Critical Role of Peripheral Actions of Intravenous Nicotine in Mediating Its Central Effects
Neuropsychopharmacol. 2011-06-08; 36(10): 2125-2138
DOI: 10.1038/npp.2011.104
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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.