Acute nicotine effects on auditory sensory memory in tacrine-treated and nontreated patients with Alzheimer's disease: An event-related potential study
Introduction
The seminal reporting of selective loss of cholinergic receptors (Chr) in brains from deceased patients with Alzheimer's disease (AD) (Davies and Mahoney, 1976), together with the early follow-up work in AD linking decreased cholinergic markers and nicotinic Chrs to cognitive decline Perry et al., 1978, Perry et al., 1997, Whitehouse et al., 1981, Whitehouse et al., 1982, stimulated the cholinergic hypothesis of AD (Bartus et al., 1982) and provided the initial momentum for the past two decades of research attempting to design specific pharmacologic approaches for the treatment of this disease (Rainer and Mucke, 1998). Of the many strategies exploited for the modulation of cholinergic neurotransmission, only inhibitors of the catabolic enzyme, acetylcholinesterase, aimed at increasing the concentration of acetylcholine in the neuronal cleft to levels sufficient for effective signal transmission, have shown the therapeutic potential required for approval as an efficacious symptomatic treatment AD (Rainer and Mucke, 1998). The best documented clinical efficacy of these inhibitors are studies of tacrine [tetrahydroaminoacridine (THA)], which evidences symptomatic improvement with short-term (2–3 months) treatment (Giacobini, 1994), and clinical trials have shown a rather similar magnitude of improvement with a number of second-generation inhibitors (Giacobini, 1997).
However, given that these treatments, which can be limited by side effects, have shown only modest improvements and only in a subset of AD patients, suggested strategies for maximizing and prolonging any positive acetylcholinesterase inhibitor effects have involved combinations with other cholinergic drugs such as muscarinic or nicotinic Chr agonists (Giacobini, 1997). Selective activation of remaining central nicotinic Chrs has itself been advocated as a promising approach to the treatment of AD (Sjöberg et al., 1998) and a recent Phase II trial in AD evidencing cognitive-enhancing effects of the novel nicotinic agonist ABT-418 has lent support to this approach (Potter et al., 1999). In addition, repeated administration of the nicotinic agonist, nicotine, has been shown to increase the synthesis and release of acetylcholine (Summers et al., 1994) and acetylcholine binding in the cerebral cortex, hippocampus and median raphe nucleus by approximately 25% (Schwartz and Kellar, 1983). In addition to increasing nicotinic Chr density (Benwell et al., 1988), nicotine has been found to induce a shift in the proportion of low- to high- affinity nicotinic Chr binding sites (Romanelli et al., 1988). Behaviorally, nicotine administration has been shown to improve the deteriorating memory of aged rodents and monkeys Buccafusco and Jackson, 1991, Widzowski et al., 1994 and has been found effective in attenuating cognitive deficits in animal models mimicking cholinergic deficiencies observed in AD (Levin, 1992). Both smoking and nicotine administration have exerted performance-enhancing effects in adult smokers Widzowski et al., 1994, Wesnes and Warburton, 1983, Heishman et al., 1994, Pritchard and Robinson, 1998 and nonsmokers Foulds et al., 1996, LeHouezec et al., 1994. Also, acute nicotine administration, although highly variable in its effects, has been reported to improve sensory acuity, attention, information processing and psychomotor vigilance functions in AD patients Katayama et al., 1995, Newhouse et al., 1988, Newhouse et al., 1990, Sahakian and Coull, 1994.
The suggestion that a combination of direct and indirect cholinergic treatment strategies may work in an additive fashion to augment cholinergic function is partially reinforced by the observation that brain uptake of acutely administered nicotine is increased in patients receiving chronic tacrine treatment (Nordberg et al., 1992). In view of the purported cholinergic hypersensitivity shown in AD patients (Sunderland et al., 1998), this investigation explored the differential central effects of a small dose of nicotine, as administered by 2 mg of nicotine polacrilex, in medication-free AD patients and in AD patients receiving ongoing THA treatment.
Scalp-recorded late (>50 ms) endogenous event-related potentials (ERP), extracted from scalp-recorded electroencephalographic (EEG) activity and reflecting a variety of psychological processes such as attention, memory and processing speed, have been proposed as unique markers in human psychopharmacological research, being well suited for the noninvasive probing and temporal tracking of perceptual cognitive processes altered by centrally acting agents (Münte et al., 1986), including cognitive-enhancing agents Delacour et al., 1994, Group 1990 et al., 1990 and agents with Chr actions (Dierks et al., 1994). The mismatch negativity (MMN) component of the ERP, exhibiting a frontal maximum amplitude with a modal latency of between 50 and 200 ms and a duration of ∼100–200 ms, is elicited by physical “deviant” (e.g., in pitch, intensity, duration and location) acoustic stimuli embedded in a homogenous sequence of “standard” stimuli, irrespective of whether the stimuli are attended to or not Näätänen and Picton, 1982, Näätänen et al., 1978. The physical features of the repetitive standard auditory stimuli are purported to be fully analyzed and encoded as neural traces in short-term echoic memory (i.e., the sensory register or preattentive store, characterized by a large-capacity passive system with a rapid decay of raw sensory data; Deutsch, 1975), and the MMN is believed to be automatically elicited each time any afferent auditory input features fail to match the features encoded in the prevailing neuronal representation Näätänen, 1984, Näätänen, 1992. The MMN, stemming from this automatic comparator process, is elicited only if the prevailing neuronal trace of the standard stimuli has not decayed by the time of deviant stimulus onset. MMN studies varying interstimulus intervals (ISIs) have shown auditory traces to be sustained up to 10 s in young healthy adults (Böttcher-Gandor and Ullsperger, 1992).
Aging has been found to alter trace decay in the human auditory system as MMNs are attenuated more with increasing ISIs in healthy elderly vs. young adult subjects Pekkonen et al., 1993, Pekkonen et al., 1996. AD patients appear to exhibit relatively normal robust MMNs with short (∼1 s) ISIs Kazmerski et al., 1997, Gaeta et al., 1999 but exhibit faster trace decay with increasing (∼3 s) ISIs than do elderly controls (Pekkonen et al., 1994). In previous studies utilizing relatively short (∼1 s) ISIs, smoke-inhaled nicotine has not consistently altered MMN amplitudes in young adults (Knott et al., 1995), while in AD patients, acute THA administration has attenuated MMNs (Riekkinen et al., 1997). This current exploratory study examined the effects of acute nicotine in nontreated and THA-treated AD patients using both short and long ISIs to elicit MMNs.
Section snippets
Subjects
Thirteen (7 males) patients (mean age 71.1 years, range 53–82 years) meeting DSM-IV (American Psychiatric Association, 1994) criteria for probable AD were included in the study once informed consent was obtained. A complete medical history was recorded and laboratory (including an EKG and blood and urine analysis), neurological (including computed tomography scans to rule out other possible causes of dementia) and psychiatric screens were performed before entry. Subjects were required to have
Results
None of the 13 subjects reported nausea, dizziness or any of the common adverse symptoms associated with the chewing of nicotine gum, and no significant Drug, Trial or Drug×Trial changes were observed with vital sign (blood pressure and heart rate) indices.
Statistical analysis of amplitudes yielded significant Drug×Trial (F=10.23, df=1/10, P<.005) and Drug×Trial×Group (F=5.17, df=1/10, P<.05) interactions. Follow-up simple main effect analysis confirmed the impression of post-placebo amplitude
Discussion
Considerable attention has been paid to nicotine's dual role as a pharmacological tool for delineating neurochemical mechanisms underlying cognition and as a putative therapeutic agent in neuropsychiatric disorders Durson and Kurcher, 1999, Le Houezec, 1998. The MMN, reflecting relatively automatic, nonsemantic sensory memory storage, has been promoted as a unique noninvasive CNS scalpel for probing the pathophysiology of preattentive processes and their modulation by psychopharmacological
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2010, Brain ResearchCitation Excerpt :If, as discussed earlier, nicotine broadens attention and augments resource pools allocated to stimulus encoding, one would expect to see an enhanced MMN post nicotine administration. Indeed, in the burgeoning literature examining nicotine's effects on the auditory mismatch negativity, nicotine has been reported to increase amplitude and shorten latency of auditory MMN in Tacrine-naïve Alzheimer's Disease patients (Engeland et al., 2002). Attempts to characterize nicotine's effects on the auditory MMN in healthy controls, however, have been fraught with inconsistencies across laboratories and paradigms, with nicotine reported to increase MMN amplitude in smokers using a roving paradigm (Baldeweg et al., 2006), and decrease MMN latency using a frequency-deviant auditory oddball paradigm in non-smokers (Inami et al., 2005, 2007), yet having no effect on MMN elicited by non-attended deviants in an auditory selective attention paradigm (Knott et al., 2006a) and evidencing no (Knott et al., 2006b) or minimal (Knott et al., 2009) effects on MMN elicited in an auditory distraction paradigm in smokers and non-smokers, respectively.
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