Despite the smaller ratio of nicotinic to muscarinic receptors, nicotine and lobeline (Figure 7–3) have important effects on the brain stem and cortex. Activation of nicotinic receptors occurs at presynaptic and postsynaptic loci. Presynaptic nicotinic receptors allow acetylcholine and nicotine to regulate the release of several neurotransmitters (glutamate, serotonin, GABA, dopamine, and norepinephrine). Acetylcholine regulates norepinephrine release via α3β4 nicotinic receptors in the hippocampus and inhibits acetylcholine release from neurons in the hippocampus and cortex. The α4β2 oligomer is the most abundant nicotinic receptor in the brain. Chronic exposure to nicotine has a dual effect at nicotinic receptors: activation (depolarization) followed by desensitization. The former effect is associated with greater release of dopamine in the mesolimbic system of humans. This effect is thought to contribute to the mild alerting action and the addictive property of nicotine absorbed from tobacco. When the β2 subunits are deleted in reconstitution experiments, acetylcholine binding is reduced, as is the release of dopamine. The later desensitization of the nicotinic receptor is accompanied by increased high-affinity agonist binding and an upregulation of nicotinic binding sites, especially those of the α4β2 oligomer. Sustained desensitization may contribute to the benefits of nicotine replacement therapy in smoking cessation regimens. In high concentrations, nicotine induces tremor, emesis, and stimulation of the respiratory center. At still higher levels, nicotine causes convulsions, which may terminate in fatal coma. The lethal effects on the central nervous system and the fact that nicotine is readily absorbed form the basis for the use of nicotine and derivatives (neonicotinoids) as insecticides.
The α7 subtype of nicotinic receptors (α7 nAChR) is detected in the central and peripheral nervous systems where it may function in cognition and pain perception. This nicotinic receptor subtype is a homomeric pentamer (α7)5 having five agonist binding sites at the interfaces of the subunits. Positive allosteric modulators (see Chapter 1) of the α7 receptor are being developed with a view to improving cognitive function in the treatment of schizophrenia.
The presence of α7 nAChR on nonneuronal cells of the immune system has been suggested as a basis of anti-inflammatory actions. Acetylcholine or nicotine reduces the release of inflammatory cytokines via α7 nAChR on macrophages and other cytokine-producing cells. In human volunteers, transdermal nicotine reduced markers of inflammation caused by lipopolysaccharide. The anti-inflammatory role of α7 nAChR has gained support from such data.
8. Peripheral nervous system—Autonomic ganglia are important sites of nicotinic synaptic action. The α3 subtype is found in autonomic ganglia and is responsible for fast excitatory transmission. Beta2 and β4 subunits are usually present with the α3 subunit to form heteromeric subtypes in parasympathetic and sympathetic ganglia and in the adrenal medulla. Nicotinic agents cause marked activation of these nicotinic receptors and initiate action potentials in postganglionic neurons (see Figure 6–8). Nicotine itself has a somewhat greater affinity for neuronal than for skeletal muscle nicotinic receptors.