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Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25mg/kg, i.p.) induce a ketanserin-sensitive (0.5mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7x in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex. Copyright © 2014. Published by Elsevier B.V.
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... Pretreatment with the 5-HT 2A receptor antagonist ketanserin completely prevented all perceptual and mind-altering effects of LSD in humans Preller et al., 2017), indicating that the hallucinogenic effects of LSD are primarily mediated through 5-HT 2A receptors. Similar to humans, tolerance to the behavioral effects of LSD is also observed in rats (Buchborn et al., 2015). Consistent with a role for 5-HT 2A receptors in the development of tolerance, daily LSD administration for 3 days decreased 5-HT 2A receptor binding in the rat frontal cortex (Buckholtz et al., 1985(Buckholtz et al., , 1990Gresch et al., 2005). ...
... Consistent with a role for 5-HT 2A receptors in the development of tolerance, daily LSD administration for 3 days decreased 5-HT 2A receptor binding in the rat frontal cortex (Buckholtz et al., 1985(Buckholtz et al., , 1990Gresch et al., 2005). However, another study reported only a non-significant trend toward a reduction of frontocortical 5-HT 2A receptor binding in rats during the development of tolerance to LSD (Buchborn et al., 2015). Additionally, no effects of acute LSD on 5-HT 2A receptor mRNA expression were found in the rat prefrontal cortex, hippocampus, or midbrain (Nichols and Sanders-Bush, 2002), although the effects of repeated LSD administration were not studied. ...
... Additionally, no effects of acute LSD on 5-HT 2A receptor mRNA expression were found in the rat prefrontal cortex, hippocampus, or midbrain (Nichols and Sanders-Bush, 2002), although the effects of repeated LSD administration were not studied. Instead, adaptations in glutamate receptors were observed (Buchborn et al., 2015). Indeed, a key mechanism of action of LSD is the activation of frontal cortex glutamate transmission secondary to 5-HT 2A receptor stimulation (Gonzalez-Maeso et al., 2008;Moreno et al., 2011;Buchborn et al., 2015). ...
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Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes. Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study. Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo. Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans.
... The most likely alternate hypothesis is a down-regulation in the sensitivity of 5-HT 2A receptors to agonist stimulation mediating the desensitization of serotonergic hallucinogen-induced head twitches. A single large dose or subchronic smaller doses of phenethylamine hallucinogens or LSD is known to decrease 5-HT 2A receptor binding in rodents (Buckholtz et al., 1985(Buckholtz et al., , 1988Leysen et al., 1989;Shi et al., 2008;Buchborn et al., 2015). Accordingly, either multiple injections within a single day or daily dosing over a week result in a tachyphylaxis for hallucinogeninduced head twitches (Leysen et al., 1989;Darmani et al., 1992;Darmani and Gerdes, 1995;Buchborn et al., 2015). ...
... A single large dose or subchronic smaller doses of phenethylamine hallucinogens or LSD is known to decrease 5-HT 2A receptor binding in rodents (Buckholtz et al., 1985(Buckholtz et al., , 1988Leysen et al., 1989;Shi et al., 2008;Buchborn et al., 2015). Accordingly, either multiple injections within a single day or daily dosing over a week result in a tachyphylaxis for hallucinogeninduced head twitches (Leysen et al., 1989;Darmani et al., 1992;Darmani and Gerdes, 1995;Buchborn et al., 2015). Serotonergic hallucinogens have been shown to increase extracellular cortical glutamate in rodents (Scruggs et al., 2003;Muschamp et al., 2004). ...
