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. 2020 Feb 21;3(3):509-523.
doi: 10.1021/acsptsci.9b00101. eCollection 2020 Jun 12.

(S)-5-(2'-Fluorophenyl)- N, N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder

Jessica L Armstrong  1 , Austen B Casey  2 , Tanishka S Saraf  1 , Munmun Mukherjee  2 , Raymond G Booth  2 , Clinton E Canal  1
Affiliations

(S)-5-(2'-Fluorophenyl)- N, N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder

Jessica L Armstrong et al. ACS Pharmacol Transl Sci. .

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clinically by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiological circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclinical effect produced by anxiolytic medications. Receptor pharmacology assays show that FPT binds competitively and possesses rapid association and dissociation kinetics at 5-HT1ARs and 5-HT7Rs, yet has slow association and rapid dissociation kinetics at 5-HT2CRs. Finally, we reassessed and report FPT's affinity and function at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
FPT is an anticonvulsant in Fmr1 knockout mice. The majority of vehicle-treated Fmr1 knockout mice (ages P23–P25) had lethal audiogenic seizures. FPT blocked audiogenic seizures in all mice tested; results were highly significant (****, P < 0.0001, relative to vehicle). WRJ = wild running and jumping. Non-lethal seizure = recovered from tonic-clonic seizure.
Figure 2
Figure 2
FPT increases social approach behavior. Shown are the number of social approaches in an open-field from paired wild-type (WT) or Fmr1 knockout (KO) mice, one treated with vehicle (Veh) and the other FPT. (a) Vehicle-treated KO mice tended to exhibit fewer social approaches than vehicle-treated WT mice. FPT significantly increased social interactions in WT mice, relative to vehicle, and increased social interactions in KO mice, normalizing social approaches to vehicle-treated WT levels. (b) Data from (a) unmasked to show social approach results of the individual pairs of mice. These data show that each FPT-treated wild-type mouse exhibited more social approaches than its vehicle-treated pair, and 7 of 9 FPT-treated Fmr1 knockout mice exhibited more social approaches than their vehicle-treated pairs.
Figure 3
Figure 3
FPT produces anxiolytic-like effects in wild-type (WT) and Fmr1 knockout (KO) mice. (a) FPT, relative to vehicle (Veh), significantly decreased marble-burying and (b) repetitive grooming in both WT and KO mice. (c) FPT significantly reduced rearing in KO mice and tended to decrease rearing in WT mice.
Figure 4
Figure 4
FPT does not affect spontaneous alternation performance in a Y-maze in either wild-type (WT) or Fmr1 knockout (KO) mice, but it tends to increase exploratory behavior. (a) There were no effects of genotype or treatment on spontaneous alternation performance. (b) FPT, relative to vehicle (Veh), tended to increase the number of arm entries by WT and Fmr1 KO mice.
Figure 5
Figure 5
FPT increases locomotor activity in an open-field. FPT, relative to vehicle (Veh), significantly increased locomotor behavior in wild-type (WT) mice, and there was a trend to increase locomotor activity in Fmr1 knockout (KO) mice. KO mice tended to exhibit increased locomotor activity relative to WT mice.
Figure 6
Figure 6
Effects of FPT on c-Fos expression in the dorsal hippocampus (a) and basolateral amygdala (b) in wild-type (WT) and Fmr1 knockout (KO) mice. Top left and bottom left: Representative 4× magnification images of cresyl violet stained dorsal hippocampus and amygdala, respectively. Top middle and bottom middle: Representative 20× magnification images of DAB-stained c-Fos in CA3 and BLAa, respectively, from WT and KO mice after treatment with vehicle (Veh) or FPT. Top right: FPT did not significantly increase c-Fos expression in CA3. Bottom right: FPT significantly increased c-Fos expression in the BLAa of KO mice and tended to increase c-Fos expression in the BLAa of WT mice.
Figure 7
Figure 7
Effects of FPT on c-Fos expression in the inferior colliculus (IC) of juvenile Fmr1 knockout mice exposed for 30 s to a 120 dB alarm. FPT, relative to vehicle (Veh), did not affect the number of c-Fos positive cells.
Figure 8
Figure 8
Determination of radioligand and FPT kinetic binding parameters at 5-HT1ARs, 5-HT2CRs and 5-HT7Rs. (a–c) Association kinetics of three concentrations of radioligand (10×, 5×, and 1× Kd) at (a) 5-HT1ARs, (b) 5-HT2CRs, and (c) 5-HT7Rs. (d–f) Plot of the observed association rate versus radioligand concentration yields a linear relationship for 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs, indicative of ligand binding to a single site. (g–i) Competition kinetics of varying concentrations of unlabeled FPT in the presence of 5–10 nM radioligand at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Data are organized in columns by receptor, and in rows by assay format. Association curves were derived from 3–5 independent experiments, normalized where the specific binding of radioligand at the latest time point is 100%, and binding at time 0 is fixed to 0%. Data reporting the kobs (kobs = (kon × [radioligand]) + koff) are presented in singlet form from an individual association binding experiment.
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