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. 2022 Dec 21;13(24):3629-3640.
doi: 10.1021/acschemneuro.2c00574. Epub 2022 Dec 6.

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice

Affiliations

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice

Tanishka S Saraf et al. ACS Chem Neurosci. .

Abstract

There are no approved medicines for fragile X syndrome (FXS), a monogenic, neurodevelopmental disorder. Electroencephalogram (EEG) studies show alterations in resting-state cortical EEG spectra, such as increased gamma-band power, in patients with FXS that are also observed in Fmr1 knockout models of FXS, offering putative biomarkers for drug discovery. Genes encoding serotonin receptors (5-HTRs), including 5-HT1A, 5-HT1B, and 5-HT1DRs, are differentially expressed in FXS, providing a rationale for investigating them as pharmacotherapeutic targets. Previously we reported pharmacological activity and preclinical neurotherapeutic effects in Fmr1 knockout mice of an orally active 2-aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT). FPT is a potent (low nM), high-efficacy partial agonist at 5-HT1ARs and a potent, low-efficacy partial agonist at 5-HT7Rs. Here we report new observations that FPT also has potent and efficacious agonist activity at human 5-HT1B and 5-HT1DRs. FPT's Ki values at 5-HT1B and 5-HT1DRs were <5 nM, but it had nil activity (>10 μM Ki) at 5-HT1FRs. We tested the effects of FPT (5.6 mg/kg, subcutaneous) on EEG recorded above the somatosensory and auditory cortices in freely moving, adult Fmr1 knockout and control mice. Consistent with previous reports, we observed significantly increased relative gamma power in untreated or vehicle-treated male and female Fmr1 knockout mice from recordings above the left somatosensory cortex (LSSC). In addition, we observed sex effects on EEG power. FPT did not eliminate the genotype difference in relative gamma power from the LSSC. FPT, however, robustly decreased relative alpha power in the LSSC and auditory cortex, with more pronounced effects in Fmr1 KO mice. Similarly, FPT decreased relative alpha power in the right SSC but only in Fmr1 knockout mice. FPT also increased relative delta power, with more pronounced effects in Fmr1 KO mice and caused small but significant increases in relative beta power. Distinct impacts of FPT on cortical EEG were like effects caused by certain FDA-approved psychotropic medications (including baclofen, allopregnanolone, and clozapine). These results advance the understanding of FPT's pharmacological and neurophysiological effects.

Keywords: 5-HT1; EEG; Fmr1; alpha power; delta power; gamma power; serotonin.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(a, b) In vitro pharmacology of FPT at human 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1FRs. Note that FPT was a full agonist at 5-HT1B and 5-HT1DRs and a high-efficacy, partial agonist at 5-HT1ARs, as determined by efficacies to decrease cAMP levels relative to 5-CT. FPT’s rank order of potency, including its binding affinities as determined in competition binding assays with [3H]5-CT and its EC50 values in cAMP assays, was 5-HT1D > 5-HT1B > 5-HT1A. FPT showed nil affinity at 5-HT1FRs, so we did not test its functional activity at them. The table at the bottom of the figure summarizes the pharmacological observations. TSP, total specific binding/no compound present.
Figure 2.
Figure 2.
Effects of genotype and sex on relative EEG power in male and female WT and Fmr1 KO mice at baseline. Power spectral density (leftmost column) shows absolute power per frequency. Scatter dot plots show relative power. Significant (P < 0.05) main effects are written on the graphs. Note there were region-dependent genotype effects on relative alpha (Fmr1 KO < WT) and gamma (Fmr1 KO > WT) power, and there were region-dependent sex effects on relative theta (female < male), alpha (female < male), and gamma (female > male) power. There was also a genotype-by-sex interaction on relative gamma power (higher power observed in female Fmr1 KO). Data were analyzed by two-way ANOVA. *P < 0.05, **P < 0.01 show significant results from Šídák’s multiple comparisons tests.
Figure 3.
Figure 3.
Effects of genotype, sex, and treatment—vehicle compared to FPT—on relative EEG power in male and female WT and Fmr1 KO mice. For clarity, only significant (P < 0.05) main effects are written on the graphs. Notably, FPT significantly increased relative delta and beta power recorded above the somatosensory cortices and decreased relative alpha power recorded above the somatosensory and auditory cortices. FPT decreased relative gamma power in the right somatosensory cortex in most groups. Note also that where FPT had significant effects, they tended to be more robust in Fmr1 KO than in WT mice. Data were analyzed by repeated measures three-way ANOVA. Results from Fisher’s LSD multiple comparisons tests are reported in the Results section.
Figure 4.
Figure 4.
EEG surgery coordinates and timelines. Electrode coordinates and channels are shown in coronal (a) and axial (b) planes. Timeline for surgery (c) and recording (d) of non-task-related, resting-state (rs) EEG. R, reference electrode; G, ground electrode.

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