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There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate2/3 (mGlu2/3) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu2 gene profoundly attenuates an effect of 5-HT2A receptor activation using the mouse head twitch response (HTR). MGlu2 and mGlu3 receptor knockout (KO) as well as age-matched ICR (CD-1) wild type (WT) mice were administered (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and observed for head twitch activity. DOI failed to produce significant head twitches in mGlu2 receptor KO mice at a dose 10-fold higher than the peak effective dose in WT or mGlu3 receptor KO mice. In addition, the mGlu2/3 receptor agonist LY379268, and the mGlu2 receptor positive allosteric modulator (PAM) CBiPES, potently blocked the HTR to DOI in WT and mGlu3 receptor KO mice. Conversely, the mGlu2/3 receptor antagonist LY341495 (10 mg/kg) increased the HTR produced by DOI (3 mg/kg) in mGlu3 receptor KO mice. Finally, the mGlu2 receptor potentiator CBiPES was able to attenuate the increase in the HTR produced by LY341495 in mGlu3 receptor KO mice. Taken together, all of these results are consistent with the hypothesis that that DOI-induced head twitches are modulated by mGlu2 receptor activation. These results also are in keeping with a critical autoreceptor function for mGlu2 receptors in the prefrontal cortex with differential effects of acute vs. chronic perturbation (e.g., constitutive mGlu2 receptor KO mice). The robust attenuation of DOI-induced head twitches in the mGlu2 receptor KO mice appears to reflect the critical role of glutamate in ongoing regulation of 5-HT2A receptors in the prefrontal cortex. Future experiments with inducible knockouts for the mGlu2 receptor and/or selective mGlu3 receptor agonists/PAMs/antagonists could provide an important tools in understanding glutamatergic modulation of prefrontal cortical 5-HT2A receptor function.
... 20,21,27 This behavioral proxy of human hallucinogenic potential is induced by psychedelics including phenethylamines such as DOI, tryptamines such as psilocybin, and ergolines such as LSD, but not by nonpsychedelic 5-HT 2A R agonists such as lisuride. Using HTR as a behavioral model of psychedelic action, previous studies demonstrate that several psychedelics recapitulate the tolerance 28,29 and cross-tolerance 30 phenomena observed in human subjective effects. ...
... A similar phenotype (i.e., partial reduction of HTR) has been reported after repeated administration of classical psychedelics such as LSD, 1-(2,5-dimethoxy-4bromophenyl)-2-aminopropane (DOB), and N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH). 28,29 This, however, contrasts with previous observations in human subjects suggesting that daily administration of psychoactive doses vanishes the hallucinogenic properties of psychedelics such as LSD and mescaline. 3−5 A potential explanation for these interspecies discrepancies could rely on dosage, length of the treatment, pharmacokinetic properties, or density of the 5-HT 2A R in the frontal cortex. ...
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Classical psychedelics represent a subgroup of serotonergic psychoactive substances characterized by their distinct subjective effects on the human psyche. Another unique attribute of this drug class is that such effects become less apparent after repeated exposure within a short time span. The classification of psychedelics as a subgroup within the serotonergic drug family and the tolerance to their effects are replicated by the murine head twitch response (HTR) behavioral paradigm. Here, we aimed to assess tolerance and cross-tolerance to HTR elicited by psychedelic and nonpsychedelic serotonin 2A receptor (5-HT 2A R) agonists in mice. We show that repeated (4 days) administration of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced a progressive decrease in HTR behavior. Tolerance to DOI-induced HTR was also observed 24 h after a single administration of this psychedelic. Pretreatment with the 5-HT 2A R antagonist M100907 reduced not only the acute manifestation of DOI-induced HTR, but also the development of tolerance to HTR. Additionally, cross-tolerance became apparent between the psychedelics DOI and lysergic acid diethylamide (LSD), whereas repeated administration of the nonpsychedelic 5-HT 2A R agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI administration led to down-regulation of 5-HT 2A R density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in β-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT 2A R, is not observable upon repeated administration of nonpsychedelic 5-HT 2A R agonists, and occurs via a signaling mechanism independent of β-arrestin-2.
... mg/kg (Fantegrossi et al., 2015;Halberstadt et al., 2016). The inverted u-shape-like dose-response curve of 25CN-NBOH (with higher doses entailing a relative loss of responsiveness) might be due to increasing occupancy of 5-HT 2C receptors (whose activity may counteract the 5-HT 2A -mediated HTR induction), and/or due to 5-HT 2 receptors requiring a tuned level of occupancy (compare for DOM, DOB, and DOI: Fantegrossi et al., 2010;Serafine and France, 2014;Buchborn et al., 2015). Consistent with its sensitivity to MDL100907 (Fantegrossi et al., 2015), one of the most selective 5-HT 2A antagonists at present (av. ...
