Poster De Conférence Année : 2023

The SB-258585, a 5-HT6 antagonist that blocks serotonin transmission in striatum can induce loss of food motivation and behavioral disturbances in non-human primate.

Mathilde Pitoy
Lisa Gauthier
  • Fonction : Auteur
Julie Maulavé
  • Fonction : Auteur
Justine Debatisse
Elise Metereau

Résumé

The development of 5-HT6 receptors (5-HT6Rs) specific antagonists or agonists has allowed to shown, in rodents, that this 5-HT transmission can modulates cognitive processes, food motivation and anxiety-related behaviors. These studies in rodent focused on 5-HT6Rs modulation with regard to prefrontal cortex, hippocampus or amygdala, but few of them focused on the striatum, despite its involvement in food intake and anxiety-related disorders. Moreover, PET imaging with [18F]2FNQ1P in non-human primates (NPH) has shown that the striatum is one of the cerebral structures expressing the highest levels of 5-HT6Rs. We thus hypothesized that the blockage of 5-HT transmission by a selective 5-HT6R antagonist, the SB-258585, will influence food motivation and modulate the behavioural expression in NHP, by acting on striatal 5-HT6Rs. The first aim of this study, carried out on six macaques, was to determine the effects of intramuscular injections of SB-258585 on food motivation and behavioural expression using a food-choice task associated with observation periods for spontaneous behaviors. In order to identify the striatum’s involvement as well as the specific role of the different striatal territories (ventral striatum, caudate nucleus and putamen) in the SB-258585’s effects, we controlled the receptor occupancy by the SB-258585. At 3 mg/kg, the SB-258585 significantly reduced food intake in five out of six animals. On five animals tested on qualitative changes in food intake, all of them decreased their speed of consumption and four of them modified their food preference between two items in a choice context. The 5HT6R antagonist also significantly affected spontaneous behaviour by increasing movements, and/or behaviour frequencies and switching between them in four out of six individuals, suggesting a hyperactive state. In four monkeys, duration and/or frequency of anxiety-related behaviours also increased. PET imaging with voxel-based analysis revealed a significant reduction of 5-HT6R-binding by the SB-258585 only in striatum and more specifically over all the antero-posterior putamen, including sub-territories that could account for the reduction of food motivation and behavioural disturbances. To conclude, our results on NPH confirm that the 5-HT6Rs blockage by SB-258585 can modulate food intake as well as impulsive and anxiety-relative behaviours by acting mainly on the striatum, which opens potential therapeutic applications for 5HT6R targeting.

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Dates et versions

hal-04983922 , version 1 (10-03-2025)

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  • HAL Id : hal-04983922 , version 1

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Léon Tremblay, Mathilde Pitoy, Lisa Gauthier, Julie Maulavé, Justine Debatisse, et al.. The SB-258585, a 5-HT6 antagonist that blocks serotonin transmission in striatum can induce loss of food motivation and behavioral disturbances in non-human primate.. NeuroFrance, May 2023, Lyon, France. ⟨hal-04983922⟩
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