Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling.
Recent reports have shown that the selective dopamine D(1)-like agonist SKF 83822 [which stimulates adenylate cyclase, but not phospholipase C] induces prominent behavioral seizures in mice, whereas its benzazepine congener SKF 83959 [which stimulates phospholipase C, but not adenylate cyclase] does not. To investigate the relative involvement of D(1) vs D(5) receptors in mediating seizures, ethological behavioral topography and cortical EEGs were recorded in D(1), D(5) and DARPP-32 knockout mice in response to a convulsant dose of SKF 83822. SKF 83822-induced behavioral and EEG seizures were gene dose-dependently abolished in D(1) knockouts. In both heterozygous and homozygous D(5) knockouts, the latency to first seizure was significantly increased and total EEG seizures were reduced relative to wild-types. The majority (60%) of homozygous DARPP-32 knockouts did not have seizures; of those having seizures (40%), the latency to first seizure was significantly increased and the number of high amplitude, high frequency polyspike EEG events was reduced. In addition, immunoblotting was performed to investigate downstream intracellular signalling mechanisms at D(1)-like receptors following challenge with SKF 83822 and SKF 83959. In wild-types administered SKF 83822, levels of ERK1/2 and GluR1 AMPA receptor phosphorylation increased two-fold in both the striatum and hippocampus; in striatal slices DARPP-32 phosphorylation at Thr34 increased five-fold relative to vehicle-treated controls. These findings indicate that D(1), and to a lesser extent D(5), receptor coupling to DARPP-32, ERK1/2 and glutamatergic signalling is involved in mediating the convulsant effects of SKF 83822.
O'Sullivan
Gerard J
GJ
Molecular & Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Dunleavy
Mark
M
Hakansson
Kerstin
K
Clementi
Mario
M
Kinsella
Anthony
A
Croke
David T
DT
Drago
John
J
Fienberg
Allen A
AA
Greengard
Paul
P
Sibley
David R
DR
Fisone
Gilberto
G
Henshall
David C
DC
Waddington
John L
JL
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000502:physiology*; D050641:Receptors, Dopamine D5 / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013912:Threonine / Q000378:metabolism; D013997:Time Factors
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D001552:Benzazepines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D048052:Mitogen-Activated Protein Kinase 3; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D013912:Threonine; C494644:3-allyl-6-chloro-7,8-dihydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; C497929:Ppp1r1b protein, mouse; C080703:SK&F 83959