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.2018 Feb 6:9:17.
doi: 10.3389/fphar.2018.00017. eCollection 2018.

Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice

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Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice

Tobias Buchborn et al. Front Pharmacol..

Abstract

The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion. 25CN-NBOH evoked HTRs with an inverted u-shape-like dose-response curve and highest efficacy at 1.5 mg/kg, i.p. HTR occurrence peaked within 5 min after agonist injection, and exponentially decreased to half-maximal frequency at ~11 min. Thorough habituation to the experimental procedures (including handling, saline injection, and exposure to the observational boxes 1 day before the experiment) facilitated the animals' response to 25CN-NBOH. 25CN-NBOH (1.5 mg/kg, i.p.) induced HTRs were blocked by the 5-HT2A antagonist ketanserin (0.75 mg/kg, 30 min pre), but not by the 5-HT2C antagonist SB-242084 (0.5 mg/kg, i.p., 30 min pre). SB-242084 instead slightly increased the number of HTRs occurring at a 3.0-mg/kg dose of the agonist. Apart from HTR induction, 25CN-NBOH also modestly increased locomotor activity of the mice. Repeated once-per-day injections (1.5 mg/kg, i.p.) led to reduced occurrence of 25CN-NBOH induced HTRs. This intermediate tolerance was augmented when a second (higher) dose of the drug (3.0 mg/kg) was interspersed. Short-interval tolerance (i.e., tachyphylaxis) was observed when the drug was injected twice at intervals of 1.0 and 1.5 h at either dose tested (1.5 mg/kg and 0.75 mg/kg, respectively). Inducing ketanserin-sensitive HTRs, which are dependent on environmental valences and which show signs of tachyphylaxis and tolerance, 25CN-NBOH shares striking features common to serotonergic hallucinogens. Given its distinctin vitro selectivity for 5-HT2A over non5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity.

Keywords: 25CN-NBOH; 5-HT2A receptor; 5-HT2C receptor; head twitch response; locomotion; serotonergic hallucinogen; tachyphylaxis; tolerance.

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Figures

Figure 1
Figure 1
25CN-NBOH induced head twitches (HTRs) (as observed for the first 20 min post-application).(A) Dose–response relation (0.5–2.5 mg/kg i.p. vs. 1.5 mg/kg s.c.) and effect of experimental habituation (0.75 vs. 1.5 mg/kg NBOH i.p. + H).(B) Effect of the 5-HT2A antagonist ketanserin [1.5 mg/kg NBOH + 0.75 mg/kg K (30 min pre-treatment), i.p.] and the 5-HT2C antagonist SB-242084 [1.5 vs. 3.0 mg/kg NBOH + 0.5 mg/kg SB (30 min pre-treatment), i.p.], respectively. Mean + SEM;n = 4–6 per group. Kruskal-Wallis,post-hoc comparison to saline,*p ≤ 05 and**p ≤ 01; or to agonist w/o habituation and w/o antagonist pre-treatment, respectively, #p ≤.05.
Figure 2
Figure 2
Time-course of 25CN-NBOH (0.5–2.5 mg/kg, i.p.) induced head twitches (HTRs) (as observed for the first 30 min post-application). Mean ± SEM;n = 6 per group. The inset replots the means of the 1.5-mg/kg dose as fitted by an exponential decay function.
Figure 3
Figure 3
Effect of 25CN-NBOH (1.5 mg/kg, i.p.) on locomotion. Three 30-min intervals for the first 90 min after injection.(A) Fractional mobility (in % of 30 min);(B) distance traveled (in m per 30 min);(C) average speed (in m/s per 30 min). Mean + SEM;n = 8 per group. Repeated measures ANOVA, Bonferroni-corrected across-timepost-hoc comparison to control,*p ≤ 05.
Figure 4
Figure 4
Tachyphylaxis of 25CN-NBOH (0.75 or 1.5 mg/kg, s.c.) induced head twitches (HTRs) (as observed for the first 30 min post-application). Agonist was applied twice at an interval of 60 and 90 min, respectively. Mean + SEM;n = 5–6 per group. Repeated measures ANOVA, Bonferroni-correctedpost-hoc comparison to respective first application (0 min), ##p ≤ 01.
Figure 5
Figure 5
Subchronic tolerance to 25CN-NBOH induced head twitches (HTRs), with a total of four [1xNBOH: Once per day, 1.5 mg/kg (morning)] and seven [2xNBOH: Twice per day, 1.5 mg/kg (morning) vs. 3.0 mg/kg (evening)] i.p. injections, respectively. Head twitches were counted for the first 20 min after the morning application). Percent values indicate percent of HTRs relative to respective first day. Mean ± SEM;n = 6 per group. Repeated measures ANOVA, Bonferroni-correctedpost-hoc comparison to respective first-day measurement,**p ≤ 01,***p ≤ 001 (brackets behind asterisks indicate interval(s) significance applied to).
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