Rapid sensitization of physiological, neuronal, and locomotor effects of nicotine: critical role of peripheral drug actions.

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.

Fluctuations in central and peripheral temperatures induced by intravenous nicotine: central and peripheral contributions.

Nicotine (NIC) is a highly addictive substance that interacts with different subtypes of nicotinic acetylcholine receptors widely distributed in the central and peripheral nervous systems. While the direct action of NIC on central neurons appears to be essential for its reinforcing properties, the role of peripheral actions of this drug remains a matter of controversy. In this study, we examined changes in locomotor activity and temperature fluctuations in the brain (nucleus accumbens and ventral tegmental area), temporal muscle, and skin induced by intravenous (iv) NIC at low human-relevant doses (10 and 30µg/kg) in freely moving rats. These effects were compared to those induced by social interaction, an arousing procedure that induces behavioral activation and temperature responses via pure neural mechanisms, and iv injections of a peripherally acting NIC analog, NIC pyrrolidine methiodide (NIC-PM) used at equimolar doses. We found that NIC at 30µg/kg induces a modest locomotor activation, rapid and strong decrease in skin temperature, and weak increases in brain and muscle temperature. While these effects were qualitatively similar to those induced by social interaction, they were much weaker and showed a tendency to increase with repeated drug administrations. In contrast, NIC-PM did not affect locomotion and induced much weaker than NIC increases in brain and muscle temperatures and decreases in skin temperature; these effects showed a tendency to be weaker with repeated drug administrations. Our data indicate that NIC's actions in the brain are essential to induce locomotor activation and brain and body hyperthermic responses. However, rapid peripheral action of NIC on sensory afferents could be an important factor in triggering its central effects, contributing to neural and physiological activation following repeated drug use.

Fluctuations in brain temperature induced by lipopolysaccharides: central and peripheral contributions.

In this study, we examined changes in central (anterior-preoptic hypothalamus) and peripheral (temporal muscle and facial skin) temperatures in freely moving rats following intravenous administration of bacterial lipopolysaccharides (LPS) at low doses (1 and 10 µg/kg) at thermoneutral conditions (28°C). Recordings were made with high temporal resolution (5-s bin) and the effects of LPS were compared with those induced by a tail-pinch, a standard arousing somato-sensory stimulus. At each dose, LPS moderately elevated brain, muscle, and skin temperatures. In contrast to rapid, monophasic and relatively short hyperthermic responses induced by a tail-pinch, LPS-induced increases in brain and muscle temperatures occurred with ~40 min onset latencies, showed three not clearly defined phases, were slightly larger with the 10 µm/kg dose, and maintained for the entire 4-hour post-injection recording duration. Based on dynamics of brain-muscle and skin-muscle temperature differentials, it appears that the hyperthermic response induced by LPS at the lowest dose originates from enhanced peripheral heat production, with no evidence of brain metabolic activation and skin vasoconstriction. While peripheral heat production also appears to determine the first phase of brain and body temperature elevation with LPS at 10 µg/kg, a further prolonged increase in brain-muscle differentials (onset at ~100 min) suggests metabolic brain activation as a factor contributing to brain and body hyperthermia. At this dose, skin temperature increase was weaker than in temporal muscle, suggesting vasoconstriction as another contributor to brain/body hyperthermia. Therefore, although both LPS at low doses and salient sensory stimuli moderately increase brain and body temperatures, these hyperthermic responses have important qualitative differences, reflecting unique underlying mechanisms.