Pharmacologic MRI Brain Imaging Studies of Serotonin 5-HT₁ Receptor Agonists in Awake Mice

Serotonin (5-hydroxytryptamine, 5-HT) type-1 G protein-coupled receptors are expressed throughout the central nervous system. 5-HT_1AR activation is the putative mechanism of approved drugs for generalized anxiety disorder and major depressive disorder and is being studied in the treatment of autism and neurological disorders. The 5-HT_1B and 5-HT_1DRs are the putative therapeutic targets for "triptan"-type migraine drugs, and the 5-HT_1BR is associated with prosocial effects, relative to autism treatment, consistent with its high expression in limbic and cortical brain regions. Under study is a recently developed drug candidate for autism, (S)-5-(2'-fluorophenyl)-2-dimethylaminotetralin (FPT), that is a full efficacy pan-5-HT₁R agonist (pEC50 = 7.4, 9.4, and 8.6 at 5-HT1_A, 5-HT1_B, and 5-HT1_DRs, respectively). FPT demonstrates anti-seizure, anxiolytic, and prosocial properties, as well as reduces stereotypic movements in Fmr1 knockout mice, a model for autism. The goal of this study was to compare brain activation patterns of the pan-5-HT₁R agonist FPT to NLX-112, a highly selective 5-HT_1AR full agonist (pEC₅₀ = 7.5) which also prevents seizures in Fmr1 knockout mice, to help establish therapeutic mechanisms in autism. We used pharmacological magnetic resonance imaging (phMRI) in awake C57BL/J6 mice to assess activation of integrated neuronal circuits as measured by blood oxygen level dependent volume of activation changes, comparing dose-related effects of FPT and NLX-112. The selective 5HT_1AR agonist NLX-112 broadly inhibited brain activity in a dose-dependent manner. In contrast, FPT increased global brain activity; however, dose-related effects were complex, suggesting FPT's polypharmacology at 5-HT₁Rs and perhaps other receptors are involved in its brain activation pattern.