Pitolisant, a wake‐promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol

Autor: Martin Giret, Isabelle Nagmar, Jean-Charles Schwartz, Marilyne Uguen, Philippe Robert, Perrin David, Olivier Finance, Isabelle Berrebi-Bertrand, Stéphane Krief, Jeanne-Marie Lecomte, Simon Belliard, Xavier Ligneau
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Dopamine
Drug Evaluation
Preclinical
Pharmacology
solriamfetol
Nucleus Accumbens
psychostimulants
chemistry.chemical_compound
Mice
Dopamine Uptake Inhibitors
Piperidines
Medicine
General Pharmacology
Toxicology and Pharmaceutics
pitolisant
Sleep Apnea
Obstructive
Adrenergic Uptake Inhibitors
Wakefulness-Promoting Agents
Neurology
rodents
Original Article
modafinil
Locomotion
medicine.drug
Pitolisant
Drug Inverse Agonism
Phenylalanine
neurochemistry
Histamine Antagonists
Disorders of Excessive Somnolence
RM1-950
Nucleus accumbens
Neurochemical
Inverse agonist
Animals
Receptors
Histamine H3
Amphetamine
Narcolepsy
Dopamine Plasma Membrane Transport Proteins
Norepinephrine Plasma Membrane Transport Proteins
business.industry
behavior
Modafinil
Feeding Behavior
Original Articles
medicine.disease
Corpus Striatum
Neostriatum
chemistry
3
4-Dihydroxyphenylacetic Acid
Carbamates
Therapeutics. Pharmacology
business
Zdroj: Pharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
Pharmacology Research & Perspectives
ISSN: 2052-1707
Popis: Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake‐promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4‐dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine‐like properties within in vivo preclinical models.
The wake‐promoting agents amphetamine, modafinil, solriamfetol and pitolisant were compared. The first three drugs cause dopamine release in the striatum, hyperlocomotion, behavioral sensitization and hypophagia, common features of psychostimulants, in contrast to pitolisant.
Databáze: OpenAIRE
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