title: Critical role of peripheral actions of intravenous nicotine in mediating its central effects.
abstract: In addition to its direct action on central neurons, nicotine (NIC) activates multiple nicotinic acetylcholine receptors localized on afferent terminals of sensory nerves at the sites of its administration. Although the activation of these receptors is important in mediating the primary sensory and cardiovascular effects of NIC, their role in triggering and maintaining the neural effects of NIC remains unclear. Using high-speed electroencephalography (EEG) and electromyography (EMG) recordings in freely moving rats, we showed that NIC at low intravenous (i.v.) doses (10-30 μg/kg) induced rapid, strong, and prolonged EEG desynchronization both in the cortex and ventral tegmental area (with decreases in α and robust increases in β and γ frequencies) and neck EMG activation that began during the injection (∼5 s). EEG and EMG effects of NIC were drastically reduced by pre-treatment with hexamethonium, a peripherally acting NIC antagonist, and the immediate EEG effects of NIC were strongly inhibited during urethane anesthesia. Although NIC pyrrolidine methiodide, a quaternary NIC analog that cannot enter the brain, also induced rapid EEG desynchronization, its effects were much shorter and weaker than those of NIC. Therefore, NIC by acting on peripheral nicotinic receptors provides a major contribution to its rapid, excitatory effects following i.v. administration. Since this action creates a sensory signal that rapidly reaches the brain via neural pathways and precedes the slower and more prolonged direct actions of NIC on brain cells, it could have a major role in associative learning and changes in the behavioral and physiological effects of NIC following its repeated use.
authors.affiliation: In-vivo Electrophysiology Unit, Behavioral Neuroscience Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Magalie
authors.initials: M
authors.lastname: Lenoir
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Kiyatkin
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D004569:Electroencephalography / Q000187:drug effects*; D004576:Electromyography / Q000187:drug effects* / Q000379:methods; D007275:Injections, Intravenous; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage* / Q000633:toxicity; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D011978:Receptors, Nicotinic / Q000378:metabolism
chemical_list: D011978:Receptors, Nicotinic; D009538:Nicotine