. A large amount of evidence demonstrates that both 5-HT 1A and 5-HT 2A receptors are responsible for the behavioral effects of indoleamine hallucinogens. This conclusion is derived extensively from drug discrimination studies and from studies on the exploratory and investigatory behavior of rats in the BPM. Additionally, indoleamine hallucinogens elicit behavioral components of the 5-HT syndrome (lateral head weaving, hindlimb abduction, backward locomotion, and lower lip retraction) and direct inhibitory effects on the firing of serotonergic DRN neurons that are rarely, if ever, induced by phenylalkylamine hallucinogens. There is also evidence that 5-HT 1 receptor activation by indoleamines acts to suppress expression of HTR, ESR, and other 5-HT 2A -mediated behavioral effects, a conclusion that is supported by some clinical data. For LSD, DA receptors appear to play an additional role in mediating certain aspects of the behavioral effects of the drug, especially in the drug discrimination paradigm. Freedman has noted that in humans there seems to be a secondary temporal phase of LSD action that involves ideas of reference or paranoid ideation, effects not seen with indolealkylamines or phenylalkylamines. Based on that observation,have theorized that the paranoid stage of the LSD intoxication may be related to the (delayed) dopaminergic discriminative stimulus effects of LSD and the delayed hyperactivity produced by LSD in the rat BPM. Nichols has also suggested that secondary non-5-HT 2A receptor-effects of LSD may be at least partially responsible for the exquisitely high behavioral potency of that drug relative to other serotonergic hallucinogens. In addition to LSD, other hallucinogens have been found to produce biphasic behavioral effects. In rats, the combination of 5-MeO-DMT and a MAO inhibitor produces an initial decrease in locomotor activity followed by a gradual increase in activity that is mediated by 5-HT 2A receptors. Similar findings have been reported for high doses of DOM and mescaline, although the receptor mechanisms responsible for the biphasic effects of those agents have not been elucidated. We have also found that administration of high doses of phenylalkylamine hallucinogens to mice can produce biphasic locomotor effects that are mediated by 5-HT 2A and 5-HT 2C receptors. Thus, both indoleamine and phenylalkylamine hallucinogens can produce effects in the drug discrimination and locomotor activity paradigms that occur in discrete temporal phases. Further studies are needed to determine whether pharmacokinetic or pharmacodynamic factors are responsible for the biphasic behavioral profiles displayed by certain hallucinogens. The finding that hallucinogens are agonists at the 5-HT 2C receptor has confounded the hypothesis that these agents act via a 5-HT 2A -dependent mechanism. There is a growing consensus, however, that the effects of hallucinogens are not mediated by the 5-HT 2C receptor, and it appears that activity at the 5-HT 2C receptor actually serves to attenuate many of the behavioral effects of hallucinogens. The ability of DOI to reduce prepulse inhibition in rats is significantly attenuated by treatment with the 5-HT 2C -selective agonist WAY-163909). We have shown that 5-HT 2A and 5-HT 2C receptors exert opposing effects on locomotor activity in mice. Similar findings have been reported for HTR. Importantly, recent clinical trials with the selective 5-HT 2C agonist lorcaserin for weight loss have shown that this compound does not produce any hallucinogen-like effects. Given the lack of significant neuropsychiatric effects of lorcaserin, it appears highly unlikely that hallucinogen binding to 5-HT 2C receptors contributes to hallucinogenesis. Recently, evidence has emerged that there are sometimes substantial differences between the effects of serotonergic and dopaminergic drugs on behaviors in rats and mice that cannot be ascribed to cross-species differences in the behavioral paradigms per se. As an example, PPI studies with DA agonists have shown that pharmacological antagonists and KO mice reveal diametrically opposite effects in mice vs rats. Similar species differences have been noted for PPI studies with hallucinogens, with indolealkylamine hallucinogens disrupting PPI in rats but increasing PPI in mouse strains. Indeed, for PPI the mouse results may actually be more predictive of effects of hallucinogens on PPI in humans, although the effects observed in human volunteers are heavily dependent on the testing parameters used. We have recently reported evidence that indoleamine and phenylalkylamine hallucinogens evoke distinct effects on exploratory and investigatory behavior in mice. This finding contrasts with data from rats, which showed that the two classes of hallucinogens evoke similar behavioral profiles. In mice, moderate doses of DOIand mescaline produce increases in locomotor activity that are mediated by the 5-HT 2A receptor. By contrast, indoleamine hallucinogens such as psilocin and 5-MeO-DMT produce decreases in locomotor activity that are mediated by the 5-HT 1A receptor. These findings demonstrate that it is possible to differentiate these two classes of hallucinogens behaviorally. Further, in light of the PPI data, it appears that mice may be highly sensitive to the 5-HT 1A -mediated behavioral effects of indoleamine hallucinogens. Thus, in contrast to rats, mice may serve as a useful rodent species to probe the contribution of 5-HT 1A receptors to indoleamine-induced behavioral effects. It is important to note that evidence has been reported previously that phenylalkylamine and indoleamine hallucinogens can be distinguished by their behavioral effects -the former but not the latter class of agents induce the ESR in mice. However, the recent evidence from the mouse BPM is among the first to demonstrate that the two structural classes of hallucinogens can induce distinct behavioral profiles. Additional studies, both in rodents and humans, are necessary to determine the significance of these behavioral differences and to explore whether there are subtle behavioral differences in the human psychopharmacology of these compounds. More generally, there is a need for clinical trials that directly compare the behavioral and subjective effects of a variety of phenylalkylamine and indoleamine hallucinogens in human volunteers. Given the recent resurgence in human testing of hallucinogens, it may be possible to conduct these trials in the near future. TableBinding of DMT to 5-HT receptors TableBinding of (+)-LSD to 5-HT and other monoamine receptors
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