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Assessing the effects of 5-HT2A and 5-HT5A receptor antagonists on DOI-induced head-twitch response in male rats using marker-less deep learning algorithms

Ewelina Cyrano, Piotr Popik

Pharmacological Reports November 27, 2024 DOI: 10.1007/s43440-024-00679-1 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Preclinical feasibility study Peer reviewed
Population Rodents
Interventions DOI ketanserin SB 699 551 ASP 5736
Dose DOI 0.3125–2.5 mg/kg; ketanserin 0.625 mg/kg; DOI 1.25 mg/kg; SB 699,551 3 and 10 mg/kg; ASP 5736 0.01 and 0.03 mg/kg
Topics Serotonin
Key points A marker-less deep learning workflow using DeepLabCut and SimBA correlated significantly with human counts of head-twitch responses. Ketanserin attenuated DOI-induced head twitches, whereas the 5-HT5A antagonists SB 699,551 and ASP 5736 did not, which the authors argue supports the head-twitch response as selective for 5-HT2A and not 5-HT5A receptor activation.

Abstract

Serotonergic psychedelics, which display a high affinity and specificity for 5-HT2A receptors like 2,5-dimethoxy-4-iodoamphetamine (DOI), reliably induce a head-twitch response in rodents characterized by paroxysmal, high-frequency head rotations. Traditionally, this behavior is manually counted by a trained observer. Although automation could simplify and facilitate data collection, current techniques require the surgical implantation of magnetic markers into the rodent’s skull or ear. This study aimed to assess the feasibility of a marker-less workflow for detecting head-twitch responses using deep learning algorithms. High-speed videos were analyzed using the DeepLabCut neural network to track head movements, and the Simple Behavioral Analysis (SimBA) toolkit was employed to build models identifying specific head-twitch responses. In studying DOI (0.3125–2.5 mg/kg) effects, the deep learning algorithm workflow demonstrated a significant correlation with human observations. As expected, the preferential 5-HT2A receptor antagonist ketanserin (0.625 mg/kg) attenuated DOI (1.25 mg/kg)-induced head-twitch responses. In contrast, the 5-HT5A receptor antagonists SB 699,551 (3 and 10 mg/kg), and ASP 5736 (0.01 and 0.03 mg/kg) failed to do so. Previous drug discrimination studies demonstrated that the 5-HT5A receptor antagonists attenuated the interoceptive cue of a potent hallucinogen LSD, suggesting their anti-hallucinatory effects. Nonetheless, the present results were not surprising and support the head-twitch response as selective for 5-HT2A and not 5-HT5A receptor activation. We conclude that the DeepLabCut and SimBA toolkits offer a high level of objectivity and can accurately and efficiently identify compounds that induce or inhibit head-twitch responses, making them valuable tools for high-throughput research.

Comparable studies

Other preclinical and animal studies on serotonin, most cited first.

Study Year Design Participants
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice 2021 Observational cohort
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models 2023 Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study

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