Head‐twitch response in rodents induced by the hallucinogen 2,5‐dimethoxy‐4‐iodoamphetamine: a comprehensive history, a re‐evaluation of mechanisms, and its utility as a model

Canal, Clint E.; Morgan, Drake

doi:10.1002/dta.1333

Cited by 170 publications

(209 citation statements)

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“…Pharmacological studies are under way to assess the role of specific a 1 -adrenergic receptor subtypes in regulating the DOI-elicited HTR, and molecular modeling studies are in progress to assess interactions between 6-OH-7-Cl-PAT enantiomers and a 1 -adrenergic receptor TMD amino acids. Regarding known affinity of PAT ligands for H 1 receptors, it is also acknowledged that H 1 receptor actions do not seem to affect the DOI-elicited HTR (Canal and Morgan, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…All compounds were administered subcutaneously at a volume of 10 ml/kg. A single dose of DOI (1 mg/kg) was used for all experiments, as it is known to reliably elicit a robust, consistent, and submaximal number of HTRs in C57Bl/6J mice (Canal et al, 2010;Canal and Morgan, 2012). Two or three doses were used to test the efficacy of novel PAT ligands for attenuating the DOI-elicited HTR.…”

Section: Doi-elicited Htrmentioning

confidence: 99%

“…The (6)-(2,5)-dimethoxy-4-iodoamphetamine (DOI)-elicited head-twitch response (HTR) in mice is an animal model that is dependent on 5-HT2A receptor activation, and the HTR is produced reliably by most hallucinogenic 5-HT2 agonists (Glennon, 1992;Canal and Morgan, 2012;Halberstadt and Geyer, 2013). Thus, use of the DOI-elicited HTR model is expedient for translating drug discovery targeting 5-HT2 receptors.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

Canal

Córdova-Sintjago

Liu

et al. 2013

J Pharmacol Exp Ther

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During translational studies to develop 4-phenyl-2-dimethylaminotetralin (PAT) compounds for neuropsychiatric disorders, the (2R,4S)-trans-(1)-and (2S,4R)-trans-(2)-enantiomers of the analog 6-hydroxy-7-chloro-PAT (6-OH-7-Cl-PAT) demonstrated unusual pharmacology at serotonin (5-HT) 5-HT2 G protein-coupled receptors (GPCRs). The enantiomers had similar affinities (K i ) at human (h) 5-HT2A receptors (∼70 nM). In an in vivo mouse model of 5-HT2A receptor activation [(6)-(2,5)-dimethoxy-4-iodoamphetamine (DOI)-elicited head twitch], however, (2)-6-OH-7-Cl-PAT was about 5-fold more potent than the (1)-enantiomer at attenuating the DOI-elicited response. It was discovered that (1)-6-OH-7-Cl-PAT (only) had ∼40-fold-lower affinity at mouse (m) compared with h5-HT2A receptors. Molecular modeling and computational ligand docking studies indicated that the 6-OH moiety of (1)-but not (2)-6-OH-7-Cl-PAT could form a hydrogen bond with serine residue 5.46 of the h5-HT2A receptor. The m5-HT2A as well as m5-HT2B, h5-HT2B, m5-HT2C, and h5-HT2C receptors have alanine at position 5.46, obviating this interaction; (1)-6-OH-7-Cl-PAT also showed ∼50-fold lower affinity than (2)-6-OH-7-Cl-PAT at m5-HT2C and h5-HT2C receptors. Mutagenesis studies confirmed that 5-HT2A S5.46 is critical for (1)-but not (2)-6-OH-7-Cl-PAT binding, as well as function. The (1)-6-OH-7-Cl-PAT enantiomer showed partial agonist effects at h5-HT2A wild-type (WT) and m5-HT2A A5.46S point-mutated receptors but did not activate m5-HT2A WT and h5-HT2A S5.46A point-mutated receptors, or h5-HT2B, h5-HT2C, and m5-HT2C receptors; (2)-6-OH-7-Cl-PAT did not activate any of the 5-HT2 receptors. Experiments also included the (2R,4S)-trans-(1)-and (2S,4R)-trans-(2)-enantiomers of 6-methoxy-7-chloro-PAT to validate hydrogen bonding interactions proposed for the corresponding 6-OH analogs. Results indicate that PAT ligand three-dimensional structure impacts target receptor binding and translational outcomes, supporting the hypothesis that GPCR ligand structure governs orthosteric binding pocket molecular determinants and resulting pharmacology.

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Section: Discussionmentioning

confidence: 99%

Section: Doi-elicited Htrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

Canal

Córdova-Sintjago

Liu

et al. 2013

J Pharmacol Exp Ther

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“…When administered alone, lorcaserin did not produce head twitching; however, lorcaserin significantly increased head twitching in rats that were pretreated with the 5-HT 2C receptor selective antagonist SB 242084. Drugs with agonist activity at 5-HT 2A receptors increase head twitching (Canal and Morgan, 2012). At doses larger than those producing head twitching, lorcaserin induced forepaw treading, an effect produced by drugs with agonist activity at 5-HT 1A receptors (Haberzettl et al, 2013).…”

Section: Discussionmentioning

confidence: 96%

Directly Observable Behavioral Effects of Lorcaserin in Rats

2015

J Pharmacol Exp Ther

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(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin) is approved by the United States Food and Drug Administration for treating obesity, and its therapeutic effects are thought to result from agonist activity at serotonin (5-HT) 2C receptors. Lorcaserin has affinity for other 5-HT receptor subtypes, although its activity at those subtypes is not fully described. The current study compared the behavioral effects of lorcaserin (0.0032-32.0 mg/kg) to the effects of other 5-HT receptor selective agonists in rats (n 5 8). The 5-HT 2C receptor selective agonist 1-(3-chlorophenyl)piperazine (mCPP, 0.032-1.0 mg/kg) and lorcaserin induced yawning which was attenuated by the 5-HT 2C receptor selective antagonist 6-chloro-5-methyl-N-(6-[(2-methylpyridin-3-yl)oxy]pydidin-3-yl)indoline-1-carboxamide (1.0 mg/kg). The 5-HT 2A receptor selective agonist 2,5-dimethoxy-4-methylamphetamine (0.1-3.2 mg/kg) induced head twitching, which was attenuated by the 5-HT 2A receptor selective antagonist R-(1)-2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL 100907, 0.01 mg/kg), lorcaserin (3.2 mg/kg), and mCPP (3.2 mg/kg). In rats pretreated with MDL 100907 (1.0 mg/kg), lorcaserin also induced head twitching. At larger doses, lorcaserin produced forepaw treading, which was attenuated by the 5-HT 1A receptor selective antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (0.178 mg/kg). While the behavioral effects of lorcaserin in rats are consistent with it having agonist activity at 5-HT 2C receptors, these data suggest that at larger doses it also has agonist activity at 5-HT 2A and possibly 5-HT 1A receptors. Mounting evidence suggests that 5-HT 2C receptor agonists might be effective for treating drug abuse. A more complete description of the activity of lorcaserin at 5-HT receptor subtypes will facilitate a better understanding of the mechanisms that mediate its therapeutic effects.

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“…The tryptamine hallucinogen, psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), is synthesized de novo in several species of hallucinogenic mushrooms and, together with its active metabolite psilocin, it also displays a low nanomolar affinity for 5-HT 2A receptors, and a somewhat lower affinity for 5-HT 1A and 5-HT 2B receptors (McKenna et al, 1990). With a K i of 0.7 nM, the 5-HT 2A receptor is also the primary target of the synthetic amphetamine hallucinogen DOI, although it also targets 5HT 2B and 5HT 2C receptors with slightly lower affinities (Canal and Morgan, 2012). Also other hallucinogens, such as N,N-dimethyltryptamine and the phenethylamine hallucinogen mescaline have significant affinity mainly to the G q/11 -coupled 5-HT 2A/C receptors (Aghajanian and Marek, 1999;Ray, 2010).…”

Section: Hallucinogensmentioning

confidence: 99%