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Deficits in early auditory sensory processing in schizophrenia have been linked to N-methyl-D-aspartate receptor (NMDAR) hypofunction, but the role of NMDARs in aberrant auditory sensory gating (SG) in this disorder is unclear. This study, conducted in 22 healthy humans, examined the acute effects of a subanesthetic dose of the NMDAR antagonist ketamine on SG as measured electrophysiologically by suppression of the P50 event-related potential (ERP) to the second (S2) relative to the first (S1) of two closely paired (500 ms) identical speech stimuli. Ketamine induced impairment in SG indices at sensor (scalp)-level and at source-level in the auditory cortex (as assessed with eLORETA). Together with preliminary evidence of modest positive associations between impaired gating and dissociative symptoms elicited by ketamine, tentatively support a model of NMDAR hypofunction underlying disturbances in auditory SG in schizophrenia.

Impairments in auditory information processing in schizophrenia as indexed electrophysiologically by P300 deficits during novelty (P3a) and target (P3b) processing are linked to N -methyl- D -aspartate receptor (NMDAR) dysfunction. This study in 14 healthy volunteers examined the effects of a subanesthetic dose of the NMDAR antagonist ketamine on P300 and their relationship to psychomimetic symptoms and cortical source activity (with eLORETA). Ketamine reduced early (e- P3a) and late (l-P3a) novelty P300 at sensor (scalp)-level and at source-level in the salience network. Increases in dissociation symptoms were negatively correlated with ketamine-induced P3b changes, at sensor-level and source-level, in both salience and central executive networks. These P3a alterations during novelty processing, and the symptom-related P3b changes during target processing support a model of NMDAR hypofunction underlying disrupted auditory attention in schizophrenia.

N-methyl- d -aspartate receptor (NMDAR) antagonists administered to healthy humans results in schizophrenia-like symptoms, which are thought in part to be related to glutamatergically altered electrophysiological connectivity in large-scale intrinsic functional brain networks. Here, we examine resting-state source electroencephalographic (EEG) connectivity within and between the default mode (DMN: for self-related cognitive activity) and salience networks (SN: for detection of salient stimuli in internal and external environments) in 21 healthy volunteers administered a subanesthetic dose of the dissociative anesthetic and NMDAR antagonist, ketamine. In addition to provoking symptoms of dissociation, which are thought to originate from an altered sense of self that is common to schizophrenia, ketamine induces frequency-dependent increases and decreases in connectivity within and between DMN and SN. These altered interactive network couplings together with emergent dissociative symptoms tentatively support an NMDAR-hypofunction hypothesis of disturbed electrophysiologic connectivity in schizophrenia.

Background: Previous studies in schizophrenia have consistently shown that deficits in the generation of the auditory mismatch negativity (MMN) – a pre-attentive, event-related potential (ERP) typically elicited by changes to simple sound features – are linked to N-methyl-D-aspartate (NMDA) receptor hypofunction. Concomitant with extensive language dysfunction in schizophrenia, patients also exhibit MMN deficits to changes in speech but their relationship to NMDA-mediated neurotransmission is not clear. Accordingly, our study aimed to investigate speech MMNs in healthy humans and their underlying electrophysiological mechanisms in response to NMDA antagonist treatment. We also evaluated the relationship between baseline MMN/electrocortical activity and emergent schizophrenia-like symptoms associated with NMDA receptor blockade. Methods: In a sample of 18 healthy volunteers, a multi-feature Finnish language paradigm incorporating changes in syllables, vowels and consonant stimuli was used to assess the acute effects of the NMDA receptor antagonist ketamine and placebo on the MMN. Further, measures of underlying neural activity, including evoked theta power, theta phase locking and source-localized current density in cortical regions of interest were assessed. Subjective symptoms were assessed with the Clinician Administered Dissociative States Scale (CADSS). Results: Participants exhibited significant ketamine-induced increases in psychosis-like symptoms and depending on temporal or frontal recording region, co-occurred with reductions in MMN generation in response to syllable frequency/intensity, vowel duration, across vowel and consonant deviants. MMN attenuation was associated with decreases in evoked theta power, theta phase locking and diminished current density in auditory and inferior frontal (language-related cortical) regions. Baseline (placebo) MMN and underlying electrophysiological features associated with the processing of changes in syllable intensity correlated with the degree of psychotomimetic response to ketamine. Conclusion: Ketamine-induced impairments in healthy human speech MMNs and their underlying electrocortical mechanisms closely resemble those observed in schizophrenia and support a model of dysfunctional NMDA receptor-mediated neurotransmission of language processing deficits in schizophrenia. HIGHLIGHTS - Neural effects of NMDA receptor blockade on speech processing were assessed in a ketamine model. - Ketamine reduced MMN, theta power, theta phase locking factor and regional cortical current density. - Psychosis-like symptoms induced by ketamine were related to baseline (placebo) neural measures of speech processing.

