Samantha E Yohn1, Daniela Alberati2, Merce Correa1,3, John D Salamone4. 1. Division of Behavioral Neuroscience, Department of Psychological Sciences, University of Connecticut, Storrs, CT, 06269-1020, USA. 2. F. Hoffmann-La Roche, Neuroscience, Ophthalmology and Rare Diseases, Pharma Research and Early Development, Grenzacherstrasse 124, CH4070, Basel, Switzerland. 3. Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071, Castelló, Spain. 4. Division of Behavioral Neuroscience, Department of Psychological Sciences, University of Connecticut, Storrs, CT, 06269-1020, USA. john.salamone@uconn.edu.
Abstract
RATIONALE: Motivated behavior can be characterized by a substantial exertion of effort, and organisms often make effort-related decisions based upon analyses of work-related response costs and reinforcement preference. Moreover, alterations in effort-based choice can be seen in people with major depression and schizophrenia. Effort-related decision making is studied using tasks offering choices between high effort options leading to highly valued reinforces vs low effort/low reward options. Interference with dopamine (DA) transmission by administration of the DA D2 family antagonist haloperidol biases behavior towards the lower effort option that can be obtained with minimal work, and previous research has shown that DA interacts with other transmitters, including adenosine and GABA, to regulate effort-based choice. OBJECTIVES: The present studies focused upon the ability of the glycine transport inhibitor bitopertin to attenuate haloperidol-induced shifts in effort-related choice behavior. METHODS: Effort-based choice in rats was assessed using the concurrent fixed ratio (FR) 5/chow feeding choice task and the T-maze barrier choice procedure. RESULTS: Haloperidol shifted effort-based choice, biasing animals towards the low effort option in each task. Co-administration of bitopertin (1.0-10.0 mg/kg) significantly attenuated haloperidol-induced shifts in choice behavior, but the same doses of bitopertin had no effect when administered alone. CONCLUSIONS: These results indicated that elevation of extracellular glycine via inhibition of glycine uptake was able to reverse the effects of D2 antagonism. Increases in extracellular glycine, possibly through actions on the glycine allosteric site on the NMDA receptor, may be a useful strategy for treating motivational dysfunctions in humans.
RATIONALE: Motivated behavior can be characterized by a substantial exertion of effort, and organisms often make effort-related decisions based upon analyses of work-related response costs and reinforcement preference. Moreover, alterations in effort-based choice can be seen in people with major depression and schizophrenia. Effort-related decision making is studied using tasks offering choices between high effort options leading to highly valued reinforces vs low effort/low reward options. Interference with dopamine (DA) transmission by administration of the DA D2 family antagonist haloperidol biases behavior towards the lower effort option that can be obtained with minimal work, and previous research has shown that DA interacts with other transmitters, including adenosine and GABA, to regulate effort-based choice. OBJECTIVES: The present studies focused upon the ability of the glycine transport inhibitor bitopertin to attenuate haloperidol-induced shifts in effort-related choice behavior. METHODS: Effort-based choice in rats was assessed using the concurrent fixed ratio (FR) 5/chow feeding choice task and the T-maze barrier choice procedure. RESULTS:Haloperidol shifted effort-based choice, biasing animals towards the low effort option in each task. Co-administration of bitopertin (1.0-10.0 mg/kg) significantly attenuated haloperidol-induced shifts in choice behavior, but the same doses of bitopertin had no effect when administered alone. CONCLUSIONS: These results indicated that elevation of extracellular glycine via inhibition of glycine uptake was able to reverse the effects of D2 antagonism. Increases in extracellular glycine, possibly through actions on the glycine allosteric site on the NMDA receptor, may be a useful strategy for treating motivational dysfunctions in humans.
Authors: Matthias N Hartmann; Oliver M Hager; Anna V Reimann; Justin R Chumbley; Matthias Kirschner; Erich Seifritz; Philippe N Tobler; Stefan Kaiser Journal: Schizophr Bull Date: 2014-07-22 Impact factor: 9.306
Authors: Allison M Mott; Eric J Nunes; Lyndsey E Collins; Russell G Port; Kelly S Sink; Jörg Hockemeyer; Christa E Müller; John D Salamone Journal: Psychopharmacology (Berl) Date: 2009-01-09 Impact factor: 4.530
Authors: Patrick A Randall; Christie A Lee; Samantha J Podurgiel; Evan Hart; Samantha E Yohn; Myles Jones; Margaret Rowland; Laura López-Cruz; Mercè Correa; John D Salamone Journal: Int J Neuropsychopharmacol Date: 2014-10-31 Impact factor: 5.176
Authors: John D Salamone; Mercè Correa; Sarah Ferrigno; Jen-Hau Yang; Renee A Rotolo; Rose E Presby Journal: Pharmacol Rev Date: 2018-10 Impact factor: 25.468