... 25CN-NBOH induced HTRs were facilitated when animals had been thoroughly habituated to the experimental procedures on the day before the drug application. The latter finding supports observations made in rats, where the presence of familiar littermates allowed hallucinogens to evoke substantially more HTRs than when observed in isolation (Buchborn et al., 2015). The dependence of 5-HT 2A related behavior in rodents on what may be described as state-environment interaction, mirrors characteristics of human psychedelia, which is critically determined by set and setting, i.e., psychological constitution and environmental circumstances (rev. ...
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The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion. 25CN-NBOH evoked HTRs with an inverted u-shape-like dose-response curve and highest efficacy at 1.5 mg/kg, i.p. HTR occurrence peaked within 5 min after agonist injection, and exponentially decreased to half-maximal frequency at ~11 min. Thorough habituation to the experimental procedures (including handling, saline injection, and exposure to the observational boxes 1 day before the experiment) facilitated the animals' response to 25CN-NBOH. 25CN-NBOH (1.5 mg/kg, i.p.) induced HTRs were blocked by the 5-HT2A antagonist ketanserin (0.75 mg/kg, 30 min pre), but not by the 5-HT2C antagonist SB-242084 (0.5 mg/kg, i.p., 30 min pre). SB-242084 instead slightly increased the number of HTRs occurring at a 3.0-mg/kg dose of the agonist. Apart from HTR induction, 25CN-NBOH also modestly increased locomotor activity of the mice. Repeated once-per-day injections (1.5 mg/kg, i.p.) led to reduced occurrence of 25CN-NBOH induced HTRs. This intermediate tolerance was augmented when a second (higher) dose of the drug (3.0 mg/kg) was interspersed. Short-interval tolerance (i.e., tachyphylaxis) was observed when the drug was injected twice at intervals of 1.0 and 1.5 h at either dose tested (1.5 mg/kg and 0.75 mg/kg, respectively). Inducing ketanserin-sensitive HTRs, which are dependent on environmental valences and which show signs of tachyphylaxis and tolerance, 25CN-NBOH shares striking features common to serotonergic hallucinogens. Given its distinct in vitro selectivity for 5-HT2A over non5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity.
... Finally, while not necessarily a limitation, the present study used repeated, chronic treatment with psilocybin, whereas most human trials typically use a much small number of doses, often in combination with psychotherapy (43,44). Repeated exposure to psychedelic drugs can result in behavioral tolerance (64) and downregulation of the 5-HT2A receptor (65). This may have even occurred in the present study, as decreased food intake diminished with time more rapidly with the psilocybin than metformin groups. ...
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Background There are currently relatively few effective pharmacological treatments for obesity, and existing ones may be associated with limiting side-effects. In the search for novel anti-obesity agents, drugs that modify central serotonergic systems have historically proven to be effective in promoting weight loss. Psilocin, which is rapidly metabolized from psilocybin, is an agonist at multiple serotonin receptors. In the present study we assessed the effects of psilocybin and a positive control (metformin) on changes in body weight in a rat model of obesity. Methods Five groups of adult male rats were pre-conditioned with a cafeteria diet until obese (>600 g) and then treated with either psilocybin (0.1, 1, or 5 mg/kg, i.p.), metformin (300 mg/kg, p.o.) or vehicle control. Treatments were for 27 consecutive weekdays, and body weights and high calorie food intake were recorded daily. Fasting glucose levels were recorded after 11 days of treatment. At the end of treatment rats completed a glucose tolerance test, and multiple fat pads were dissected out to assess adiposity. Results The medium dose psilocybin group had to be terminated from the study prematurely. Both the low and high dose psilocybin groups caused a significant decrease in changes in body weight compared to controls. The metformin group produced a greater decrease in change in body weight than either psilocybin groups or controls. Both high dose psilocybin and metformin decreased consumption of the high calorie diet, and exhibited decreased central adiposity. Conclusion Psilocybin demonstrated modest but significant effects on weight gain. Further study is recommended.
... The videos were analyzed by visually scoring the number of head twitches. A 5-day wash-out period was left between the testing days in order to avoid possible tolerance induced by serotonergic hallucinogens (Buchborn et al., 2015, Buchborn et al., 2018. Each mouse received the same treatment on the same day. ...
