title: Rapid sensitization of physiological, neuronal, and locomotor effects of nicotine: critical role of peripheral drug actions.
abstract: Repeated exposure to nicotine and other psychostimulant drugs produces persistent increases in their psychomotor and physiological effects (sensitization), a phenomenon related to the drugs' reinforcing properties and abuse potential. Here we examined the role of peripheral actions of nicotine in nicotine-induced sensitization of centrally mediated physiological parameters (brain, muscle, and skin temperatures), cortical and VTA EEG, neck EMG activity, and locomotion in freely moving rats. Repeated injections of intravenous nicotine (30 μg/kg) induced sensitization of the drug's effects on all these measures. In contrast, repeated injections of the peripherally acting analog of nicotine, nicotine pyrrolidine methiodide (nicotine(PM), 30 μg/kg, i.v.) resulted in habituation (tolerance) of the same physiological, neuronal, and behavioral measures. However, after repeated nicotine exposure, acute nicotine(PM) injections induced nicotine-like physiological responses: powerful cortical and VTA EEG desynchronization, EMG activation, a large brain temperature increase, but weaker hyperlocomotion. Additionally, both the acute locomotor response to nicotine and nicotine-induced locomotor sensitization were attenuated by blockade of peripheral nicotinic receptors by hexamethonium (3 mg/kg, i.v.). These data suggest that the peripheral actions of nicotine, which precede its direct central actions, serve as a conditioned interoceptive cue capable of eliciting nicotine-like physiological and neural responses after repeated nicotine exposure. Thus, by providing a neural signal to the CNS that is repeatedly paired with the direct central effects of nicotine, the drug's peripheral actions play a critical role in the development of nicotine-induced physiological, neural, and behavioral sensitization.
authors.affiliation: In-Vivo Electrophysiology Unit, Behavioral Neuroscience Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
authors.forename: Magalie
authors.initials: M
authors.lastname: Lenoir
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Tang
authors.forename: Amina S
authors.initials: AS
authors.lastname: Woods
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Kiyatkin
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004569:Electroencephalography; D004576:Electromyography; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology; D018738:Hexamethonium / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D020318:Rats, Long-Evans; D012867:Skin; D012879:Skin Physiological Phenomena / Q000187:drug effects; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D018738:Hexamethonium; D009538:Nicotine