title: The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.
abstract: The 5-HT1A/1B-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, The Netherlands; Department of Biopsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr-University Bochum, Germany. Electronic address: s.m.korte@uu.nl.
authors.forename: S Mechiel
authors.initials: SM
authors.lastname: Korte
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Prins
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, The Netherlands.
authors.forename: Filip S
authors.initials: FS
authors.lastname: Van den Bergh
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, The Netherlands.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Oosting
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, The Netherlands.
authors.forename: Rudy
authors.initials: R
authors.lastname: Dupree
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, The Netherlands.
authors.forename: Gerdien A H
authors.initials: GA
authors.lastname: Korte-Bouws
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University, The Netherlands.
authors.forename: Koen G C
authors.initials: KG
authors.lastname: Westphal
authors.affiliation: Groningen Institute for Evolutionary Life Sciences, University of Groningen, The Netherlands.
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Damiaan A
authors.initials: DA
authors.lastname: Denys
authors.affiliation: Department of Biopsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr-University Bochum, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Garland
authors.affiliation: Department of Biopsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr-University Bochum, Germany.
authors.forename: Onur
authors.initials: O
authors.lastname: Güntürkün
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D007175:Impulsive Behavior / Q000187:drug effects*; D008297:Male; D009042:Motivation / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D012201:Reward; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C063828:eltoprazine; D004298:Dopamine
keywords: 5-HT(1A/1B)-receptor; Eltoprazine; Eltoprazine (PubChem CID: 65853); Impulsivity; Microdialysis; Monoamines; Prefrontal cortex