A major factor in the perpetuation of tobacco smoking addiction is the increased salience of environmental cues that stimulate the desire to smoke. Nicotine induced desensitization of B2 containing Ach receptors on both GABA presynaptic terminals in the VTA and Da terminals in the nucleus accumbens has the effect of decreasing tonic Da release and increasing phasic Da release in the nucleus accumbens. This is a possible mechanism by which nicotine increases salience of environmental cues, which in turn perpetuates the smoking cycle.

• Nicotine Increases Phasic Firing of Dopamine Cells in the VTA and Decreases Tonic Release and Increases Phasic Release of Dopamine in the Nucleus Accumbens, This Can Result in Increased Salience of Environmental Cues
• 1, At baseline without nicotine, acetylcholine (Ach) from cholinergic brain stem nuclei is released in the ventral tegmental area (VTA) where it supports both tonic and phasic dopamine (Da) cell firing. This involves both the regulation of increased Da cell excitability from Ach acting on homomeric α7 Ach receptors on presynaptic terminals of glutamatergic synapses to increase glutamate (Glu) release and the regulation of decreased Da cell excitability from Ach acting on B2 containing Ach receptors on presynaptic terminals of gamma amino butyric acid (GABA) synapses to increase GABA release. There are also direct effects of Ach increasing Da cell excitability through Ach receptors on Da cells.
• 2. In the nucleus accumbens Ach interneurons release Ach onto Ach receptors located on terminals of Da neurons, which allows tonic firing of Da cells to produce significant Da release.
• 3. Nicotine exposure increases Da cell firing in part due to glutamate release, which is regulated by α7 Ach receptors that do not desensitize. The B2 containing Ach receptors on GABA presynaptic terminals desensitize following nicotine, which reduces GABA release, which can increase Da cell firing.
• 4. In the nucleus accumbens the nicotine induced desensitization of B2 containing receptors on Da terminals decreases the effect of tonic firing to increase Da release but maintains the effect of phasic firing to stimulate Da release.
• 5. Thus, nicotine by decreasing tonic DA release and increasing phasic DA release increases the relative effectiveness of phasic firing which produces the increased salience of environmental cues.
• * = other subunits may be present(Constructed from data reviewed and presented in Picciotto, M.R. et al. Progress in Neurobiology, 84: 329 - 342, 2008) ©2011 NBEP