While nicotine is often associated with the neuropsychological effects of tobacco smoke, the robust monoamine oxidase (MAO) inhibition observed in chronic smokers is also likely to play a role. Electroencephalographically-indexed alterations in baseline neural oscillations by nicotine have previously been reported in both smokers and non-smokers, however, little is known about the effects of MAO inhibition in combination with nicotine on resting state EEG. In a sample of 24 healthy non-smoking males, the effects of 6 mg nicotine gum, as well as MAO-A inhibition via 75 mg moclobemide, were investigated in separate and combined conditions over four separate test sessions. Drug effects were observed in the alpha2, beta2, and theta band frequencies. Nicotine increased alpha2 power, and moclobemide decreased beta2 power. Theta power was decreased most robustly by the combination of both drugs. Therefore, this study demonstrated that the nicotinic and MAO inhibiting properties of tobacco may differentially influence fast-wave oscillations (alpha2 and beta2), while acting in synergy to influence theta oscillations.

Diminished auditory sensory gating and associated neurocognitive deficits in schizophrenia have been linked to altered expression and function of the alpha-7 nicotinic acetycholinergic receptor (α7 nAChR), the targeting of which may have treatment potential. Choline is a selective α7 nAChR agonist and the aim of this study was to determine whether cytidine 5′-diphosphocholine (CDP-choline), or citicoline, a dietary source of choline, increases sensory gating and cognition in healthy volunteers stratified for gating level. In a randomized, placebo-controlled, double-blind design involving acute administration of low, moderate doses (500 mg, 1000 mg) of CDP-choline, 24 healthy volunteers were assessed for auditory gating as indexed by suppression of the P50 event-related potential (ERP) in a paired-stimulus (S1, S2) paradigm, and for executive function as measured by the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery. CDP-choline improved gating (1000 mg) and suppression of the S2 P50 response (500 mg, 1000 mg), with the effects being selective for individuals with low gating (suppression) levels. Tentative support was also shown for increased GMLT performance (500 mg) in low suppressors. These preliminary findings with CDP-choline in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with choline as a pro-cognitive strategy.

Comorbidity between depression and tobacco use may reflect self-medication of serotonergically mediated mood dysregulation, which has been associated with aberrant cortical activation and hemispheric asymmetry in patients with major depressive disorders (MDD). This randomized, double-blind study in 28 remitted MDD patients examined the moderating effects of acute nicotine and smoker vs. nonsmoker status on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). In smokers, who exhibited greater posterior high alpha power and increased left frontal low alpha power (signs of deactivation) compared to nonsmokers, ATD increased self-ratings of depressed mood and elevated left frontal and right parietal high alpha power (i.e. further cortical deactivation). Smokers were not affected by nicotine administration. In nonsmokers, ATD did not influence depression ratings, but it reduced vigor ratings and increased frontal and posterior theta power; both of which were blocked by acute nicotine. These findings indicate a role for nicotinic receptors in disordered mood.

