Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

Abstract

The 5-HT₂A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT₂A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT₂A/₂C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT₂A knockout mice, indicating the effect is a consequence of 5-HT₂A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT₂A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT₂A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT₂A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT₂A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT₂A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT₂A activation and hallucinogenesis.

Figure 1

Chemical structures of the phenylalkylamines.

Figure 2

Effects of phenylalkylamine hallucinogens on distance traveled (in cm), a measure of locomotor activity. (A) Mescaline, (B) DOET, (C) DOPR, (D) TMA-2. Mice used were male C57BL/6J. Data are presented as group means±SEM for successive 10-min intervals. *p<0.05, **p<0.01, significant difference from vehicle control group.

Figure 3

Effect of TCB-2 on locomotor activity. Mice used were male C57BL/6J. Data are presented as group means±SEM for successive 10-min intervals. *p<0.05, **p<0.01, significant difference from vehicle control group.

Figure 4

Effect of DOTB on locomotor activity. Mice used were male C57BL/6J. Data are presented as group means±SEM for successive 10-min intervals.

Figure 5

Effect of 5-HT_2A gene deletion on the locomotor response to mescaline. Effect of vehicle or 25 mg/kg mescaline on distance traveled in male and female WT mice (top panel) and male and female 5-HT_2A KO mice (bottom panel). Data are presented as group means±SEM for successive 10-min intervals. *p<0.05, **p<0.01, significant difference from the respective vehicle control group.

Figure 6

Effect of 5-HT_2A gene deletion on TCB-2-induced increases in locomotor activity. Effect of vehicle or 3 mg/kg TCB-2 on distance traveled in male WT mice (top panel) and male 5-HT_2A KO mice (bottom panel). Data are presented as group means±SEM for successive 10-min intervals. *p<0.05, **p<0.01, significant difference from the respective vehicle control group.

Figure 7

Effect of 5-HT_2A gene deletion on the changes in investigatory activity induced by TCB-2. TCB-2 was tested at 3 mg/kg in male 5-HT_2A WT and KO mice. Data are presented as group means±SEM over 30-min blocks. *p<0.05, **p<0.01, significant difference from the respective vehicle control group.

Figure 8

Effect of pretreatment with the 5-HT_2A antagonist M100907 on the locomotor response to 25 mg/kg mescaline. Mice were pretreated with 0.03 mg/kg M100907 (A) or 0.1 mg/kg M100907 (B). Mice used were male C57BL/6J. Data are presented as group means±SEM for successive 10-min intervals. *p<0.05, **p<0.01, significant difference from vehicle control group. #p<0.05, ##p<0.001, significant difference from mescaline alone.

Figure 9

Effect of pretreatment with the 5-HT_2A antagonist M100907 on the locomotor response to 3 mg/kg TCB-2. Mice were pretreated with 0.03 mg/kg M100907 (A) or 0.1 mg/kg M100907 (B). Mice used were male C57BL/6J. Data are presented as group means±SEM for successive 10-min intervals. *p<0.05, **p<0.01, significant difference from vehicle control group. #p<0.05, ##p<0.001, significant difference from TCB-2 alone.