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. 2014 Feb:77:200-7.
doi: 10.1016/j.neuropharm.2013.08.025. Epub 2013 Sep 4.

Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response

Adam L Halberstadt  1 , Mark A Geyer  2
Affiliations

Affiliations

  • 1 Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. Electronic address: ahalberstadt@ucsd.edu.
  • 2 Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.

Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response

Adam L Halberstadt et al. Neuropharmacology. 2014 Feb.
. 2014 Feb:77:200-7.
doi: 10.1016/j.neuropharm.2013.08.025. Epub 2013 Sep 4.

Authors

Adam L Halberstadt  1 , Mark A Geyer  2

Affiliations

  • 1 Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. Electronic address: ahalberstadt@ucsd.edu.
  • 2 Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.

Abstract

N-benzyl substitution markedly enhances the affinity of phenethylamine hallucinogens at the 5-HT(2A) receptor. N-benzyl substituted derivatives of 2,5-dimethoxy-4-iodophenethylamine (2C-I), such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD), have appeared recently as designer drugs, but have not been characterized behaviorally. The head twitch response (HTR) is induced by 5-HT(2A) receptor activation in rats and mice, and is widely used as a behavioral proxy for hallucinogen effects in humans. Nevertheless, it is not clear whether phenethylamine hallucinogens reliably provoke this behavior. Hence, we investigated whether 2C-I, 25I-NBOMe and 25I-NBMD induce head twitches in C57BL/6J mice. The HTR was assessed using a head-mounted magnet and a magnetometer coil. 2C-I (1-10 mg/kg SC), 25I-NBOMe (0.1-1 mg/kg SC), and 25I-NBMD (1-10 mg/kg SC) induced the HTR. 25I-NBOMe displayed 14-fold higher potency than 2C-I, and the selective 5-HT(2A) antagonist M100,907 completely blocked the HTR induced by all three compounds. These findings show that phenethylamine hallucinogens induce the HTR by activating 5-HT(2A) receptors. Our results demonstrate that 25I-NBOMe is a highly potent derivative of 2C-I, confirming previous in vitro findings that N-benzyl substitution increases 5-HT(2A) affinity. Given the high potency and ease of synthesis of N-benzylphenethylamines, it is likely that the recreational use of these hallucinogens will become more widespread in the future.

Keywords: 5-HT2A; Head twitch; LSD; Psychedelic.

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Figures

Figure 1

Figure 1

Chemical structures of phenethylamines.

Figure 1

Chemical structures of phenethylamines.

Figure 1
Chemical structures of phenethylamines.
Figure 2

Figure 2

(A, B) Magnetometer coil responses…

Figure 2

(A, B) Magnetometer coil responses induced by head twitches. The left panels show…

Figure 2
(A, B) Magnetometer coil responses induced by head twitches. The left panels show the voltage response of the magnetometer coil, and the right panels are periodograms showing the spectral density of the responses. The response in (A) peaked at 83.8 Hz and the response in (B) peaked at 64.4 Hz. The magnetometer recordings were band-pass filtered (40–200 Hz) to attenuate the response to extraneous head movements and high-frequency noise. (C) Correlation between head-twitch counts in simultaneous video and the magnetometer coil recordings from 6 mice (r=0.997).
Figure 3

Figure 3

Plots of magnetometer coil voltage…

Figure 3

Plots of magnetometer coil voltage responses showing the temporal distribution of head twitches…

Figure 3
Plots of magnetometer coil voltage responses showing the temporal distribution of head twitches induced by 2C-I during the 30-min test sessions. At this time resolution, head twitches appear as high-amplitude bipolar deflections. The numbers of head twitches detected were 5 (vehicle), 16 (0.3 mg/kg), 65 (1 mg/kg), 84 (3 mg/kg), and 89 (10 mg/kg).
Figure 4

Figure 4

Effect of 2C-I on the…

Figure 4

Effect of 2C-I on the head twitch response. ( Top panel ) Total…

Figure 4
Effect of 2C-I on the head twitch response. (Top panel) Total counts over the 30-min test session. (Bottom panel) Time-course of the head twitch response induced by 2C-I (in 2-min blocks). Data are presented as group means±SEM. **p<0.01, significant difference from the vehicle control group.
Figure 5

Figure 5

Effect of 25I-NBOMe on the…

Figure 5

Effect of 25I-NBOMe on the head twitch response. ( Top panel ) Total…

Figure 5
Effect of 25I-NBOMe on the head twitch response. (Top panel) Total counts over the 30-min test session. (Bottom panel) Time-course of the head twitch response induced by 25I-NBOMe (in 2-min blocks). Data are presented as group means±SEM. **p<0.01, significant difference from the vehicle control group.
Figure 6

Figure 6

Effect of 25I-NBMD on the…

Figure 6

Effect of 25I-NBMD on the head-twitch response. ( Top panel ) Total counts…

Figure 6
Effect of 25I-NBMD on the head-twitch response. (Top panel) Total counts over the 30-min test session. (Bottom panel) Time-course of the head twitch response induced by 25I-NBMD (in 2-min blocks). Data are presented as group means±SEM. **p<0.01, significant difference from the vehicle control group.
Figure 7

Figure 7

Effect of pretreatment with the…

Figure 7

Effect of pretreatment with the 5-HT 2A antagonist M100,907 on the head twitch…

Figure 7
Effect of pretreatment with the 5-HT2A antagonist M100,907 on the head twitch response induced by phenethylamines. Mice were pretreated with varying doses of M100,907 and then treated with 3 mg/kg 2C-I (top panel), 0.3 mg/kg 25I-NBOMe (middle panel), or 3 mg/kg 25I-NBMD (bottom panel). Data are presented as group means±SEM for the entire 20-min test sessions. **p < 0.01, significant difference from 2C-I, 25I-NBOMe, or 25I-NBMD alone.
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