Given the cognitive-promoting properties of the nicotinic acetylcholinergic receptor (nAChR) agonist, nicotine, the increased prevalence of smoke-inhaled nicotine in schizophrenia has been interpreted as an attempt to self-correct cognitive deficits, which have been particularly pronounced in the attentional domain. As glutamatergic abnormalities have been implicated in these attentional deficiencies, this study attempted to shed light on the separate and interactive roles of the N-methyl- d -aspartate receptor (NMDAR) and nAChR systems in the modulation of attention by investigating, in healthy volunteers, the separate and combined effects of nicotine and the NMDAR antagonist ketamine on neural and behavioural responses in a sustained attention task. In a randomized, double-blind, placebo controlled study, performance and the P300 event-related brain potential (ERP) in a visual information processing (RVIP) task were examined in 20 smokers and 20 non-smokers (both male and female). Assessment involved intravenous injection of a low subperceptual bolus dose (.04 mg/kg) of ketamine or placebo, which was accompanied by acute treatment with nicotine (4 mg) or placebo gum. Nicotine-enhanced attentional processing was most evident in nonsmokers, with both performance accuracy and P300 amplitude measures. Ketamine's detrimental effects on these behavioural and electrophysiologic measures were negatively moderated by acute nicotine, the synergistic effects being expressed differently in smokers and nonsmokers. These findings support the view that acute alterations and individual differences in nAChR function can moderate even subtle glutamatergic-driven cognitive deficiencies in schizophrenia and can be important therapeutic targets for treating cognitive impairments in schizophrenia.

This study assessed the effects of acute tryptophan depletion (ATD), which transiently lowers CNS 5-HT, on electrocortical responses to facial expression processing in individuals with a family history of depression (FH+). Electroencephalograph (EEG)-derived event-related potentials (ERPs) were acquired from 18 FH+ individuals during a facial expression recognition task (neutral and sad, joy and surprise at 50% and 100% intensities). Both early positive (P1 and P2) and the face-specific N170 ERP components were differentially altered by emotional intensity and valence. Increased depression, confusion and total mood disturbance scores, and decreased calmness, were observed with ATD (versus placebo). ATD was also associated with enhanced P1 and P2 amplitudes for sad versus joyful expressions. The N170 was not modulated by treatment, but was affected by emotive valence. Therefore, ATD enhanced ERP-indexed early processing of sad facial expressions, and altered the processing of positive ones, in FH+ individuals.

Alpha 7 nicotinic acetylcholine receptors (α7 nAChR) are prioritized molecular targets for the development of new pharmacological treatments for impaired cognition in schizophrenia. The use of schizophrenia-associated biomarkers both as endpoints and for segmentation of homogeneous populations for early detection of cognitive enhancing agents has been advanced to enhance the drug discovery process. In this study, the mismatch negativity (MMN) event-related brain potential (ERP), considered one of the few fully developed biomarkers in schizophrenia, was employed: a) to stratify 24 healthy volunteers into subgroups exhibiting low, medium, or high auditory sensory discrimination based on pre-attentive detection of deviant auditory features, and b) to assess their acute response to a low (500 mg) and moderate dose (1000 mg) of CDP-choline, a dietary supplement with selective agonist actions at α7 nAChRs. No significant whole group effects were observed with CDP-choline, and MMN changes were observed only with analysis of subgroups. The effects of CDP-choline interacted both with deviant type and auditory deviance detection level, with individuals exhibiting low MMNs showing enhanced amplitudes, while those with high MMNs evidenced reduced amplitudes with acute dosing of CDP-choline. These preliminary findings of improved auditory deviance detection with CDP-choline in our biomarker-defined healthy surrogate group supports the contention that α7 nicotinic cholinergic agonism be studied as a potential pro-cognitive mechanism in patients with schizophrenia.

The mismatch negativity (MMN) auditory event-related potential (ERP) has been extensively studied as a potential biomarker for abnormal auditory processing in schizophrenia (SZ), a population which exhibits abnormally high smoking rates. The relationship between nicotinic activation and cognition in SZ may be related to underlying nicotinic and NMDA receptor dysfunction within the disease. However, transient cognitive improvements via smoking in patients may also result from monoamine oxidase (MAO) inhibition, achieved through tobacco smoke. In 24 healthy non-smoking males, we investigated the separate and combined effects of nicotine and MAO-A inhibition via moclobemide (75mg) on the optimal-5 variation of the MMN paradigm. No significant drug effects were observed in our total sample, however, stratification of individuals into low (N=12) and high (N=12) baseline MMN amplitude groups revealed increases in duration MMN amplitude relative to placebo by nicotine, as well as moclobemide, but not after the combination of the two. Because previous research has shown there was no effect of monoamine modulation on MMN, this study shows an unexpected effect of moclobemide on duration MMN.

CDP-choline (cytidine-5'-diphosphocholine) is a phospholipid used to treat cognitive disorders, presumably repairing and maintaining brain cell membranes. Additional mechanisms may include enhanced cholinergic neurotransmission as the α7 nicotinic receptor actions of choline and increased acetylcholine synthesis accompanying CDP-choline administration may modulate brain oscillations underlying cognitive processes. This study utilizes electroencephalographic (EEG) recordings in healthy volunteers to evaluate CDP-choline induction of an oscillatory response profile associated with nicotinic stimulation. Resting state EEG was acquired in 24 male volunteers administered low (500mg) and moderate (1000mg) doses of CDP-choline in a randomized placebo-controlled, crossover trial. Consistent with nicotinic agonist treatment, spectral analysis showed dose-dependent reductions in delta and increases in alpha oscillations, which were also accompanied by decreases in beta and gamma oscillatory activity. These findings support the posit that CDP-choline cognitive enhancement involves multiple mechanisms including facilitated nicotinic cholinergic action.

ResumenLos datos de investigaciones precl ínicas en organismos no humanos, ensayos clínicos al descubierto y un ensayo controlado individual encontraron que el tratamiento de nicotina agudo potenciaba hasta 4 semanas las reducciones inducidas por neurolépticos de los síntomas discinéticos que caracterizan al síndrome de la Tourette (ST). Dadas las perturbaciones de la atención asociadas con este síndrome, y las mejorías en los procesos atencionales comunicadas con la nicotina, este ensayo distribuido al azar doble ciego controlado con placebo exa- minó los efectos agudos (4 h) y sostenidos (2 semanas) de una dosis individual de nicotina transdérmica sobre los síntomas clínicos (es decir, los tics), atencionales (una tarea de ejecución continua, potenciales evocados cognitivos, los informes de los pacientes y los padres) y conductuales en 23 niños y adolescentes con ST que recibían tratamiento neuroléptico. En los 14 pacientes evaluables con datos de efi- cacia primarios completos, la nicotina (comparado con el placebo) no alteró los síntomas a las 4 h pero contrarrestó los signos de aten ción disminuida de la onda P300 de los potenciales evocados cognitivos (PEC) vistos 2 semanas después del tratamiento con placebo. Las medidas de eficacia secundarias, incluidos los autoinformes de los pacientes y las evaluaciones de los padres, encontraron que la nicoti na reducía los tics complejos y mejoraba las conductas relacionadas con el déficit de atención. Se requiere más trabajo con programas de dosis intermitentes para caracterizar los efectos clínicos y cognitivos óptimos con el tratamiento de nicotina.

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.

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.

Novel pharmacological treatments targeting alpha 7 nicotinic acetylcholine receptor (α7 nAChR) hypofunction in schizophrenia have shown mixed success in ameliorating cognitive impairments associated with this disorder. Choline, a selective agonist at α7 receptors is increased with oral administration of cytidine 5'-diphosphocholine (CDP-choline), the cognitive effects of which were assessed in healthy volunteers. Using the CogState test battery, behavioral performance in schizophrenia-relevant cognitive domains was assessed in 24 male participants following a single low (500mg) and moderate (1000mg) dose of CDP-choline. Relative to placebo, CDP-choline improved processing speed, working memory, verbal learning, verbal memory, and executive function in low baseline performers, while exerting no effects in medium baseline performers, and diminishing cognition in high baseline performers. Dose effects varied with cognitive domain but were evident with both the 500mg and 1000mg doses. These preliminary findings of cognitive enhancement in relatively impaired performers are consistent with the α7 receptor mechanism and support further trials with CDP-choline as a potential pro-cognitive strategy for cognitive impairment in schizophrenia.

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. ( J Geriatr Psychiatry Neurol 2000; 13:1-8).

Previous findings of cognitive deficits and EEG slowing in Alheimer’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.

Anticholinergic drugs have been proposed as possible acute model for investigating geriatric-associated cognitive deficits, but the interactive effect of muscarinic and nicotinic cholinergic blockade on cognitive processes has yet to be examined. Behavioural performance and P300 event-related potential (ERP) measures were assessed in visual and auditory continuous performance (CPT) takes in 10 young adults before and after the double-blind acute administration of a placebo, a centrally acting nicotinic blocker (20 mg mecamylamine), a centrally acting muscarinic blocker (0·6 mg scopolamine) and a combination dose of mecamylamine and scopolamine. Relative to placebo, single and combined drug administration failed to alter response accuracy, but slowed reaction times in both tasks and decreased subjective alertness. Mecamylamine along significantly reduced P300 amplitudes, but only during the visual CPT. The results are discussed in relation to cholinergic functioning in normal and pathological cognition. Copyright © 1999 John Wiley & Sons, Ltd.

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.

Anticholinergic drugs have been proposed as a possible acute model for human electroencephalographic (EEG) studies focused on dementia but the interactive effects of muscarinic and nicotinic cholinergic receptor system blockade on the regulation of electrocortical activity has yet to be examined. EEG recordings were carried out in 15 normal subjects before and after the double-blind acute administration of a placebo, a centrally acting nicotinic blocker (20 mg of mecamylamine), a centrally acting muscarinic blocker (0·6 mg of scopolamine) and a combination dose of mecamylamine and scopolamine. Mecamylamine decreased absolute and relative beta power and increased relative theta power. Scopolamine increased relative power in both theta and beta frequency bands. Mecamylamine produced greater theta increments than scopolamine, while combined administration of the two central blockers induced changes similar to that observed with mecamylamine administered alone. Results are discussed in relation to electrocerebral activity in normal and pathological aging. © 1997 John Wiley & Sons, Ltd.

Nicotine amelioration of serotonergically mediated mood dysregulation may contribute to the comorbidity between cigarette smoking and depression, a disorder which is associated with aberrant activation and hemispheric asymmetry in frontal and posterior cortical regions. This randomized, double-blind study in 20 healthy volunteers with a positive family history of depression examined the effects of transdermal nicotine on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). Increased self-ratings of depressed mood and elevation in left frontal high alpha power (decreased activation) were evidenced with ATD (vs. balanced mixture) in participants treated with the placebo but not the nicotine treated group. Nicotine alone increased vigor and posterior high alpha bilaterally, and during ATD it prevented the reduction in left frontal high alpha that was evident in the placebo patch group. These findings indicate that in depression prone individuals, nicotine acts to stabilize the mood lowering and associated frontal functional asymmetry elicited by an acute decrease in brain serotonin.

Background: Depression, which is associated with dysfunctional serotonin (5-HT) activity, may be characterized by impaired emotional information processing. This study assessed the effects of acute tryptophan depletion (TRP–), which transiently lowers CNS 5-HT, on the emotion-sensitive vertex positive potential (VPP) and late positive potential (LPP) event-related potentials (ERPs) and mood in individuals with a family history of depression. The VPP and LPP are thought to index the early and later stages of motivated attentional processing, respectively. Method: Within a double-blind balanced design, ERPs were acquired in 18 individuals with a family history of depression (12 females) after TRP– and TRP+ (balanced) treatment while participants were presented with facial expressions (neutral, as well as sad, joy and surprise at 50 and 100% intensity) and responded to surprised faces. Results: TRP– increased total mood disturbance and maintained depression scores. The VPP and LPP were larger to intense versus mild expressions. Enhanced processing of emotional versus neutral faces, as indexed by the VPP, was primarily evident with TRP–. Speeded and enhanced processing of intensely joyful versus mildly sad faces was found with TRP– (VPP indexed). Compared with TRP+, TRP also increased the VPP to mildly joyful faces. Conclusion: Transient 5-HT decreases in individuals with a family history of depression induce subtle changes in early stages of motivated emotional processing, though not in later ones.

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.

Evidence from pre-clinical infrahuman investigations, open-label clinical trials, and a single controlled trial found acute nicotine treatment potentiated up to 4 weeks neuroleptic-induced reductions of dyskinetic symptoms characterizing Tourette’s syndrome (TS). Given the attentional disturbances associated with this syndrome, and the improvements in attentional processes reported with nicotine, this randomized, double-blind, placebo-controlled trial examined the acute (4 h) and sustained (2 weeks) effects of a single dose of transdermal nicotine on clinical (i.e., tics), attentional (continuous performance task, event-related potentials, patient and parental reports) and behavioral symptoms in 23 children and adolescents with TS receiving neuroleptic treatment. In the 14 evaluable patients with complete primary efficacy data, nicotine (compared to placebo) failed to alter symptoms at 4 h but counteracted ERP-P300 signs of diminished attention seen 2 weeks following placebo treatment. Secondary efficacy measures, including patient self-reports and parental ratings, found nicotine to reduce complex tics and improve behaviors related to inattention. Additional work with intermittent dosing schedules is required to characterize optimal clinical and cognitive effects with nicotine treatment.

Given the arousal eliciting actions of smoking and nicotine, and the contributing role of noradrenaline in brain arousal systems, this study examined the neuroelectric and affective correlates of cigarette smoking following acute pre-treatment with the alpha 2-noradrenergic auto-receptor agonist, clonidine. In a double-blind placebo-controlled crossover design, quantitative electroencephalography (EEG), mood, and smoking withdrawal symptoms were assessed in 12 overnight smoking abstinence smokers, before and after sham and cigarette smoking. Orally administered clonidine (0.1 mg) failed to alter overnight smoking abstinence symptoms or the EEG arousal and mood-elevating response seen with the smoking of a single cigarette. The results are discussed in relation to neural mechanisms underlying the acute reinforcement maintaining nicotine use.

Given the putative role of serotonin in the modulation of smoking withdrawal and the central actions of nicotine, this study examined the affective and neuroelectric correlates of smoking abstinence and cigarette smoking following depletion of the serotonin precursor, tryptophan. In a randomized, double-blind two session (tryptophan depletion [TD] vs. nondepletion), placebo-controlled design, spectrally analyzed electroencephalogram (EEG), self-ratings of withdrawal symptoms and mood states were assessed in 18 male cigarette smokers before smoking abstinence, 5 h postsmoking abstinence and again following sham smoking and the smoking of one cigarette. Compared to a nutritionally balanced amino acid (AA) mixture containing tryptophan (i.e., placebo mixture), oral ingestion of a similar mixture devoid of tryptophan resulted in a 70% reduction of plasma tryptophan but failed to alter the appearance or reversal (by acute cigarette smoking) of withdrawal symptoms, negative mood states and increased slow wave EEG in male smokers deprived of cigarettes. These results, although not supporting a role for the serotonergic system in acute smoking and early smoking abstinence symptoms, are discussed in relation to the neuropharmacology of smoking behavior and suggestions for future work.

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 (µV) and relative (%) amplitudes in slow-frequency bands (δ, Θ, α1) were reduced and absolute and relative amplitudes in fast-frequency bands (α2, β) were increased following cigarette smoking as compared to sham smoking. Haloperidol pretreatment inhibited the smoking-induced increase in absolute β 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, α2 increments were associated with increases in alertness and decreases in euphoria while β 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 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.

Introduction Contributing to poor global functioning, auditory hallucinations (AH) also interfere with elementary cognitive processes, including auditory discrimination. This is evidenced in schizophrenic (SZ) hallucinators (vs. non-hallucinators) by a greater reduction of the MMN, an auditory event-related brain potential (ERP) generated in part by NMDA receptor activity and normalized with nicotinic (nACh) agonist treatment. Objectives To increase our understanding of NMDA-nACh interactions with auditory processing, using healthy young adults varying in their degree of experience with AH, thereby reducing the confounding influence of illness chronicity and medication associated with the study of SZ patients. Aims To investigate MMN differences between low and high AH subjects during separate and combined administration of ketamine, an NMDA antagonist, and nicotine, an nACh agonist. Methods In 40 healthy controls, all rated for AH with the Bell Object Relations and Reality Testing Inventory, MMN to frequency deviants was assessed in a randomized, placebo-controlled crossover design involving the separate and combined administration of a intravenous sub-psychotomimetic dose of ketamine (0.04 mg/kg) and a dose of nicotine gum (4 mg). Results In high AH subjects, ketamine reduced MMN, with the resulting amplitude being smaller than that of low AH subjects. This ketamine-induced MMN reduction was evident only with placebo gum; furthermore combined nicotine-ketamine treatment acted to increase MMN in high scorers. Conclusions AH in otherwise healthy individuals is associated with heightened sensitivity to NMDA receptor blockade, the effects of which are moderated by nicotinic neurotransmission. Both neurotransmitters may interact to moderate auditory processing and AH in SZ.