Cognitive deficits in schizophrenia: focus on neuronal nicotinic acetylcholine receptors and smoking

Abstract

Patients with schizophrenia present with deficits in specific areas of cognition. These are quantifiable by neuropsychological testing and can be clinically observable as negative signs. Concomitantly, they self-administer nicotine in the form of cigarette smoking. Nicotine dependence is more prevalent in this patient population when compared to other psychiatric conditions or to non-mentally ill people. The target for nicotine is the neuronal nicotinic acetylcholine receptor (nAChR). There is ample evidence that these receptors are involved in normal cognitive operations within the brain. This review describes neuronal nAChR structure and function, focusing on both cholinergic agonist-induced nAChR desensitization and nAChR up-regulation. The several mechanisms proposed for the nAChR up-regulation are examined in detail. Desensitization and up-regulation of nAChRs may be relevant to the physiopathology of schizophrenia. The participation of several subtypes of neuronal nAChRs in the cognitive processing of non-mentally ill persons and schizophrenic patients is reviewed. The role of smoking is then examined as a possible cognitive remediator in this psychiatric condition. Finally, pharmacological strategies focused on neuronal nAChRs are discussed as possible therapeutic avenues that may ameliorate the cognitive deficits of schizophrenia.

Fig. 1

(A) Putative subunit arrangements of some nAChR subtypes. The nAChRs have a pentameric structure consisting of five membrane-spanning subunits around a central ion channel. (B) Topology of nAChR subunit. All nAChR subunits share a similar hydrophobicity profile: a large hydrophilic N-terminal domain that faces the extracellular environment, four transmembrane segments (M1, M2, M3, and M4), a variable cytoplasmic domain between M3 and M4, and a short extracellular carboxylic domain

Fig. 2

Schematic cross section of the nAChR showing ion channel, ACh binding site and multiple type of ligands (NCA, CA, NCB, AA, AI, and CB) extracellular domains and ion-channel pathway of the receptor

Fig. 3

Overview of the proposed mechanisms for up-regulation of the α4β2 nAChR. A resting α4β2 nAChR is desensitized (D _nic) after acute nicotine exposure. Recovery from D _nic to the resting is relatively fast (5 min). After chronic exposure the D _nic enters into a long-lived desensitized state from which recovery is very slow (hours) depending on the period of exposure). The long-lived desensitized state D*_nic represents a different conformation than R and D _nic. The majority of studies in heterologous and natural expression experimental systems have indicated that chronic nicotine induces a persistent inactivation (loss of functional responsiveness) and a numerical up-regulation of α4β2-nAChR. Mechanistically, the relation between numerical up-regulation and inactivation remains to be defined. Several posttranscriptional mechanisms have been demonstrated to contribute to the functional changes and numerical up-regulation (i.e. phosphorylation of the M3/M4 loop, increase in transport of the α4β2 nAChR from the ER to the plasma membrane and changes in α4/β2 subunit ratio). A subset of studies has suggested that chronic nicotine exposure does not produce a numerical up-regulation of the α4β2 nAChR. Rather than proposing numerical receptor up-regulation, these studies suggest that after chronic nicotine exposure the receptor increases its functional response and its sensitivity to the agonist