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While interest in psychedelic drugs in the fields of psychiatry and neuroscience has re-emerged in recent last decades, the general understanding of the effects of these drugs remains deficient. In particular, there are gaps in knowledge on executive functions and goal-directed behaviors both in humans and in commonly used animal models. The effects of acute doses of psychedelic lysergic acid diethylamide (LSD) on reward-driven decision making were explored using the mouse version of the Iowa Gambling Task. A total of 15 mice were trained to perform in a touch-screen adaptation of the rodent version of the Iowa Gambling Task, after which single acute doses of LSD (0.025, 0.1, 0.2, 0.4 mg/kg), serotonin 2A receptor-selective agonist 25CN-NBOH (1.5 mg/kg), D-amphetamine (2.0 mg/kg), and saline were administered before the trial. 25CN-NBOH and the three lowest doses of LSD showed no statistically significant changes in option selection or in general functioning during the gambling task trials. The highest dose of LSD (0.4 mg/kg) significantly decreased premature responding and increased the omission rate, but had no effect on option selection in comparison with the saline control. Amphetamine significantly decreased the correct responses and premature responding while increasing the omission rate. In conclusion, mice can perform previously learned, reward-driven decision-making tasks while under the acute influence of LSD at a commonly used dose range.
... The hallucinogenic effects of LSD are thought to be mediated by several mechanisms: partial agonism at the 5-HT 2A receptor, binding to the 5-HT 1A , 5-HT 2C , and 5-HT 2B receptors (with affinity in descending order), and binding at dopamine D 2 receptors. It also causes glutamate release in the frontal cortex and increased functional connectivity and excitability in thalamic and cortical structures (11,(54)(55)(56)(57)(58). LSD does not interact with monoamine transporters and is more potently bound than all other tryptamines to the 5-HT 2A and 5-HT 1A receptors (11). ...
Article
Objective: The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders. Methods: Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on "psilocybin," "lysergic acid diethylamide," "LSD," "ayahuasca," "3,4-methylenedioxymethamphetamine," and "MDMA," in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms "clinical trial," "therapy," or "imaging" in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care. Results: The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as "breakthrough therapies" for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders. Conclusions: Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.
... Lysergic acid diethylamide (LSD) in humano, for instance, has been shown to induce pupil dilatation, patellar hyperreflexia, temperature dysregulation, as well as increases in breath rate, heart rate, and blood pressure (Isbell, 1959;Schmid et al., 2015). In animals, stereotypical movements, including head twitches and wet dog shakes (e.g., Corne and Pickering, 1967;Buchborn et al., 2015) as wells as other motor symptoms taken together referred to as serotonin syndrome have been described (Sloviter et al., 1980). Beyond neuro-summative EEG and MEG recordings, our knowledge of the neurophysiological correlates of the human psychedelic brain state largely feeds from BOLD-fMRI and PET based research. ...
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Background Serotonin 2A receptors, the molecular target of psychedelics, are expressed by neuronal and vascular cells, both of which might contribute to brain haemodynamic characteristics for the psychedelic state. Aim Aiming for a systemic understanding of psychedelic vasoactivity, here we investigated the effect of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine – a new-generation agonist with superior serotonin 2A receptor selectivity – on brain-supplying neck-arterial blood flow. Methods We recorded core body temperature and employed non-invasive, collar-sensor based pulse oximetry in anesthetised mice to extract parameters of local blood perfusion, oxygen saturation, heart and respiration rate. Hypothesising an overlap between serotonergic pulse- and thermoregulation, recordings were done under physiological and elevated pad temperatures. Results N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (1.5 mg/kg, subcutaneous) significantly increased the frequency of heart beats accompanied by a slight elevation of neck-arterial blood flow. Increasing the animal-supporting heat-pad temperature from 37°C to 41°C enhanced the drug’s effect on blood flow while counteracting tachycardia. Additionally, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine promoted bradypnea, which, like tachycardia, quickly reversed at the elevated pad temperature. The interrelatedness of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine’s respiro-cardiovascular effects and thermoregulation was further corroborated by the drug selectively increasing the core body temperature at the elevated pad temperature. Arterial oxygen saturation was not affected by N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine at either temperature. Conclusions Our findings imply that selective serotonin 2A receptor activation modulates systemic cardiovascular functioning in orchestration with thermoregulation and with immediate relevance to brain-imminent neck (most likely carotid) arteries. As carotid branching is a critical last hub to channel cardiovascular output to or away from the brain, our results might have implications for the brain haemodynamics associated with psychedelia.
