COPI polices nicotine-mediated up-regulation of nicotinic receptors

49 C o m m e n t a r y Mayans, Aztecs, and indigenous Americans cultivated tobacco for medicinal and religious purposes well over 2,000 years ago. The subsequent trade and industrial-scale production of tobacco have led to its global recreational use with devastating health consequences. It is currently responsible for the greatest number of preventable deaths worldwide by any single agent, estimated to be 5 million per year by the Center for Disease Control and Prevention. The active ingredient of tobacco, nicotine, efficiently permeates the blood brain barrier and activates neuronal nicotinic acetylcholine receptors (nAChRs) in the brain. In addition, nicotine exposure of the brain during childhood and adolescence is likely to increase susceptibility to neuropsychiatric and addiction disorders. A multitude of distinct nAChR subtypes is formed by the assembly of 1–7, 9, and 1–4 subunits in mammals. These nAChR subtypes are expressed in different populations of neurons and other types of cells. The nAChRs most relevant to the study of nicotine addiction are expressed in dopaminergic, glutamatergic, and GABAergic neurons, where they modulate the probability of neurotransmitter release at presynaptic terminals (Wonnacott, 1997). Studies in rodents show that nicotine use affects various behaviors (Russo et al., 2010), including (a) impulse control and attention by modulating prefrontal cortex functions, (b) reward salience by modulating the ventral tegmental area (VTA)-striatum functions, and (c) aversive salience by modu lating the medial habenula-interpenducular nucleus functions. Multiple nAChR subtypes mediate nicotine's actions in the brain at the nanomolar concentrations found in smok-ers' serum. The 42 nAChRs in VTA projections to the nucleus accumbens (Picciotto et al., 1998; Tapper et al., 2004), the 6423 and 623 in substantia nigra pars compacta projections to the striatum (Quik et al., 2011), and the 354 and/or 452 in medial habenula projections to the interpeduncular nucleus (Fowler et al., 2011) collectively mediate nicotine's complex behavioral effects. These nAChRs exhibit different channel kinetics, rates of desensitization, and affinities for the endogenous neurotransmitter, acetylcholine, and nicotine. Nicotine exposure, unlike exposure to most other drugs of abuse, results in the " up-regulation " of its cognate nAChRs mediated by an increase in their abundance at the cell surface membrane in human, rodent, and are up-regulated when nAChR-expressing cells are exposed to nanomolar nicotine concentrations as found in smokers' brains. In rodent brains, up-regulation appears to be a posttranscriptional effect: mRNA for neither the 4 nor the 2 nAChR subunits change …