Effects of the 5-HT2A receptor antagonist volinanserin on head-twitch response and intracranial self-stimulation depression induced by different structural classes of psychedelics in rodents

Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 receptors in the head twitch response induced by 5-hydroxytryptophan and psilocybin: Translational implications

“…We have categorized the effect on HTR induction by 5-HTP and PSIL of pre-treatment with 5-HT2A and 5-HT2C antagonists and a 5-HT1A agonist. We found complete ablation of HTR induced by 5-HTP and PSIL following pre-treatment with the 5-HT2A antagonist M100907, similar to the effect of M100907 on HTR induced by DOI (Canal et al, 2013; de la Fuente Revenga et al, 2020), 2-CI (Halberstadt and Geyer, 2014), N,N-dipropyltryptamine (DPT) (Fantegrossi et al, 2008), and LSD (Brandt et al, 2016; Rodriguiz et al, 2021; Jaster et al, 2022). The 5-HT1A agonist, 8-OH-DPAT, significantly attenuated HTR induced by 5-HTP and PSIL.…”

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice

“…The lower dose of M100907 (0.1 mg/kg) was only partially effective at blocking the hours-long effect of DOI on HTR and the development of tolerance the day after. This corroborates our recent findings characterizing the pharmacodynamic (dose−response and time-course studies) properties of M100907 on DOI-induced HTR in mice 45 �we reported that low doses of M100907 (e.g., 0.032 mg/kg) were able to completely abolish LSD-induced HTR for up to 90 min, whereas during these time-course studies, DOI-induced HTR was similar in the vehicle + DOI and volinanserin + DOI groups at the 75 and 90 min time points. Our results in the present study hint toward a magnitude-matching effect on the ability of M100907 to antagonize the acute HTR to DOI and the posterior development of tolerance.…”

“…Although the effect of age on HTR is not the focus of this study, we have previously reported that HTR declines with age, which suggests that aging may be one of the independent factors affecting interexperimental variation throughout. Our previous reports in which all assays were conducted under almost identical experimental parameters ultimately resulted in more homogeneous HTR counts. , However, it is important to remark that all the statistical methods for each experiment presented here correspond to groups of mice selected randomly from cohorts with identical age, strain (C57BL/6 and B6J/B6N), residence time in the vivarium, exposure to the testing room, and washout period between experiments. These cohorts were tested on the same or consecutive days, and with the same HTR reporter system.…”

Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants

“…The HTR effect is directly linked to the activation of 5-HT 2A R, as demonstrated by many studies, and mice lacking the 5-HT 2A R do not exhibit the HTR response when administered psychedelics . Additionally, the HTR effects induced by psychedelics can be effectively blocked by 5-HT 2A R antagonists . The consistency of the HTR response across animal models, as well as its correlation with the effects observed in rats and humans, further support its validity as a preclinical model for assessing the hallucinogenic potential of 5-HT 2A R agonists.…”

“…Psychedelics are a family of psychoactive substances capable of inducing altered states of consciousness, resulting in profound changes in thoughts, emotions, and perceptions. − While numerous chemical compounds exhibit psychoactive properties, such as cannabinoids (e.g., tetrahydrocannabinol), entactogens (e.g., MDMA) and the dissociatives (e.g., ketamine), the term “psychedelics” predominantly refers to classic serotonergic hallucinogens . These substances exert their effects by acting as full or partial agonists at the serotonin 2A receptor (5-HT 2A R). − Psychedelics are strictly regulated by the government in most countries, rendering their manufacture and distribution illegal except for authorized research purposes. However, recent developments in this field, exemplified by the FDA’s designation of psilocybin as a “Breakthrough Therapy” for treating TRD and MDD, have sparked renewed research interests in psychedelics. , …”