Nicotinic Receptors and Schizophrenia

Nadège Ripoll; Marie Bronnec; Michel Bourin


Curr Med Res Opin. 2004;20(7) 

In This Article

Nicotinic Receptors

Nicotinic receptors belong to the superfamily of polymeric transmembrane channel receptors.[40] In addition to nicotinic receptors, this family comprises gamma-aminobutyric acid A (GABAA) receptors, 5-HT3 serotonin receptors, glycine receptors and excitatory amino acid receptors.[40,41,42,43,44] The study of recombinant nicotinic receptors expressed by Xenopus oocytes showed that the functional receptors are pentameric, glycoprotein, homo- or hetero-oligomers.[42,45] the 5 polypeptide subunits are organized around an ion channel constituting a pseudo axis of symmetry.[46,47,48] On the basis of the combined results of analysis of the amino acid sequence of the subunits, and the physiological and pharmacological properties of receptors, nicotinic receptors can be classified into three subfamilies.[49] The first subfamily comprises nicotinic receptors of skeletal muscles (composed of α1, β1, γ, δ and ε subunits) and the electrical organ of torpedo fish (Torpedo californica), composed of α1, β1, γ1 and δ1 subunits in the foetal form and α1, β1, ε and δ1 subunits in the mature form. These nicotinic receptors are selectively recognized and blocked by α-bungarotoxin (α-Bgtx), a toxin isolated from cobra venom. The two other subfamilies correspond to neuronal nicotinic receptors.[49] The first subfamily comprises hetero-oligomeric nicotinic receptors composed of various combinations of α2, α4 and α6 subunits and β2 or β4 subunits and, more rarely, α5 and α3 subunits. The second subfamily comprises homo-oligomeric nicotinic receptors composed of α7, α8 or α9 subunits.[49] The genes for the various subunits are carried on different chromosomes. At the present time, seventeen genes, all derived from a common ancestor, have been cloned in vertebrates.[50] The existence of genetic variants and polymorphisms constitutes another source of heterogeneity of nicotinic receptors.[51,52,53]

The expression of nicotinic receptors varies according to age and the stage of neuronal development.[54] Increased expression of nicotinic receptors coincides with the period of formation of presynaptic and postsynaptic connections in neurons of the central and peripheral nervous system.[55,56,57] Almost all of the mammalian brain is innervated by the cholinergic system, but a relatively small number of cholinergic neurons innervate the various cerebral areas.[58,59] Among the numerous subtypes of nicotinic receptors expressed in mammalian brain, the α4, β2 and α7 subtypes are the most frequent.[60,61,62,63,64,65,66] The distribution of subunits in the brain varies according to the species; for example, the distribution of α3 subunits is different in man and rodents.[61,67,68] In Human, nicotinic receptors compounds of α4 β2 and α7 subunits are essentially localized in the cortex, thalamus, hippocampus and cerebellum.[69] The various subunits present in the cortex are unequally distributed among the various layers.[70] One class of receptors is often predominant in a given cerebral region.[71] High levels of nicotine binding and mRNA of α3, α4 and β2 subunits have been demonstrated in the human corpus striatum.[72,73] High levels of α7 subunit mRNA and binding to α-Bgtx have been demonstrated in reticular nuclei of the thalamus, lateral and medial geniculate bodies, basal pontine nucleus, Broca's diagonal band, Meynert's basal nucleus and the inferior olivary nucleus.[74]( Table 1 ). Receptors composed of α4and β2 subunits are essentially located in the thalamus, hippocampus, substantia nigra, striatum, cerebral cortex and cerebellum.[75]( Table 1 ). Neurons also express different classes of receptors inducing various types of responses.[76] In rodents, α4, α7 and β2 subunits are present in most regions of the CNS.[60,61,65] The α7 subunits are predominantly observed in the rat hippocampus.[77,78,79,80] They are located on cholinergic and non-cholinergic presynaptic terminals,[44] such as GABAergic interneurons[81] α4β2 receptors are located on presynaptic and postsynaptic terminals of GABAergic interneurons.[78]

Postsynaptic nicotinic receptors located in the hippocampus and cortex participate in the modulation of cognitive functions by controlling ganglionic and fast cholinergic transmission of these cerebral regions.[82] Presynaptic receptors play an important physiological role by controlling neurotransmitter release. Stimulation of nicotinic receptors influences eye movements, produces a state of euphoria, decreases fatigue and anxiety, has a central analgesic action,[83,84,85] and controls locomotor activity and body temperature.[69] They also control a large number of cognitive functions, such as attention, learning, sensory perception, memory consolidation and arousal.[85,86,87,88,89,90,91,92,93] The beneficial effect of nicotine on attention tests was demonstrated in patients with Alzheimer's disease [94,95] and attention deficit hyperactivity disorder.[96,97] Nicotine and nicotinic agonists improve attention performances not only in man, but also in rodents[98,99,100,101] and primates.[102,103] According to the study by Grottick et al.,[104] the effect of nicotine on attention is mediated by α4β2 receptors. Other studies have also demonstrated the role of α7 receptors in sensory processes, such as auditory sensitivity.[105,106,107,108]

Nicotinic receptors involved in cognitive functions are likely to be located in the hippocampus.[109] Nicotinic receptors can modulate the rhythmic activity of the hippocampus and other cerebral regions.[110] This stimulation is important for synaptic plasticity, the basis for learning and memory.[111] Nicotine improves memorization performances[112,113,114] and learning[89] in rats. This effect is also observed in man[115,116] and monkeys.[117] α7 and α4β2 receptors appear to play an important role in memory processes.[118,119,120,121,122] Nicotinic receptors are also involved in neuronal survival and in the regulation of pineal function.[123] Nicotinic stimulation of hippocampal cell cultures activates CREB (a transcription factor) and leads to the expression of genes essential for neuronal development and plasticity.[124,125] Nicotinic receptors therefore appear to play an important role during neuronal development and plasticity.[43,126] Various studies suggest a neuroprotective effect of nicotine in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.[127,128,129,130] Studies have shown that nicotine protects nigrostriatal dopaminergic neurons from degeneration.[127,131] Elderly β2 knockout mice present hypotrophy of the neocortex, loss of neurons in the hippocampus and astrogliosis and microgliosis.[132] These pathophysiological disorders are associated with impaired spatial learning.[132] Nicotine and GTS-21, an α7 receptor agonist, also exert a protective role against the neuropathological modifications induce by administration of either glutamate to neocortical neurons[133] or NGF associated with serum deprivation in PC12 cell cultures.[134] ABT-418, an α4β2 receptor agonist, exerts a neuroprotective effect against glutamate-induced neurotoxicity.[135] The protection of cortical neurons from the cytotoxicity of glutamate is abolished by administration of α7 receptor antagonists[134,135] protein kinase C[134] and by the absence of extracellular Ca2+.[135]