Nicotine addiction and nicotinic receptors: lessons from genetically modified mice

The contribution of different nicotinic acetylcholine (ACh) receptor (nAChR) oligomers to nicotine addiction is being explored in mice, using novel strategies including deletion of nAChR subunit genes or targeted knock-in gene mutations; re-expression of a deleted gene using stereotaxic injection of a lentiviral vector carrying the missing gene; repression of a wild-type gene using stereotaxic injection of the relevant small interfering RNA; and the quantitative analysis of the neuronal firing patterns and the behaviours elicited by nicotine in these mice.Spontaneous locomotor and cognitive behaviour is under the control of α4-containing (α4*), α6* and β2*nAChR activation by endogenous ACh, with a possible contribution of the β3 subunit.α4*, β2* and α6*nAChRs mediate the rewarding effects of nicotine, with a possible contribution of the α7 subunit.In addition to the β2 subunit, the α4 subunit (but not the α6 subunit) is required for the transition from tonic to phasic firing of dopaminergic neurons in the ventral tegmental area (VTA) that is crucial for reinforcement.α4 and α6 subunits are necessary for efficient dopamine release in the nucleus accumbens.There is evidence that, through activation of α4β2* and α7*nAChRs, acute nicotine exposure influences a global 'gating' circuit that includes the striatum, hippocampus and amygdala and is under top-down control of the prefrontal cortex.Several mechanisms may account for the sensitization of dopaminergic neurons in the VTA that occurs during long-term exposure to nicotine, including upregulation of nAChR expression, presynaptic compensation by α7-mediated cholinergic transmission, and a top-down increase in bursting activity of dopamine neuron activity in the VTA.Nicotine withdrawal syndromes mobilize brain circuits that are distinct from those involved in reward processing, with α2, α5, α6, α7 and β4 nAChR subunits regulating the expression of somatic symptoms, and β2 and α6 subunits contributing to affective symptoms.