Abstract
Head-twitch behavior (HTR) is the behavioral signature of psychedelic drugs upon stimulation of the serotonin 5-HT2A receptor (5-HT2AR) in rodents. Following the previous report of a semi-automated detection of HTR based on the dynamics of mouse’s head movement, here we present a system for the identification of individual HTR events in a fully automated fashion. The validity of this fully automated HTR detection system was tested with the psychedelic drug DOI in 5-HT2AR-KO mice, and via evaluation of potential sources of false-positive and false-negative HTR events. The increased throughput in data processing achieved via automation afforded the possibility of conducting otherwise time consuming HTR time-course studies. To further assess the versatility of our system, we also explored the pharmacological interactions between 5-HT2AR and the metabotropic glutamate receptor 2 (mGluR2). Our data demonstrate the potentiation effect of the mGluR2/3 antagonist LY341495 on DOI-induced HTR, as well as the HTR-blocking effect of the mGluR2/3 agonist and antipsychotic drug in development LY404039. This fully automated system can contribute to speed up our understanding of 5-HT2AR’s pharmacology and its characteristic behavioral outputs in rodents.
Highlights
The study of rodent behavior has experienced in recent years a significant degree of automation, which is consonant with the demand of reproducibility in biomedical research[1]
Previous findings based on both pharmacological blockade with relatively selective serotonin 5-HT2A receptor (5-HT2AR) antagonists, such as volinanserin (M100907) and ketanserin, and genetic deletion of certain G protein-coupled receptors (GPCRs) in knockout (KO) mice have provided convincing evidence that the Head-twitch behavior (HTR) induced by psychedelics is at least in part mediated via serotonin 5-HT2AR-dependent signaling[5,8,9,10,11,12,13]
We previously reported that HTR is exclusively induced by hallucinogenic 5-HT2AR agonists, and not by closely related non-hallucinogenic 5-HT2AR agonists, further highlighting the parallelism between the psychedelic drugs’ subjective effect in humans and induction of HTR in rodents[5]
Summary
The study of rodent behavior has experienced in recent years a significant degree of automation, which is consonant with the demand of reproducibility in biomedical research[1]. Psychedelics produce a characteristic side-to-side movement of the head commonly known as head-twitch response (HTR). This characteristic behavior is not induced by other psychoactive drugs, such as cocaine, phencyclidine (PCP), scopolamine, or amphetamine, and is widely employed to study the behavioral pharmacology of psychedelics in rodent models[5,6,7]. Www.nature.com/scientificreports psilocybin, are 5-HT2AR agonists, but yet closely related 5-HT2AR agonists, such as lisuride and ergotamine, do not exhibit hallucinogen activity. We previously reported that HTR is exclusively induced by hallucinogenic 5-HT2AR agonists, and not by closely related non-hallucinogenic 5-HT2AR agonists, further highlighting the parallelism between the psychedelic drugs’ subjective effect in humans and induction of HTR in rodents[5]. Despite the lack of face validity, the strong correlation between the behavioral characteristics induced by psychedelics among species supports the use of the HTR as a rodent behavioral proxy for human psychedelic action
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