Nicotine reverses consolidated long-term potentiation in the hippocampal CA1 region.
Long-term potentiation (LTP) has a memory-like consolidation period during which it becomes progressively stabilized. However, it is unknown how the consolidation is achieved. The present study demonstrates that nicotine reverses stabilized LTP in the hippocampal CA1 region, providing the first evidence that consolidated LTP can be reversed. The nicotine-induced reversal appeared to work by reversing cellular processes involved in stabilizing LTP, as LTP was readily induced again after reversal. The effect of nicotine was mediated, in large part, via desensitization of alpha7 nicotinic acetylcholine receptors (nAChRs), as an alpha7 nAChR-selective antagonist mimicked the nicotine effect. A non-selective N-methyl-d-aspartate receptor (NMDAR) antagonist completely abolished the nicotine-induced reversal, whereas an NR2B-containing NMDAR-selective antagonist had no effect. Furthermore, both the protein phosphatase 1/protein phosphatase 2A inhibitor okadaic acid and the protein phosphatase 2B (calcineurin) inhibitor cyclosporin A blocked the nicotine-induced reversal. Taken together, our results suggest that the reversal of stabilized LTP depends on the activation of NR2A-containing NMDARs and dephosphorylation. Thus, the consolidation of LTP appears to be the interruption of signaling leading to NR2A-containing NMDAR-dependent activation of protein phosphatases, which can be circumvented by nicotine-induced signaling. LTP induced in chronic nicotine-treated hippocampi contained a component that is immune to reversal, and thus acute nicotine was no longer effective to reverse consolidated LTP. These results demonstrate the differential effects of acute and chronic nicotine exposure on the cellular processes that are potentially involved in learning and memory.
Guan
Xin
X
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA.
Nakauchi
Sakura
S
Sumikawa
Katumi
K
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C084934:1-norokadaone; D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010080:Oxazoles; D019319:Okadaic Acid; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; D009538:Nicotine; D000157:Aconitine