Synergism Between a Serotonin 5-HT_2A Receptor (5-HT_2AR) Antagonist and 5-HT_2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction

Abstract

Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT 2A receptor (5-HT 2A R) and 5-HT 2C R; either a selective 5-HT 2A R antagonist or a 5-HT 2C R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT 2A R antagonist plus 5-HT 2C R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT 2A R antagonist M100907 plus the 5-HT 2C R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue-and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT 2A R antagonist plus a 5-HT 2C R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules. KEYWORDS: 1-Choice serial reaction time task, 5-HT 2A receptor, 5-HT 2C receptor, cocaine, cue reactivity, impulsivity, self-administration, serotonin D ependence on the psychostimulant cocaine is marked by problematic vulnerability to relapse even years into abstinence. 1,2 Two important liability factors that contribute to relapse are impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) 3 and cue reactivity (sensitivity to cues associated with cocaine-taking that can promote cocaine-seeking). 4,5 Impulsivity and cue reactivity appear to be interrelated in human cocaine users, 6 and new pharmacotherapeutic strategies that effectively diminish both are likely to enhance abstinence in the highly vulnerable population of cocaine-dependent individuals.The underlying neurobiology of these liability factors includes a regulatory role for serotonin (5-HT; 5-hydroxytryptamine) neurotransmission. The actions of 5-HT in neurons are transduced by at least 14 subtypes of 5-HT receptors (5-HT X Rs) which are presently grouped into seven families (5-HT 1 R−5-HT 7 R) according to their structural and functional characteristics. 7−9 Selective blockade of the 5-HT 2A R 10−12 or activation of the 5-HT 2C R 10,13,14 consistently reduces impulsivity as measured by premature responses assessed in the 1-or 5-choice serial reaction time (1-or 5-CSRT) task, a preclinical Special Issue: Celebratin...

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

“…Drugs that activate 5-HT 2C receptors hold promise for the treatment of psychoses and psychostimulant abuse, in part because of their ability to modulate central dopamine signaling and their effectiveness in preclinical models and at least one clinical study (Di Matteo et al, 2004;Shen et al, 2010;Higgins et al, 2012;Cunningham et al, 2013). Herein is described (2)-MBP, a novel and potent 5-HT 2C receptorspecific agonist with 5-HT 2A and 5-HT 2B competitive antagonist and inverse agonist properties that is effective in preclinical mouse models of psychoses, does not affect locomotion on its own, and reduces palatable food intake, important properties distinguishing it from available antipsychotic drugs that suppress locomotion and increase appetite, leading to obesity (Stip et al, 2012).…”

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…c Filip et al, 2004, 2006Filip, 2005. d Callahan andCunningham, 1995;Filip and Cunningham, 2003;Filip et al, 2004;Acosta, 2007. e Burbassi andCervo, 2008;Fletcher et al, 2008Fletcher et al, , 2011Grottick et al, 2000;Manvich et al, 2012a. f Navarra et al, 2008Cunningham et al, 2011Cunningham et al, , 2013Anastasio et al, 2014a. g Katsidoni et al, 2011 h SB242084 alone supported self-administration in squirrel monkeys (Manvich et al, 2012b).…”

“…The enhancement observed between the 5-HT 2A R antagonist M100907 plus WAY 163909 was achieved at doses that are much lower than the doses of each ligand necessary to affect the given behavior when administered alone, suggesting that there may be combination approaches that would potentially minimize side effects of the medications. At present, there are no FDA-approved medications known to exhibit this exact pharmacological profile; however, efforts to chemically synthesize such molecules are ongoing (Booth et al, 2009;Shashack et al, 2011;Cunningham et al, 2013).…”

Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

“…Drug discovery programs targeting 5-HT2 receptors are focused on treating psychosis (5-HT2A antagonists), sleep disorders (5-HT2A antagonists), cluster headaches (5-HT2 agonists), anxiety (5-HT2B/2C antagonists), and obesity (5-HT2C agonists) (Sewell et al, 2006;Abbas and Roth, 2008;Smith et al, 2010). In addition, compounds with combined 5-HT2C agonist plus 5-HT2A/2B antagonist activity, similar to certain trans-4-phenyl-2-dimethylaminotetralins (PATs), may be useful for treating substance abuse and other compulsive behavioral disorders Canal et al, 2013;Cunningham et al, 2013;Higgins et al, 2013;Morgan et al, 2013).…”