title: D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus.
abstract: The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.
authors.affiliation: Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
authors.forename: Yan-You
authors.initials: YY
authors.lastname: Huang
authors.forename: Amir
authors.initials: A
authors.lastname: Levine
authors.forename: Denise B
authors.initials: DB
authors.lastname: Kandel
authors.forename: Deqi
authors.initials: D
authors.lastname: Yin
authors.forename: Luca
authors.initials: L
authors.lastname: Colnaghi
authors.forename: Bettina
authors.initials: B
authors.lastname: Drisaldi
authors.forename: Eric R
authors.initials: ER
authors.lastname: Kandel
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000187:drug effects / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D000077337:Vorinostat; D009538:Nicotine; D003042:Cocaine