Proceedings of the National Academy of Sciences of the United States of America
September 3, 2002
Bryan L Roth, Karen Baner, Richard Westkaemper et al.
782 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, potently and selectively activates kappa opioid receptors while having no effect on the serotonin 5-HT(2A) receptor targeted by classical hallucinogens like LSD. This makes it the first known naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A produces perceptual distortions, the findings suggest that kappa opioid receptors play a key role in modulating human perception and that kappa opioid-selective antagonists could be developed as novel treatments for disorders involving perceptual distortions, such as schizophrenia, dementia, and bipolar disorders.
Psychopharmacology
September 1, 2005
William E Fantegrossi, Andrew W Harrington, Justin R Eckler et al.
72 citations
The hallucinogen 2C-T-7 produces head twitch responses in mice and serves as a discriminative stimulus in rats, effects that are blocked by a selective 5-HT2A antagonist. In drug discrimination tests, 2C-T-7 partially generalized (75%) to the LSD cue in rats and acted as a discriminative stimulus itself, with those interoceptive effects also attenuated by the 5-HT2A antagonist. Binding studies show 2C-T-7 has nanomolar affinity for 5-HT2A and 5-HT2C receptors and lower affinity for 5-HT1A receptors. The antagonism of its behavioral effects strongly suggests the 5-HT2A receptor is an important site of action for this compound.
Neuropharmacology
November 1, 2018
Joshua S Elmore, Ann M Decker, Agnieszka Sulima et al.
59 citations
N-methoxybenzylated derivatives of 2C compounds, specifically 25C-NBOMe and 25I-NBOMe, show higher affinity for 5-HT2A receptors than their parent 2C compounds but are weaker in functional cellular assays. In rats, NBOMes were much more potent at inducing wet dog shakes and back muscle contractions compared to 2C-C and 2C-I. A selective 5-HT2A antagonist reversed these behaviors, confirming receptor involvement. Binding affinities correlated with potencies for back muscle contractions but not wet dog shakes. These findings indicate NBOMes are highly potent 5-HT2A agonists in rats, consistent with reported hallucinogenic effects in humans.
The Journal of pharmacology and experimental therapeutics
February 1, 2008
Jun-Xu Li, Kenner C Rice, Charles P France
51 citations
In rhesus monkeys trained to distinguish the hallucinogen DOM from a placebo, the drug's effects lasted up to two hours and were blocked by serotonin 5-HT2A receptor antagonists but not by the dopamine antagonist haloperidol. Other hallucinogens such as LSD and 2C-T-7 produced DOM-like effects, but the kappa-opioid hallucinogen salvinorin A did not, nor did several other psychoactive drugs. These results confirm that 5-HT2A receptors play a key role in the discriminative stimulus effects of certain hallucinogens in nonhuman primates, and they reveal that different classes of hallucinogens produce qualitatively distinct effects.
Neuropsychopharmacology
September 1, 2017
Elizabeth G Pitts, Adelaide R Minerva, Erika B Chandler et al.
20 citations
MDMA and its enantiomers increase affiliative social behaviors and vocalizations in group-housed squirrel monkeys, while methamphetamine has only modest effects. Pretreatment with a 5-HT_2A receptor antagonist or a 5-HT_2C receptor agonist reduces MDMA-induced social behaviors, whereas a 5-HT_1A receptor antagonist does not affect affiliative vocalizations and even increases social contact. These results indicate that the prosocial effects of MDMA depend on 5-HT_2A, but not 5-HT_1A, receptors, aligning with findings in humans and rodents. Understanding these neurochemical mechanisms may aid in developing therapeutics that retain MDMA's social benefits with fewer drawbacks.
The Journal of pharmacology and experimental therapeutics
April 1, 2010
Jun-Xu Li, Wouter Koek, Kenner C Rice et al.
17 citations
Serotonin (5-HT)1A receptor agonists attenuated the effects of the 5-HT2A receptor agonist DOM in rhesus monkeys but not in rats, indicating a species difference in how these receptor systems interact. DOM and other 5-HT2A agonists produced similar discriminative stimulus effects in both species, and these effects were blocked by a 5-HT2A antagonist. The 5-HT1A agonists 8-OH-DPAT and F13714 reduced DOM's effects only in monkeys, an effect prevented by a 5-HT1A antagonist. The findings suggest that while the DOM stimulus is mediated by 5-HT2A receptors in both species, the modulatory role of 5-HT1A receptors differs markedly between rats and monkeys, which has implications for studying drugs with multiple mechanisms.
The Journal of pharmacology and experimental therapeutics
March 1, 2009
Jun-Xu Li, Kenner C Rice, Charles P France
16 citations
In rhesus monkeys trained to distinguish the hallucinogen DOM from a placebo, three related compounds—DOM, 2C-T-7, and DPT—all produced dose-dependent increases in drug-appropriate responding. Three antagonists (MDL100907, ketanserin, and ritanserin) each shifted the dose-response curves of all three agonists rightward in a parallel, competitive manner. The calculated apparent affinities (pA₂ values) for each antagonist were similar across agonists and correlated with their binding affinities at 5-HT₂A receptors, not at 5-HT₂C or alpha₁ adrenergic receptors. These results provide quantitative evidence that the 5-HT₂A receptor subtype predominantly, if not exclusively, mediates the discriminative stimulus effects of these hallucinogenic drugs in rhesus monkeys.
Pharmacology, biochemistry, and behavior
September 1, 2011
J C Winter, D J Amorosi, Kenner C Rice et al.
10 citations
In mice genetically modified to express human CYP2D6 (Tg-CYP2D6) and wild-type mice, the psychedelic 5-MeO-DMT produced similar rates of learning a drug discrimination task. Bufotenine did not substitute for 5-MeO-DMT, while its lipid-soluble analog acetylbufotenine produced intermediate substitution. Combining harmaline with 5-MeO-DMT significantly increased drug-appropriate responding in both mouse types, indicating harmaline enhances 5-MeO-DMT's stimulus effects. Harmaline alone also produced significant 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice, suggesting metabolic interactions. No differences between wild-type and Tg-CYP2D6 mice were found in acquisition or responses to bufotenine and acetylbufotenine.