Hypocretin mechanisms in nicotine addiction: evidence and speculation

The hypocretin/orexin system has been implicated in arousal mechanisms, sleep, and sleep disorders, including narcolepsy, and more recently in drug addiction. Theoretically, hypocretin (hcrt) mechanisms appear to be potential substrates for nicotine addiction: arousal and attentional mechanisms influence use and withdrawal symptoms, and hcrt systems overlap anatomically with a number of brain regions associated with nicotine addiction. This review summarizes the studies that have examined hcrt mechanisms in the effects of nicotine and describes hcrt innervation of, and effects in, several brain regions implicated in nicotine addiction. The review speculates on the possible mechanisms by which hcrt may contribute to nicotine addiction in these regions, with the objective of encouraging research in this area. In a small literature, both experimenter-administered and self-administered nicotine have been shown to elicit or depend on hcrt signaling. However, although untested in experimental designs, there is compelling evidence that hcrt mechanisms in the ventral tegmental area, the pontine region, thalamocortical circuits, the prefrontal cortex, and the amygdala could have a broad influence on nicotine addiction. Evidence reviewed leads to the conclusion that hcrt mechanisms could mediate several dimensions of nicotine addiction, including a multi-faceted regulation of mesocorticolimbic dopaminergic function, but beyond dopaminergic mechanisms, hcrt could influence nicotine use and relapse during abstinence through broadly based arousal/attentional effects. These speculative ideas need to be examined experimentally; the potential gains are a more thorough understanding of the pathophysiology of nicotine addiction, and the discovery of novel targets for the development of pharmacotherapeutics.