Cholinergic innervation is widespread throughout the brain innervating nearly every neural zone. Many cholinergic projections do not terminate at synapses, but rather nonsynaptically where they contribute to diffuse volume transmission (Dani and Bertrand 2007). This could be the case for most hippocampal and cortical projections

(Descarries et al. 1997), and would be similar to the action of other neurotransmitters including serotonin, dopamine, and noradrenaline (Vizi et al. 2010). Inhibitors,research,lifescience,medical What differentiates cholinergic transmission from these other neurotransmitters is that movement of acetylcholine (ACh) is via diffusion that is limited by acetylcholinesterase hydrolysis and not a reuptake pump (Dani and Bertrand 2007). Differently located nAChRs appear to exert different effects. Unlike in the periphery, where nAChR activation underpins fast neurotransmission at neuromuscular junctions, the role of fast transmission appears limited centrally although Inhibitors,research,lifescience,medical recent results suggest a possible role in hippocampal pyramidal neurons (Grybko et al. 2011). Many

studies have CP-868596 ic50 identified a role for nAChRs in modulating neurotransmitter concentrations, with activation of presynaptic nAChRs known to enhance release of neurotransmitters acetylcholine, dopamine, noradrenaline, serotonin, glutamate, Inhibitors,research,lifescience,medical and gamma-aminobutyric acid (GABA) (Dani and Bertrand 2007). This appears to be consequence of facilitating

increasing concentration of intracellular Ca2+ through augmenting calcium influx and altering activity of voltage-gated Ca2+ channels within the terminal. Alterations in multiple Inhibitors,research,lifescience,medical receptor regulated intracellular Ca2+ pathways are linked to mood and anxiety disorders (Plein and Berk 1999, 2001; Berk et al. 2001). Numerous investigations have explored how activation of nAChRs by nicotine can exert effects on mood and anxiety symptoms. Nicotine can lead Inhibitors,research,lifescience,medical to both anxiogenic and anxiolytic effects that appear to depend upon the animal strain, medroxyprogesterone dosing regimen, and experimental paradigm utilized. Exposure to nicotine in rat models leads to upregulation of nAChRs (Slotkin 2004) that is shortly followed by desensitization as exposure is continued. Activation of nAChRs, particularly the α4β2 and α7 subtypes, appears to enhance release of serotonin in several brain regions, including the dorsal raphe nucleus (Reuben and Clarke 2000; Ma et al. 2005). Interestingly, α4β2 receptor knockout mice demonstrate an increase in basal anxiety (Ross et al. 2000), suggesting a role for these receptors in anxiety regulation. These receptors also upregulate dopamine and noradrenergic neurons (Lichtensteiger et al. 1988), with these effects likely important in mediating the anxiolytic effects of nicotine (McGranahan et al. 2011).