Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction.
Many individuals with mental retardation exhibit chronic aberrant behaviors (CABs) that includes hyperactive, stereotyped, aggressive, and self-injurious behaviors. Brain imaging studies have found that several of these individuals have abnormalities in their dopaminergic neurotransmitter systems that are thought to be responsible in part, for the development of these behaviors. The present study evaluated the effects of a selective dopamine re-uptake blocker, GBR-12909 in three animal models of varying striatal dopamine concentrations. The three animal models included the neonatal 6-hydroxydopamine (6-OHDA)-lesioned rat, a model of dopamine neuronal depletion, the prenatal methylazoxymethanol (MAM)-exposed rat, a model of hyper-dopaminergic innervation and control rats, a model of normal dopaminergic function. The animals were given five daily injections of GBR-12909 and videotaped observations were conducted immediately following the injections and 6h later. The results of the study indicate that the MAM-treated rats exhibited more hyperactive behaviors than either the 6-OHDA or the control animals in response to the GBR-12909 injections. However, the 6-OHDA and control rats exhibited more self-injurious behaviors than the MAM rats. Interestingly, the topography of the self-injurious behavior exhibited differed from that we have previously observed in 6-OHDA lesioned rats following dopamine agonists and resembles the mouthing behaviors seen in some individuals with mental retardation, in particular those with Rett syndrome. These findings indicate the models of varying dopaminergic function interact differently with a dopamine re-uptake blocker than dopamine agonists and that the partially dopamine depleted model may model the behaviors seen in individuals with Rett syndrome.
Loupe
Pippa S
PS
Schiefelbusch Institute for Life Span Studies, University of Kansas, Lawrence 66045, USA. loupe@ku.edu
Bredemeier
Jonna D
JD
Schroeder
Stephen R
SR
Tessel
Richard E
RE
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002648:Child; D002658:Developmental Disabilities / Q000150:complications* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D001523:Mental Disorders / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D016728:Self-Injurious Behavior / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011954:Receptors, Dopamine; D012701:Serotonin; C043425:vanoxerine; D004298:Dopamine; D009638:Norepinephrine