Rapid sensitization of physiological, neuronal, and locomotor effects of nicotine: critical role of peripheral drug actions.
Journal of Neuroscience. 2013-06-12; 33(24): 9937-9949
DOI: 10.1523/JNEUROSCI.4940-12.2013
Lire sur PubMed
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.