Nicotine and smoker status moderate brain electric and mood activation induced by ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist.

As the increased smoking prevalence in schizophrenics may be interpreted as an adaptive response to an underlying biological defect, investigations into nicotine's actions within N-methyl-d-aspartate (NMDA) antagonist drug models of schizophrenia may improve our understanding of the role of glutamatergic neurotransmission in initiating and maintaining nicotine dependence in this disorder. In this double-blind, placebo-controlled, randomized study, the electroencephalographic (EEG) and subjective response to a sub-psychotomimetic intravenous dose of the NMDA antagonist ketamine was examined in 20 regular smokers and 20 non-smokers pretreated with placebo or nicotine gum. Although nicotine increased EEG arousal, ketamine produced electrocerebral signs of brain activation (decreased slow wave power) and sedation (decreased fast wave power and frequency), which were not affected by nicotine pretreatment and were evident only in non-smokers. Ketamine increased a number of self-report indices of subjective arousal, some of which were attenuated and potentiated by nicotine in smokers and non-smokers, respectively. These findings suggest that long-term (evidenced by smoker vs. non-smoker comparisons) and short-term (acute) nicotine exposure may alter NMDA receptor-mediated arousal and mood systems in a way that promotes nicotine dependence in smokers, and addresses neurobiological deficiencies in smokers with schizophrenia.

Effects of acute nicotine administration on cognitive event-related potentials in tacrine-treated and non-treated patients with Alzheimer's disease.

Earlier studies of cognitive event-related brain potentials (ERPs) reporting diminished amplitudes and delayed latencies of the P300 potential in dementia of the Alzheimer type (DAT), together with independent findings of the P300- and performance-enhancing properties of nicotine in normal adults, stimulated this study to explore the single-dose effects of nicotine on auditory and visual P300s in DAT. Thirteen patients, 6 currently receiving treatment with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine; THA) and the remaining being medication free, were administered 2 mg of nicotine polacrilex under double-blind, randomized, placebo-controlled conditions. Prior to nicotine administration, THA-treated patients exhibited shorter auditory P300 latencies than non-treated patients. Acutely administered nicotine failed to alter auditory P300, but increased the amplitudes of visual P300s in both DAT patient groups. Neither THA treatment nor single-dose nicotine altered behavioural performance in the visual and auditory task paradigms. The results are discussed in relation to nicotinic cholinergic, attentional and cognitive processes in DAT.

Acute nicotine effects on auditory sensory memory in tacrine-treated and nontreated patients with Alzheimer's disease: an event-related potential study.

The auditory mismatch negativity (MMN) event-related brain potential (ERP) reflects the storage of information in acoustic sensory memory. Thirteen patients with Alzheimer's disease (AD), 6 receiving treatment with the cholinesterase inhibitor, tacrine [tetrahydroaminoacridine (THA)], and 7 receiving no treatment, were administered 2 mg of nicotine polacrilex and placebo. MMNs were recorded with 1- and 3-s interstimulus intervals (ISIs) during pre- and post-placebo/nicotine administration. Amplitudes decreased from pre- to post-placebo recordings in nontreated patients but remained stable in THA-treated patients. Comparison of pre- and post-nicotine MMNs found amplitude increases with nicotine in nontreated but not in THA-treated patients. MMN latencies were shortened by nicotine in both treatment groups. These exploratory findings suggest that nicotine-improved strength of acoustic sensory memory traces and speed of acoustic sensory discrimination in AD are differentially affected by chronic tacrine treatment.

Nicotine and sensory memory in Alzheimer's disease: an event-related potential study.

The auditory mismatch negativity (MMN) event-related brain potential (ERP) reflects the storage of information in acoustic sensory memory. Thirteen patients with probable Alzheimer's disease (AD), 6 receiving treatment with the cholinesterase inhibitor (ChEI) tacrine (tetrahydroaminoacridine, THA) and 7 receiving no treatment, were administered 2 mg of nicotine polacrilex and placebo. MMNs were recorded with 1- and 3-s interstimulus intervals pre- and postplacebo/nicotine administration. In nontreated patients, amplitudes were decreased from pre- to postplacebo recordings but remained stable in THA-treated patients. Comparison of pre- and postnicotine MMNs found amplitude increases with nicotine in nontreated but not THA-treated patients. MMN latencies were shortened by nicotine in both treatment groups. These exploratory findings suggest that nicotine-improved strength of acoustic sensory memory traces and speed of acoustic sensory discrimination in AD are differentially affected by chronic ChEI treatment.

Quantitative electroencephalography in Alzheimer's disease: comparison with a control group, population norms and mental status.

OBJECTIVE: Given that quantitative electroencephalography (EEG) has repeatedly shown excessive slow wave activity in dementia of the Alzheimer type (DAT) that increases with disease progression, we assessed the clinical utility of this tool by comparing various approaches used to assess slowing. DESIGN: Cross-sectional study comparing quantitative EEG data from patients with DAT with normative data from an elderly control group and from EEG norms derived from a large population. PARTICIPANTS: 35 subjects diagnosed with probable DAT and 30 elderly controls. OUTCOME MEASURE: EEG recorded from 21 scalp sites of each patient and elderly control during vigilance-controlled, eyes-closed, resting conditions was spectrally analyzed to yield measures of absolute and relative power in delta, theta, alpha and beta bands and indices of mean alpha band and total band frequency. RESULTS: Group comparisons of raw or age-regressed z-score population normative values yielded different profiles with respect to direction of frequency band changes, regional topography and clinical rating correlations, but both procedures evidenced overall patterns of EEG slowing in DAT. However, both methodologies yielded only modest (75%) classification rates. CONCLUSION: Quantitative EEG remains a valuable research tool but, as yet, an unproven diagnostic tool, for DAT.

Effects of haloperidol pretreatment on the smoking-induced EEG/mood activation response profile.

This study examined the role of dopamine in modulating the CNS response to cigarette smoking. In a randomized, double-blind, repeated-measures design, quantitative electroencephalographic (EEG) changes and self-reports induced by the smoking of a single cigarette were assessed in 16 smokers following pretreatment with placebo and a dopamine antagonist, haloperidol (2 mg). Following placebo pretreatment, absolute (muV) and relative (%) amplitudes in slow-frequency bands (delta, theta, alpha1) were reduced and absolute and relative amplitudes in fast-frequency bands (alpha2, beta) were increased following cigarette smoking as compared to sham smoking. Haloperidol pretreatment inhibited the smoking-induced increase in absolute beta frequency. Self-ratings indicated that cigarette smoking induced increases in alertness, contentedness and calmness but not euphoria, and reduced cigarette cravings as compared to the sham smoking conditions. Smoking-induced, alpha2 increments were associated with increases in alertness and decreases in euphoria while beta increments were associated with increased calmness. Smoking-related self-ratings of mood and cigarette acceptability were not altered by haloperidol, but subjects were less content overall in the haloperidol condition as compared to placebo. Discussion of these results focuses on transmitter systems and their relationship to neuro-electric and behavioural activities associated with the smoking habit.

Acute nicotine administration in Alzheimer's disease: an exploratory EEG study.

Previous findings of cognitive deficits and EEG slowing in Alzheimer's patients, together with independent reports of the performance enhancing and electrocortical activating properties of nicotine in normal adults, stimulated this study to examine the acute effects of nicotine on spectrum-analyzed EEG in patients with dementia of the Alzheimer type (DAT). Thirteen patients, 6 currently receiving cholinesterase inhibitor treatment and the remaining being medication free, were administered 2 mg of nicotine polacrilex under randomized, placebo-controlled conditions. Compared to age-regressed EEG norms, the pretreatment EEG spectrums of patients in general were characterized by excessive slow (delta and theta)-wave power, diminished fast (alpha and beta)-wave power and slow mean alpha and total band frequencies. Although postnicotine EEG indices remained within the abnormal range, nicotine, compared to placebo, significantly shifted EEG towards normal values by reducing slow wave (relative delta and theta) power and augmenting fast (relative alpha-1, alpha-2, beta-1) wave power. No differences were observed between treated and nontreated patients in response to nicotine. The results are discussed in relation to cholinergic and brain arousal systems and their relationship to cognitive processes.

Pharmaco-EEG test dose response predicts cholinesterase inhibitor treatment outcome in Alzheimer's disease.

Previous investigations have indicated that a single dose pharmaco-EEG may predict the outcome of 4-7 weeks of tetrahydroaminoacridine (THA) treatment in dementia of the Alzheimer type (DAT). This open trial study further examined the relationship of quantitative EEG in relation to treatment response by assessing 24 probable DAT patients at baseline, 2 h after their first oral dose (30 mg), and after 12 weeks of THA treatment. Compared to EEG norms, patients, in general, evidenced EEG slowing, as shown by excessive slow (theta) and diminished fast (alpha and beta) wave power as well as reduced mean frequencies which were present prior to treatment as well as at the end of treatment. The EEG of patients exhibiting stable or improved scores on the Mini-Mental State examination (MMSE) at 12 weeks showed a significantly faster baseline mean alpha frequency as well as a significant reduction in relative theta power following the single THA test dose compared to deteriorated patients. A discriminant analysis using test dose response EEG variables correctly classified 75-79% of these two patient groups, suggesting that this procedure may be a useful approach for optimizing patient selection for antidementia treatments.

Electroencephalographic coherence in Alzheimer's disease: comparisons with a control group and population norms.

Previous research from independent laboratories has shown reduced electroencephalographic coherence in patients diagnosed with dementia of the Alzheimer type (DAT). This study added to this work by comparing interhemispheric and intrahemispheric coherence in nonmedicated DAT patients (n = 35) with that of a normal control group (n = 30), as well as with a data bank of population norms. Raw and Z-score transformed values showed reduced coherence, interhemispherically (in delta, theta, alpha, and beta bands) and intrahemispherically (delta and theta bands) in DAT patients with both comparison procedures. Discriminant analysis correctly classified 73% to 75% of patients. The results are discussed in relation to earlier research, "trait" versus "state" factors, the cholinergic system, and cognitive processes in dementia.

Transdermal nicotine: single dose effects on mood, EEG, performance, and event-related potentials.

A 21-mg dose of nicotine was administered transdermally to 16 overnight smoking-deprived smokers in a double-blind, placebo-controlled design. Mood ratings, electroencephalography (EEG), behavioral performance and event-related potential (ERP: P300) indices of attention and information processing speed were assessed before and 4 h after placebo/nicotine treatment. Although nicotine, relative to placebo, failed to alter mood, it increased absolute and relative power indices of EEG arousal, shortened reaction times, and increased P300 amplitudes. The results are discussed in relation to nicotine's actions on cholinergic transmission and its role in smoking behavior.

The cholinergic basis of the smoking-induced EEG activation profile.

Acute quantitative electroencephalographic effects of cigarette smoking were examined in 15 smokers within a repeated-measures design which assessed changes in power-spectral estimates following acute pre-treatment with placebo, a dose (20 mg) of mecamylamine, a dose (0.6 mg) of scopolamine and a combined dose of mecamylamine and scopolamine. Compared to sham smoking, the smoking of a single cigarette following placebo pre-treatment reduced absolute and relative power in slow (delta, theta) frequency bands, increased absolute and relative power in alpha and beta frequency bands and accelerated mean frequency. These smoking-induced power changes in slow- and fast-frequency bands were differentially affected by the separate and combined actions of the cholinergic antagonists with treatments involving mecamylamine tending to abolish smoking-induced slow-frequency absolute power reductions and fast-frequency relative power increments. Self-ratings of smoking-induced increases in alertness were altered by mecamylamine and combined treatments while sensory aspects of cigarette smoking were only altered with combined mecamylamine and scopolamine pre-treatment. The results are discussed with respect to brain-behaviour relationships and mechanisms maintaining the smoking habit.

Huntington's disease: pathogenesis, diagnosis and treatment.

This review of the clinical features of Huntington's disease incorporates recent developments in pathophysiology, preclinical diagnosis and treatment. Although the mechanism initiating and guiding the cell destruction in this illness is currently unknown, the excitatory neurotoxin and the energy metabolism models may provide a valuable direction for future research. Similarly, although the precise relation between the neuroanatomical damage in Huntington's disease and the functional disability is not clear, applications of recently developed neural connection models have implicated a number of important brain-behavior associations. Preclinical diagnostic procedures have evolved through successive iterations that have each contributed to increased reliability. New functional brain imaging techniques are sure to add to this promising domain in the future. Preclinical diagnosis has been stimulated by the recent isolation of the Huntington's gene which has also rekindled awareness of the importance of informed genetic counselling and the inherent ethical dilemmas in genetic testing. Treatment approaches to Huntington's disease have been confined to palliative care with secondary symptom management and psychotherapeutic support. Experimental therapeutic strategies for the illness itself have had a rather disappointing record to date. Further developments in NMDA antagonism and neural cell grafting may provide some hope for the future.