Ropinirole regulates emotionality and neuronal activity markers in the limbic forebrain.
Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompanied by emotional and cognitive deficits. Although D3/D2 receptor agonists are effective against motor and non-motor deficits in RLS and PD, the exact behavioral and neurochemical effects of these drugs are not clearly defined. This study aimed to evaluate the effects of acute ropinirole (0, 0.1, 1 or 10 mg/kg, i.p.), a preferential D3/D2 receptor agonist, on intracranial self-stimulation (ICSS), spontaneous motor activity, anxiety- and depression-like behaviors, spatial reference and working memory in rats as well as on certain markers of neuronal activity, i.e. induction of immediate early genes, such as c-fos and arc, and crucial phosphorylations on GluA1 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and NA1, NA2A and NA2B subunits of N-methyl-D-aspartate (NMDA) receptors. Ropinirole decreased ICSS thresholds and induced anxiolytic- and antidepressive-like effects without affecting motor activity or spatial memory. The effects on emotionality were associated with a decrease in p-Ser897-NA1 and an increase in p-Tyr1472-NA2B in the ventral striatum as well as an increased induction of c-fos messenger RNA (mRNA) in the prefrontal cortex (PFC) and decreased expression of arc mRNA in the striatum and the shell of the nucleus accumbens. Our data indicate that ropinirole significantly affects emotionality at doses (1-10 mg/kg, i.p.) that exert no robust effects on locomotion or cognition. The data reinforce the use of D3/D2 receptor agonists in the treatment of RLS and PD patients characterized by emotional deficits and suggest that altered NMDA-mediated neurotransmission in the limbic forebrain may underlie some of ropinirole's therapeutic actions.
Translational Neuropharmacology, Department of Clinical Neuroscience,Center for Molecular Medicine, Karolinska Institute,171 76 Stockholm,Sweden.
Maria
M
Mavrikaki
Translational Neuropharmacology, Department of Clinical Neuroscience,Center for Molecular Medicine, Karolinska Institute,171 76 Stockholm,Sweden.
Nicoletta
N
Schintu
Astellas Pharma Global Development, Inc.,Northbrook, Illinois 60062,USA.
George G
GG
Nomikos
Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Sciences,University of Crete,74100 Rethymno, Crete,Greece.
George
G
Panagis
Translational Neuropharmacology, Department of Clinical Neuroscience,Center for Molecular Medicine, Karolinska Institute,171 76 Stockholm,Sweden.
Per
P
Svenningsson
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects* / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects* / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012653:Self Stimulation / Q000187:drug effects / Q000502:physiology; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000188:drug therapy / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D003598:Cytoskeletal Proteins; D018491:Dopamine Agonists; D007211:Indoles; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D016194:Receptors, N-Methyl-D-Aspartate; C092069:activity regulated cytoskeletal-associated protein; C046649:ropinirole