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.

Psychedelics

“…Thus, they conclude that the mGlu5 receptor acts to attenuate 5-HT 2A receptor-induced hyperactivity, and either the loss of the mGlu5 receptor, or a negative allosteric regulator of mGlu5, essentially unmasks the influence of the 5-HT 2A receptor. Halberstadt et al (2013) tested a series of phenylalkylamine psychedelics in C57BL/6J mice using the BPM to determine whether they increased locomotor activity by activating the 5-HT 2A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOEt), 2,5-dimethoxy-4-n-propylamphetamine (DOPr), 2,4,5-trimethoxyamphetamine (TMA-2), and 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity, whereas a nonhallucinogenic phenethylamine DOTB did not alter activity at any dose tested.…”

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

“…In contrast to rats, phenylalkylamine and indolealkylamine hallucinogens produce disparate effects on exploratory and investigatory behavior in C57BL/6J mice. Phenylalkylamines, including DOI, mescaline, and TCB-2, inhibit investigatory behavior and alter locomotor activity in a dose-dependent manner, increasing activity at low to moderate doses and reducing activity at high doses (Halberstadt et al, 2009, 2013). Other groups have reported similar findings with DOM and DOI in mice (Yamamoto and Ueki, 1975; Darmani, 1996; Brookshire and Jones, 2009; Carlsson et al, 2011).…”

Preclinical models of antipsychotic drug action

“…The psychedelic 5-HT 2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) has been shown to affect locomotor activity in mice (Gonzalez-Maeso et al, 2007; Halberstadt et al, 2009, 2013) and rats (Krebs-Thomson et al, 1998; Van Oekelen et al, 2003; Marona-Lewicka et al, 2005). Low doses of DOI significantly increase locomotor activity, an effect that is absent in 5-HT 2A knockout mice (Halberstadt et al, 2009).…”

“…A more detailed characterization of the effects of phenylalkylamine psychedelics, including low doses of DOI, mescaline, 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxy-4-propylamphetamine, 2,4,5-trimethoxyamphetamine and 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl-methylamine (TCB-2), shows increased locomotor activity in wild-type mice, an effect that is blocked by M100907 and abolished in 5-HT 2A knockout mice (Halberstadt et al, 2013). Interestingly, the effect on locomotor hyperactivity induced by phenylalkylamine psychedelics is not induced by the non-psychedelic phenylalkylamine 2,5-dimethoxy-4- tert -butylamphetamine (DOTB; Halberstadt et al, 2013). These findings suggest that activation of the 5-HT 2A receptor by psychedelics, but not by non-psychedelics, increases locomotor activity in mice, which may serve as a model of hallucinogenic potential in humans.…”