title: Impaired cognition after stimulation of P2Y1 receptors in the rat medial prefrontal cortex.
abstract: We hypothesize that cortical ATP and ADP accumulating in the extracellular space, eg during prolonged network activity, contribute to a decline in cognitive performance in particular via stimulation of the G protein-coupled P2Y1 receptor (P2Y1R) subtype. Here, we report first evidence on P2Y1R-mediated control of cognitive functioning in rats using bilateral microinfusions of the selective agonist MRS2365 into medial prefrontal cortex (mPFC). MRS2365 attenuated prepulse inhibition of the acoustic startle reflex while having no impact on startle amplitude. Stimulation of P2Y1Rs deteriorated performance accuracy in the delayed non-matching to position task in a delay dependent manner and increased the rate of magazine entries consistent with both working memory disturbances and impaired impulse control. Further, MRS2365 significantly impaired performance in the reversal learning task. These effects might be related to MRS2365-evoked increase of dopamine observed by microdialysis to be short-lasting in mPFC and long-lasting in the nucleus accumbens. P2Y1Rs were identified on pyramidal cells and parvalbumin-positive interneurons, but not on tyrosine hydroxylase-positive fibers, which argues for an indirect activation of dopaminergic afferents in the cortex by MRS2365. Collectively, these results suggest that activation of P2Y1Rs in the mPFC impairs inhibitory control and behavioral flexibility mediated by increased mesocorticolimbic activity and local disinhibition.
authors.affiliation: 1] Rudolf-Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstrasse 16-18, Leipzig, Germany [2] Translational Centre for Regenerative Medicine (TRM) Leipzig, University of Leipzig, Philipp-Rosenthal-Strasse 55, Leipzig, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Koch
authors.affiliation: AbbVie, Neuroscience Research, Knollstrasse 50, Ludwigshafen, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Bespalov
authors.affiliation: AbbVie, Neuroscience Research, Knollstrasse 50, Ludwigshafen, Germany.
authors.forename: Karla
authors.initials: K
authors.lastname: Drescher
authors.affiliation: Rudolf-Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstrasse 16-18, Leipzig, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Franke
authors.affiliation: Rudolf-Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstrasse 16-18, Leipzig, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Krügel
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D007175:Impulsive Behavior / Q000187:drug effects* / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C511689:(N)-methanocarba-2MeSADP; D010320:Parvalbumins; D058912:Purinergic P2Y Receptor Agonists; D058472:Receptors, Purinergic P2Y1; D000244:Adenosine Diphosphate; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine