Anne Millar

Increased Serotonin-1A (5-HT1A) Autoreceptor Expression and Reduced Raphe Serotonin Levels in Deformed Epidermal Autoregulatory Factor-1 (Deaf-1) Gene Knock-out Mice

Background: Dysregulation of 5-HT1A receptors is associated with depression, but the transcriptional mechanisms are unclear. Results: Deaf-1 binds the 5-HT1A promoter, and loss of Deaf-1 results in altered expression of 5-HT1A receptors and reduced serotonin levels. Conclusion: Deaf-1 is a key regulator of 5-HT1A expression in vivo that is affected by a promoter polymorphism prevalent in human depression. Significance: Understanding transcriptional regulators of serotonin could lead to improved antidepressant strategies. Altered regulation of the serotonin-1A (5-HT1A) receptor gene is implicated in major depression and mood disorders. The functional human 5-HT1A C(−1019)G promoter polymorphism (rs6295), which prevents the binding of Deaf-1/NUDR leading to dysregulation of the receptor, has been associated with major depression. In cell models Deaf-1 displays dual activity, repressing 5-HT1A autoreceptor expression in serotonergic raphe cells while enhancing postsynaptic 5-HT1A heteroreceptor expression in nonserotonergic neurons. A functional Deaf-1 binding site on the mouse 5-HT1A promoter was recognized by Deaf-1 in vitro and in vivo and mediated dual activity of Deaf-1 on 5-HT1A gene transcription. To address regulation by Deaf-1 in vivo, Deaf-1 knock-out mice bred to a C57BL/6 background were compared with wild-type siblings for changes in 5-HT1A RNA and protein by quantitative RT-PCR, in situ hybridization, and immunofluorescence. In the dorsal raphe, Deaf-1 knock-out mice displayed increased 5-HT1A mRNA, protein, and 5-HT1A-positive cell counts but reduced 5-HT levels, whereas other serotonergic markers, such as tryptophan hydroxylase (TPH)- or 5-HT-positive cells and TPH2 RNA levels, were unchanged. By contrast, 5-HT1A mRNA and 5-HT1A-positive cells were reduced in the frontal cortex of Deaf-1-null mice, with no significant change in hippocampal 5-HT1A RNA, protein, or cell counts. The region-specific alterations of brain 5-HT1A gene expression and reduced raphe 5-HT content in Deaf-1−/− mice indicate the importance of Deaf-1 in regulation of 5-HT1A gene expression and provide insight into the role of the 5-HT1A G(−1019) allele in reducing serotonergic neurotransmission by derepression of 5-HT1A autoreceptors.

Sensory gating and source analysis of the auditory P50 in low and high suppressors

Impairments in sensory gating in schizophrenia have been reflected by diminished suppression of the scalp-recorded middle latency auditory P50 event-related potential (MLAERP) elicited by the second (S(2)) of a pair (S(1)-S(2)) of clicks. As understanding the functional neural substrates of aberrant gating would have important implications for schizophrenia, this study examined the location and time-course of the neural generators of the P50 MLAERP and its gating on subgroups of healthy volunteers exhibiting low (n=12) and high (n=12) P50 suppression. Suppressor differences were observed with S(1) P50 (high>low) and S(2) P50 (high<low) amplitudes, and current source density analysis with standardized Low Resolution Electromagnetic Tomography (sLORETA) evidenced an S(1) P50-related activation of limbic, temporal and parietal regions in the high but not the low suppressors. Distributed source localization of the Gating Difference Wave (GDW), obtained by subtracting the S(2) P50 response from the S(1) P50 response, also revealed a later and sustained frontal activation to characterize high suppressors. These findings suggest that impaired gating of the kind evident in schizophrenia may involve the deficient functioning of multiple interconnected and temporally overlapping activated brain regions.

MMN responsivity to manipulations of frequency and duration deviants in chronic, clozapine-treated schizophrenia patients

Event-related potential (ERP) probing of abnormal sensory processes in schizophrenia with the mismatch negativity (MMN) has shown impairments in auditory change detection, but knowledge of the acoustic features leading to this deficit is incomplete. Changes in the duration and frequency properties of sound stimuli result in diminished MMNs in schizophrenia but it is unclear as to whether this reduced responsiveness is seen with more subtle changes in sound frequency. In a sample of 19 healthy controls and 21 patients with chronic schizophrenia treated with clozapine, MMN was assessed in response to tone frequency changes of 5%, 10% and 20%, and to tone duration changes. Patients exhibited reduced amplitudes and shorter latencies than controls to all frequency changes, and attenuated amplitudes to tone duration increments and decrements. Clozapine dose was related to MMN, with increasing dose being positively associated with frequency-MMN amplitudes (10% ∆f, 20% ∆f) and negatively associated with the amplitude and latency of duration-MMNs. These data support the well-established findings of auditory sensory abnormality in schizophrenia and underscore the sensitivity of MMN to relatively small auditory change detection deficits that may appear to characterize chronic schizophrenia.

