Hippocampal neurotrophin and trk receptor mRNA levels are altered by local administration of nicotine, carbachol and pilocarpine.
Cholinergic receptor agonists nicotine (nicotinic), carbachol (nicotinic/muscarinic) and pilocarpine (muscarinic) were administered into the hippocampus and mRNA levels of neurotrophins and their receptors determined using in situ hybridisation. Drug doses were carefully chosen to avoid the potentially confounding effects of seizure and cell death. Nicotine caused a long-lasting increase in nerve growth factor (NGF) mRNA in all subfields of the hippocampus. The increase was evident from 24 h up to 72 h after drug administration. This increase was dependent on excitatory amino acid neurotransmission as it was blocked by administration of an AMPA or NMDA receptor antagonist. In contrast, carbachol and pilocarpine produced a transient increase in NGF mRNA levels present 4-8 h after drug administration. Pilocarpine caused a transient increase in hippocampal brain-derived neurotrophic factor (BDNF) levels, with carbachol and nicotine showing the same trend. Nicotine and carbachol caused transient decreases in NT-3 mRNA levels in dentate gyrus and CA2 with pilocarpine showing a similar trend. Increases in mRNA encoding full-length trkB were seen 8 h after nicotine, with nicotine also causing elevations in a mRNA encoding a truncated isoform (trkB.T2). TrkC mRNA was not altered by any of the conditions used. The study suggests that muscarinic and nicotinic receptor activation in the hippocampus causes transient changes in all of the neurotrophins, but that NGF levels are selectively up-regulated by nicotinic receptor stimulation. The reciprocal interaction between NGF and ascending cholinergic systems may be a component of the cognitive enhancing effects of nicotine.
French
S J
SJ
Biochemical Neuropharmacology Group, Neuroscience Research Centre and Division of Biochemistry and Molecular Biology, GKT School of Biomedical Sciences, Guy's Hospital Campus, London SE1 9RT, UK.
Humby
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T
Horner
C H
CH
Sofroniew
M V
MV
Rattray
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M
D000109:Acetylcholine / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002217:Carbachol / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D018679:Cholinergic Agonists / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000737:chemistry / Q000502:physiology; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology; D017403:In Situ Hybridization; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000235:genetics*; D018696:Neuroprotective Agents / Q000378:metabolism; D020933:Neurotrophin 3; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010862:Pilocarpine / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D012686:Septal Nuclei / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D018679:Cholinergic Agonists; D018721:Muscarinic Agonists; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D018722:Nicotinic Agonists; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D010862:Pilocarpine; D018698:Glutamic Acid; D009538:Nicotine; D002217:Carbachol; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020812:Receptor, trkC; D000109:Acetylcholine