Synergistic effects of genetic variation in nicotinic and muscarinic receptors on visual attention but not working memory

Abstract

It is widely appreciated that neurotransmission systems interact in their effects on human cognition, but those interactions have been little studied. We used genetics to investigate pharmacological evidence of synergisms in nicotinic/muscarinic interactions on cognition. We hypothesized that joint influences of nicotinic and muscarinic systems would be reflected in cognitive effects of normal variation in known SNPs in nicotinic (CHRNA4 rs1044396) and muscarinic (CHRM2 rs8191992) receptor genes. Exp. 1 used a task of cued visual search. The slope of the cue size/reaction time function showed a trend level effect of the muscarinic CHRM2 SNP, no effect of the nicotinic CHRNA4 SNP, but a significant interaction between the 2 SNPs. Slopes were steepest in individuals who were both CHRNA4 C/C and CHRM2 T/T homozygotes. To determine the specificity of this synergism, Exp. and phasic modes of cholinergic activity, we argue that reorienting attention to the target after invalid cues requires a phasic response, dependent on the nicotinic system, whereas orienting attention to valid cues requires a tonic response, dependent on the muscarinic system. Consistent with that, shifting and scaling after valid cues (tonic) were strongest in CHRNA4 C/C homozygotes who were also CHRM2 T/T homozygotes. This shows synergistic effects within the human cholinergic system. cholinergic ͉ genetics ͉ synergism ͉ cognition

The receptor architecture of the pigeons’ nidopallium caudolaterale: an avian analogue to the mammalian prefrontal cortex

“…The nACh receptors are fast-acting ligand-gated ion channels producing EPSPs. A recent genetic approach showed that both, fast-acting nicotinic receptors and slow-acting muscarinic receptors influence in a synergistic system the efficiency of shifting visuospatial attention in the PFC (Greenwood et al 2009). In pigeons, central cholinergic systems are important for temporal memory processes and spatial orientation during homing, two processes that also involve the NCL (Gagliardo and Divac 1993;Santi and Weise 1995;Kohler et al 1996;.…”

The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction

“…nicotine abstinence model of cognitive impairment). We used the nicotine abstinence model of cognitive impairment because : (a) synergistic interactions between muscarinic and nicotinic receptors at both a molecular and behavioural level have been reported (Ellis et al 2006 ;Greenwood et al 2009) ; (b) nicotine abstinence (for at least 12 h) in chronic smokers can reduce baseline cognitive function, including memory, as previously demonstrated (Myers et al 2008).The primary hypothesis was that the M 1 allosteric agonist GSK1034702 would attenuate the nicotine abstinence-induced impairments in episodic memory. The effects of GSK1034702 on other aspects of cognitive function shown to be relevant to AD and schizophrenia were then investigated in exploratory analyses.…”

Polymorphism in the CHRNA4 gene is associated with rapid scene categorization performance

“…A multiple-object tracking (MOT) task study revealed an association between CHRNA4 and sustained attention (Espeseth, Sneve, Rootwelt, & Laeng, 2010). Besides single-gene effects, synergistic effects of nicotinic and muscarinic cholinergic receptor genes (CHRNA4 and CHRM2) on attentional scaling have been reported (Greenwood, Lin, Sundararajan, Fryxell, & Parasuraman, 2009). Cognitive genetic studies using neuroimaging techniques have further confirmed the relationship between CHRNA4 and attention.…”

“…Furthermore, in behavioral experiments, Tallele carriers exhibited greater slowing of responses for invalid cues . Greenwood et al (2009) speculated that the higher nicotine receptor sensitivity of Tallele carriers might be a factor in the consistency between the brain and cognitive measurements. Thus, in the present study, varying nicotine receptor sensitivity by CHRNA4 SNPs may have contributed to differences in behavioral performance.…”

“…CHRM2 is also a gene for a type of acetylcholine receptor, a muscarinic receptor that is known to enhance the response of the receptive field to natural images (Goard & Dan, 2009). Investigations into the SNP interaction will require much larger sample sizes than those used in the present study (Greenwood et al, 2009). Thirdly, it will be desirable to obtain evidence for the nicotinic acetylcholine receptor effect by means of other experimental manipulations.…”