D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus
- Yan-You Huang1,3,9,
- Amir Levine2,3,8,
- Denise B. Kandel2,3,4,
- Deqi Yin6,
- Luca Colnaghi1,6,
- Bettina Drisaldi1,7 and
- Eric R. Kandel1,2,3,5,6,9
- 1Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA
- 2Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA
- 3New York State Psychiatric Institute, New York, New York 10032, USA
- 4Mailman School of Public Health, Columbia University, New York, New York 10032, USA
- 5Kavli Institute for Brain Science, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA
- 6Howard Hughes Medical Institute, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA
- 7Italian Academy for Advanced Studies at Columbia University, New York, New York 10022, USA
- 8Center for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada
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.
Footnotes
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↵9 Corresponding authors
E-mail erk5{at}columbia.edu
E-mail yyh3{at}columbia.edu
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Freely available online through the Learning & Memory Open Access option.
- Received July 2, 2013.
- Accepted December 9, 2013.
This article, published in Learning & Memory, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
