Effects of acute treatments with the serotonin 2A antagonist M100907 alone or in combination with the serotonin 2C agonist WAY163909 on methamphetamine self-administration in rhesus monkeys

Abstract

Background: Serotonin 5-HT2A receptor antagonists and 5-HT2C receptors agonists have been proposed as important candidates for the development of pharmacotherapies for psychostimulant abuse, with evidence suggesting that those receptors may act together to control behavior. However, the role of 5-HT2A receptors on the reinforcing effects of psychostimulant drugs has not been fully elucidated. Methods: In the present study, we investigated the effects of the selective 5HT2A receptor antagonist M100907 alone or in combination with the selective 5HT2C agonist WAY 163909 on intravenous methamphetamine self-administration in rhesus macaques (N = 3). Methamphetamine self-administration (0.01-0.03 mg/kg/inf) was evaluated under a fixed-ratio 20-schedule of reinforcement, and acute pretreatments were conducted 1h (M100907) or 45min (WAY 163909) prior to the beginning of self-administration sessions at the EDMax dose of methamphetamine once stability criteria were met. Results: Pretreatment with M100907 (0.03-0.3 mg/kg, i.m.) dose-dependently attenuated methamphetamine self-administration, with the highest dose significantly decreasing response rates compared to vehicle. Combined administration of ineffective doses of M100907 and WAY 163909 had no effects on methamphetamine self-administration. Conclusions: Our study indicates that acute selective 5-HT2A receptor blockade decreases peak methamphetamine intake in nonhuman primates. Combination approaches with sub-threshold doses of 5-HT2A receptor antagonists and 5-HT2C receptor agonists, on the other hand, do not seem to be effective in decreasing methamphetamine reinforcement. Further studies are needed in order to investigate the effects of chronic treatments with M100 on complete METH SA dose-response curves.

Recent developments in enantio- and diastereoselective hydrogenation of N-heteroaromatic compounds

“…29 In addition, WAY-163909 has been shown to have potential uses in anti-obesity drugs and the treatment of certain drug addictions. 30…”

“…29 In addition, WAY-163909 has been shown to have potential uses in anti-obesity drugs and the treatment of certain drug addictions. 30 To accelerate the development of the indoline moiety in drugs, more methods are required to produce their substituted cores in enantiomerically pure forms. Indoles are a challen-ging structure for EH to afford indolines.…”

Blockade of 5-Hydroxytryptamine 2A Receptor Attenuates Precipitation of Naloxone-Induced Withdrawal Symptoms in Opioid-Exposed Mice

“…5-Hydroxytryptamine (serotonin) 2A receptors regulate neuropsychological functions ( Pogorelov et al, 2017 ; Mora et al, 2018 ; Odabas-Geldiay et al, 2019 ) and have been shown to play a role in a number of neurological disorders, including Alzheimer’s disease ( Ballard et al, 2018 ), Parkinson’s disease ( Cummings et al, 2014 ; Ohno et al, 2015 ), obsessive–compulsive disorder ( El Mansari and Blier, 2006 ; Steeves and Fox, 2008 ; Simpson et al, 2011 ; Sinopoli et al, 2017 ), schizophrenia ( Girgis et al, 2020 ), autism spectrum disorder ( Chen et al, 2013 ), depression ( Underwood et al, 2018 ), anxiety ( Weisstaub et al, 2006 ), insomnia ( Teegarden et al, 2008 ), and obesity ( Morris, 2017 ). The 5-HT2AR antagonist volinanserin or MDL100907 (Aventis Pharmaceuticals) has been used to treat neuropsychological dysfunctions in drug-addicted patients ( Cunningham et al, 2013 ), and a synergism between the 5-HT2AR and 5-HT2CR affects the severity of addictive behaviors ( Cunningham et al, 2013 ; Perez-Aguilar et al, 2014 ; Prabhakaran et al, 2015 ; Felsing et al, 2018 ).…”