Dementia praecox redux: A systematic review of the nicotinic receptor as a target for cognitive symptoms of schizophrenia

Abstract

Most individuals with schizophrenia suffer some cognitive dysfunction: such deficits are predictive of longer-term functioning; and current dopamine-blocking antipsychotics have made little impact on this domain. There is a pressing need to develop novel pharmacological agents to tackle this insidious but most disabling of problems. The acetylcholinergic system is involved in cognitive and attentional processing, and its metabotropic and nicotinic receptors are widespread throughout the brain. Deficits in acetylcholinergic functioning occur in schizophrenia, and high rates of tobacco smoking have been posited to represent a form of self-medication. The nicotinic acetylcholine receptor (nAChR) has emerged as a putative target to improve cognitive deficits in schizophrenia, and this study systematically reviewed the emerging data. Nineteen studies were identified, covering three compound classes: agonists at the α7 and α 4β2 nAChRs, and positive allosteric modulators. Overall data are underwhelming: some studies showed significant improvements in cognition but as many studies had negative findings. It remains unclear if this represents drug limitations or nascent study methodology problems. The literature is particularly hindered by variability in inclusion of smokers, generally small sample sizes, and a lack of consensus on cognitive test batteries. Future work should evaluate longer-term outcomes, and, particularly, the effects of concomitant cognitive training.

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

“…For example, carriers of smaller deletions, encompassing only CHRNA7, manifest similar phenotypes (Gillentine and Schaaf, 2015); CHRNA7 promoter mutations downregulating transcription are associated with schizophrenia and auditory gating deficits (Leonard et al, 2002), although this mutation is a weaker predictor of the schizophrenia phenotype, thus suggesting that other 15q13.3 CNV genes also contribute to the phenotype. Schizophrenia patients have reduced levels of nAChA7Rs in the hippocampus, reticular nucleus of thalamus, dentate gyrus and frontal cortex (Rowe et al, 2015); and expression of CHRNA7 is reduced in autism (Yasui et al, 2011).…”

Cannabinoids and Schizophrenia: Risks and Therapeutic Potential

“…In addition, rather than a causal association, it is possible that cannabis use may represent selfmedication of early symptoms of a psychotic diathesis (e.g., anxiety) or that both the predilection for early use of cannabis and the risk for psychosis are related to a third factor [8]. For example, the high rates of cigarette smoking in individuals with schizophrenia represents a strong association, which is not viewed as causal, but rather is interpreted as reflecting a third factor, dysregulation of nicotinic acetycholine transmission in schizophrenia [9]. Consistent with this model, schizophrenia risk alleles have been linked both to risk for cannabis use and the quantity of use among the general population [10].…”

Pharmacotherapy of cognition in schizophrenia

“…The release of cortical and hippocampal DA and ACh, two neurotransmitters, in cortex and hippocampus, has been shown by microdialysis in freely moving rodents to be selectively enhanced by AAPDs, but not typical APDs [44]. It has been suggested that this produces cognitive enhancement, in part, through stimulation of D 1 , D 4 , nicotinic and muscarinic receptors [37,[44][45][46][47]. DA and ACh efflux may also overcome possible adverse effects of APD-induced D 2 or muscarinic receptor blockade, or both [12,44].…”

“…DA and ACh efflux may also overcome possible adverse effects of APD-induced D 2 or muscarinic receptor blockade, or both [12,44]. There is extensive post-mortem and PET evidence for decreased dopaminergic [8 ] and cholinergic [46,47] activity in schizophrenia. The ability to enhance cortical and hippocampal DA release by AAPDs has been shown to be related, in part, to potent serotonin (5-HT) 2A , less potent D 2 antagonism, and functionally effective 5-HT 1A partial agonism [44].…”