D1/5 receptor-mediated enhancement of LTP requires PKA, Src family kinases, and NR2B-containing NMDARs.
The efficacy of the D1/5 agonist SKF38393 (100nM-60microM) to increase long-term potentiation (LTP) in the CA1 region was investigated in the rat hippocampal slice preparation. The receptor specificity of this enhancing effect was confirmed using the D1/5 antagonist SKF83566 (2microM). Although the ability of D1/5 receptors to increase both the persistence and the early magnitude of LTP has previously been linked to activation of the cAMP/PKA pathway, the subsequent molecular events leading to the enhancement of LTP have not been characterized. In experiments using SKF38393 (20microM), a requirement for the activation of both protein kinase A (PKA) and Src family tyrosine kinase pathways was demonstrated, as pretreatment with either H89 (10microM) or PP2 (10microM) kinase inhibitors prevented the D1/5-mediated enhancement of LTP. In addition, NMDA receptors containing the NR2B subunit were identified as a potential downstream target for this signaling pathway, as pretreatment with the selective antagonist Ro 25-6981 (1microM) also prevented the D1/5-mediated enhancement of LTP. The results identify a crucial role for NR2B-containing NMDA receptors in the modulation of LTP by D1/5-receptors in the CA1, suggesting that endogenously released dopamine may act through this mechanism as a modulator of hippocampal-dependent learning and memory tasks.
Stramiello
Michael
M
Department of Physiology & Pharmacology, University of Georgia, Athens, GA 30602-7389, USA.
Wagner
John J
JJ
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology*
D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; C120997:NR2A NMDA receptor; D010636:Phenols; D010880:Piperidines; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases