Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness.
It has previously been shown that the reinforcing and dependence-producing properties of nicotine depend to a great extent on activation of nicotinic receptors within the ventral tegmental area (VTA), i.e. the site of origin of the mesolimbocortical dopaminergic projection. Based on the data reviewed in the present study, it is suggested that nicotine by stimulating presynaptic alpha7 nicotinic receptors within the VTA, that are probably localized on glutamatergic afferents from the medial prefrontal cortex, produces sequentially an increase in glutamate concentrations, stimulation of NMDA receptors found on dopamine (DA)-containing neurons in the VTA, enhanced firing activity of VTA-DA neurons, augmented DA release in the nerve terminal regions, and enhanced c-fos expression in the dopaminergic projection areas through activation of D1-DA receptors. In addition, it appears that alpha7 nicotinic receptors within the VTA are directly involved in nicotine-related reward and withdrawal responses. These data may be instrumental in understanding how nicotine interacts with the mesolimbocortical dopaminergic system, which is perhaps the most important component of the neural mechanisms underlying nicotine dependence. These results may also contribute to unraveling the cellular basis of nicotine's association with neuropsychiatric disorders, thereby offering the prospect of new therapeutic advances for their treatment.
Nomikos
G G
GG
Eli Lilly & Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN 46285-0510, USA. gnomikos@lilly.com
Schilström
B
B
Hildebrand
B E
BE
Panagis
G
G
Grenhoff
J
J
Svensson
T H
TH
D000818:Animals; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D004298:Dopamine / Q000502:physiology; D006801:Humans; D009042:Motivation; D011978:Receptors, Nicotinic / Q000502:physiology*; D012559:Schizophrenia / Q000503:physiopathology*; D014029:Tobacco Use Disorder / Q000503:physiopathology*; D017557:Ventral Tegmental Area / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004298:Dopamine