Evaluation of the head twitch response in male C57BL/6J mice as a measure of 5-HT2a receptor activation

Abstract

The head twitch response (HTR) is a rhythmic paroxysmal rotational head movement that occurs in mice following 5-HT_2A receptor activation. This test may be used to evaluate the potential for novel drugs to activate the 5-HT_2A receptor, to produce a synergistic effect when co-administered with medications which elevate serotonin levels or antagonize hallucinogenic-like behavior for the purpose of treating aspects of brain disorders, including positive symptoms of Schizophrenia. The HTR was characterized in male C57BL/6J mice using psilocybin (0.5 to 2 mg/kg, IP), psilocin (0.3 to 1.0 mg/kg, IP), LSD (0.05 to 0.2 mg/kg, IP) and DOI (0.25 to 1.0 mg/kg, IP). Immediately following administration, mice were placed into observation chambers and observed continuously for 60 min. The number of head twitches were recorded in 10-min bins. Head twitch was observed in all treatment groups and varied in terms of frequency and time of peak effect. DOI produced an inverted ‘U'-shaped dose response, peaking between 21 and 30 min postdose, with a group total of 85 head twitches (0.5 mg/kg). Psilocybin and psilocin (the pharmacologically active agent of psilocybin) produced a dose-related response, peaking between 11 and 20 and 0 and 10 min postdose, respectively, with a group total of 70 (2 mg/kg) and 55 (1 mg/kg) head twitches, respectively. LSD produced a dose-related response, peaking between 11 and 20 min postdose, with a group total of 63 head twitches (0.2 mg/kg). For the purpose of characterizing attenuation of the HTR, clozapine (atypical antipsychotic) at 1.25 to 5.0 mg/kg, IP or haloperidol (typical antipsychotic) at 0.15 to 0.6 mg/kg, IP, were administered to mice. Thirty minutes later, the hallucinogen DOI (0.5 mg/kg, IP) was administered to induce the HTR. Animals were observed continuously for 30 min from 10 min post-DOI administration. Clozapine (1.25 mg/kg) and haloperidol (0.6 mg/kg) attenuated HTR by 68 and 64 %, respectively, when compared to DOI alone. Clozapine (2.5 and 5 mg/kg) attenuated the HTR, however the animals were highly sedated. These findings validated the HTR test in male C57BL/6J mice.