... This might explain the strong tolerance effect of 5-HT hallucinogens (221). Recently, it was shown that 5-HT hallucinogens can also reduce either 5-HT2A-R binding sites or glutamate-binding sites and that tolerance effects were correlated with changes in both binding sites (222). ...
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A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug’s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine (“Kratom”), synthetic cannabinoids (e.g., “Spice”), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.
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(Reprinted with permission from The American Journal of Psychiatry 2020; 177:391-410).
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The first reports on tolerance to the serotonergic hallucinogen lysergic acid diethylamide (LSD) were published half a century ago, yet hitherto, a systematic review on this topic is not available. In this chapter, we discuss tolerance to LSD with regard to its psychedelic and somatic effects in humans, as well as selected behaviors in animals. In humans, mental tolerance to LSD substantially manifests 24 h after its first administration and reaches a maximum by around the fourth day. Once established, tolerance cannot be overcome even if the initial dose is quadrupled. Mental tolerance to LSD generalizes to psilocybin and mescaline but not to tetrahydrocannabinol or amphetamine. As to LSD’s somatic effects, mental tolerance most reliably is accompanied by tolerance to mydriasis. Five days of abstinence is sufficient for tolerance to be reversed; symptoms of withdrawal are not encountered. In animals, LSD-induced shaking behavior, limb flicking, and hallucinogenic pausing are undermined by tolerance, too; the first-mentioned behaviors, for instance, are subject to tachyphylaxis. Mechanistically, pharmacodynamic adaptations of serotonin 5-HT2A and/or (downstream) glutamate receptors are likely to account for tolerance; a learning-related precipitation, however, has also been described. The rapid onset of mental tolerance probably is a main reason LSD generally is not taken on an everyday basis by humans. Given its rapid reversal, on the other hand, a once-per-week abuse cannot be excluded.
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A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.
Chapter
The neuropsychological effects of naturally occurring psychoactive ­substances have been recognized for millennia. Hallucinogens, which include naturally occurring chemicals, such as mescaline and psilocybin, as well as synthetic compounds, such as lysergic acid diethylamide (LSD), induce profound alterations of human consciousness, emotion, and cognition. The discovery of the hallucinogenic effects of LSD, and the observations that LSD and the endogenous neurotransmitter serotonin share chemical and pharmacological profiles, led to the suggestion that biogenic amines like serotonin were involved in the psychosis of mental disorders such as schizophrenia. Understanding the mechanism by which hallucinogens elicit unique neurobehavioral effects may open up new avenues in drug abuse research, as well as contributing to the understanding of the endogenous psychosis of psychiatric diseases. Here we summarize recent advances in our understanding of the molecular mechanism of action of hallucinogenic drugs, as well as findings obtained in animal models.
Article
We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity. Copyright © 2015. Published by Elsevier Ltd.
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Numerous studies have brought evidence for reciprocal relationships between glucocorticoids and 5-HT2 receptors; however, whether glucocorticoids affect 5-HT2 receptor regulation is still unknown. Herein, we have analyzed whether 5-HT2 receptor down-regulation following repeated administration of the 5-HT2/5-HT1C receptor agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) is affected by glucocorticoid removal. Compared with sham surgery, adrenalectomy (11–15 days before-hand) did not affect either frontal cortex [³H]ketanserin binding nor the number of head shakes elicited by a single administration of DOI (2.5 mg/kg s.c.). Pretreatment with DOI (2.5 mg/kg s.c. × 4 in 48 h) decreased to similar extents the head shake response to DOI injection in sham (−88%) and adrenalectomised (−95%) rats. Confirmingly, this paradigm was found to diminish the Bmax for [³H]ketanserin binding in sham and adrenalectomised rats by 64% and 46%, respectively. From these data, it is concluded that glucocorticoid removal does not alter 5-HT2 receptor binding and function nor does it affect 5-HT2 receptor down-regulation.