Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictions.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in different brain regions that include the ventral tegmental area (VTA), nucleus accumbens (NAc), hippocampus, prefrontal cortex (PFC), and amygdala. Activation of nAChRs in these brain areas significantly contribute to the rewarding effects of ethanol and nicotine and play a role in modulating synaptic plasticity. GABAergic (red), glutamatergic (green), and dopaminergic (blue) connections between these structures constitute a major neural circuitry underlying addictive disorders.

Schematic representation of nAChR subtypes and circuit function in the mesolimbic dopaminergic system. (A) Pyramidal cells in layer V of the PFC lack nAChRs but their activity is modulated by excitatory and inhibitory neurons that do express them. There are two types of GABAergic interneurons, fast spiking and non-fast spiking, with only the latter bearing nAChRs (α7 and α4β2*). Distinct populations of glutamatergic inputs express either α7 or α4β2* nAChRs while DA terminals projecting from the VTA contain α4β2* nAChRs. Cholinergic inputs into the PFC arise from the nucleus basalis of Meynert (nBM). (B) In the NAc, nAChRs (α4β2*, α6β2*, and α6α4β2*) expressed on DAergic terminals from the VTA mediate DA release based on the neuronal activity firing rate. A small population of tonically active cholinergic interneurons (~2%) is synchronized with DA cell firing. Glutamatergic inputs from the PFC endow α7 nAChRs. (C) The VTA receives cholinergic innervation from the pedunculopontine (PPn) and laterodorsal tegmental nuclei (LDTn). In addition to the nAChRs localized on DA cell bodies, DAergic cell firing is modulated by α4β2* (and possibly α7) nAChRs expressed on GABAergic interneurons and excitatory glutamatergic afferents from the PFC and the PPn.

Schematic representation of nAChR subtypes and circuit function in the hippocampus and amygdala. (A) In the hippocampus, α7 and α4β2* nAChRs are abundantly expressed on pyramidal cells and inhibitory interneurons. GABAergic interneurons have pre-synaptic α7 nAChRs and somato-dendritic expression of α7 and α4β2* nAChRs. Glutamatergic afferents have predominately pre-synaptic α7 nAChRs and only low levels of α3β4*. (B) In the amygdala, cholinergic inputs from the basal forebrain synapse in proximity to pre-synaptic nAChRs that modulate both excitatory and inhibitory synaptic transmission. Glutamatergic afferents and pyramidal neurons endow α7 nAChRs and GABAergic interneurons express multiple nAChRs (α7, α4β2*, and α3β4*).