Knowledge of the structure and distribution of nicotinic acetylcholine receptors (nAChRs) has been ever increasing in detail, while clear elucidation of the physiological significance and involvement of nAChRs in cognition and cognitive dysfunction has lagged somewhat behind. Nonetheless, nicotinic mechanisms have been implicated in the pathogenesis of cognitive dysfunction in a number of disorders including Parkinson’s disease (PD). Furthermore, nicotine, a nAChR agonist, has been shown to modulate aspects of cognition such as attention and memory. An influence of nicotine on lexical-semantic processing, however, is relatively uncharted, although investigations of the effects of nicotine on mnemonic processing in minimally-deprived smokers (e.g., Rusted, Graupner, Tennant, & Warburton, 1998; Warburton, Skinner, & Martin, 2001) suggest that nicotine might selectively modulate processes concerned with associative memory. Such findings provided the main impetus for the present thesis which investigated the effects of acute transdermal nicotine (7 mg/ 24 h) on lexical-semantic processing in healthy young adults, and people with PD and matched controls in a double-blind, placebo-controlled, crossover design.
The first two aims of the thesis involved examining the effects of nicotine on lexical-semantic processing in young adults. On a cognitively demanding strategy-based priming paradigm, nicotine influenced controlled processing but not automatic processing, consistent with the notion that nicotine effects are typically mediated by attentional and effortful processing (Edginton & Rusted, 2003; Rusted et al., 1998; Warburton et al., 2001). Specifically, under controlled processing conditions, facilitation effects were dominant on placebo compared to a dominance of inhibition effects on nicotine. The pattern of results indicated that nicotine may have enhanced the application of controlled processing mechanisms, such as expectancy or semantic matching, and enhanced active inhibitory mechanisms. Contrastingly, the young adults did not show an influence of nicotine on
controlled processing under general priming procedures, probably due to an insufficient taxing of limited-capacity resources or cognitive effort under the comparatively simple, non-demanding general priming procedures. Under both the strategy-based and general priming procedures, there was no interplay between nicotine and relatedness in contrast with reports from mnemonic processing studies, indicating that a nicotinic modulation of relatedness per se may best be mediated by encoding/consolidation mechanisms.
The next two aims of the thesis involved examining the effects of nicotine on lexical-semantic processing in PD and matched controls. Under cognitively demanding strategy-based priming procedures, the elderly controls demonstrated a subtle influence of nicotine with enhanced inhibition for an unexpected-related condition, in line with the suggestion that nicotine may strengthen prepotent competitor inhibition under effortful processing conditions (Edginton & Rusted, 2003). An effect of nicotine on inhibitory mechanisms was also speculated to underlie inhibition dominance and a general effect of expectancy that emerged under nicotine for the PD group. In contrast, there was no evidence of facilitation/inhibition or expectancy for the PD group under placebo. An alternative but not mutually exclusive account was that nicotine enhanced controlled processing mechanisms generally in PD.
Under general priming procedures, nicotine unexpectedly ameliorated compromised automatic priming in the elderly controls, indicating that although nicotine effects are typically mediated by attentional and effortful processing, effects on automatic priming may materialise when performance levels are suboptimal. Nicotine did not, however, normalise impaired automatic priming in the PD group, which was consistent with a slowed time course of activation in this population (Angwin, Chenery, Copland, Murdoch, & Silburn, 2004, 2007; Arnott, Chenery, Murdoch, & Silburn, 2001; Grossman et al., 2002). This finding indicated that impairments in the early stages of automatic lexical-semantic processing in PD may be different to those in elderly controls and thus impervious to the ameliorating effects
of nicotine. In contrast, when the general priming procedures promoted controlled processing, nicotine appeared to enhance priming in PD but not elderly controls. This differential effect was speculated to be due to a nicotinic modulation of residual levels of activation which were higher in PD due to greater alterations in the time course of automatic activation.
Overall, the findings of the current thesis demonstrate that nicotine can influence controlled lexical-semantic processing, probably via inhibitory mechanisms, when such processing is cognitively demanding and effortful in both young and older adults as well as in PD. Second, although an influence of nicotine on relatedness may best be mediated by encoding/consolidation mechanisms, nicotinic modulations of semantic activation may materialise when processing is compromised by age or disease. The findings of the current thesis likely reflect a complex influence of nicotine on different neurophysiological phenomena and neural substrates underlying both top-down and bottom-up processing mechanisms. Although preliminary, the findings endorse future exploration and development of novel nicotinic therapies for disorders with evidenced changes in central nAChRs and impairments in information processing, such as PD, schizophrenia and Alzheimer’s disease.