Effects of nicotine on the amplitude and gating of the auditory P50 and its influence by dopamine D2 receptor gene polymorphism

Evidence of normalized auditory P50 suppression with acute nicotine in schizophrenia has supported the contention that elevated smoking rates in this disorder may be an attempt to correct a nicotinic receptor pathophysiology that may underly impaired sensory gating in these patients. There is very little information regarding the neurochemical or genetic pathways through which nicotine regulates P50 amplitude and its suppression in human studies. In a randomized, double-blind, placebo-controlled design with 24 non-smokers, this study examined the influence of TaqIA dopamine D2 receptor gene polymorphisms on P50 and its inhibition during nicotine gum (6 mg) administration. Within a paired click (S(1)-S(2)) paradigm, placebo treated A1(+) and A1(-) allele groups differed with respect to P50 amplitude and gating. While nicotine (relative to placebo) attenuated S(1) P50 amplitude in A1(+) allele carriers, in the A1(-) carriers it increased S(2) P50 amplitude and increased P50 gating as indexed by an augmented gating difference wave (GDW). These findings suggest that nicotine exerts mixed gating properties in healthy nicotine naive volunteers and that dopamine functions to alter both P50 and its gating as well as their response to acute nicotine agonist treatment.

Differential effects of nicotine on P50 amplitude, its gating, and their neural sources in low and high suppressors.

Sensory gating impairment in schizophrenia has been documented in the form of aberrant middle latency P50 event-related brain potential responses to S(1) and/or S(2) stimuli in a paired (S(1)-S(2)) auditory stimulus paradigm. Evidenced by a failure to suppress S(2) P50 or by attenuated S(1) P50s, these sensory deficits have been associated with increased smoking behaviour in this disorder, and may be related to the putative ameliorating effects of smoke-inhaled nicotine on neural mechanisms regulating gating. Comparison of healthy controls with low versus high gating efficiency has been forwarded as a model for investigating the actions of antipsychotic agents on aberrant gating functions. In the current study, the effect of a single dose (6 mg) of nicotine gum on P50, gating indices, and their cortical sources indexed with sLORETA (standardized low resolution electromagnetic tomography), was examined in healthy non-smokers (n=24) stratified for low and high gating levels. Scalp surface recordings revealed nicotine modulation of P50 and its gating to be differentially exhibited in high (decreasing gating) and low (increasing gating) suppressors while the underlying cortical sources influenced by nicotine (middle frontal gyrus, inferior/superior parietal lobules, pre- and post-central gyri) were seen only in low suppressors. These findings suggest that nicotine impacts sensory gating in healthy volunteers and as the gating enhancing effects were dependent on low baseline gating efficiency, nicotinic receptor agonists may be associated with unique P50 modulating actions in schizophrenia.

Acute Nicotine Fails to Alter Event-Related Potential or Behavioral Performance Indices of Auditory Distraction in Cigarette Smokers

Behavioral studies have shown that nicotine enhances performance in sustained attention tasks, but they have not shown convincing support for the effects of nicotine on tasks requiring selective attention or attentional control under conditions of distraction. We investigated distractibility in 14 smokers (7 females) with event-related brain potentials (ERPs) and behavioral performance measures extracted from an auditory discrimination task requiring a choice reaction time response to short- and long-duration tones, both with and without embedded deviants. Nicotine gum (4 mg), administered in a randomized, double-blind, placebo-controlled crossover design, failed to counter deviant-elicited behavioral distraction (i.e., slower reaction times and increased response errors), and it did not influence the distracter-elicited mismatch negativity, the P300a, or the reorienting negativity ERP components reflecting acoustic change detection, involuntary attentional switching, and attentional reorienting, respectively. Results are discussed in relation to a stimulus-filter model of smoking and in relation to future research directions.

Nicotine, auditory sensory memory, and sustained attention in a human ketamine model of schizophrenia: moderating influence of a hallucinatory trait

Background: The procognitive actions of the nicotinic acetylcholine receptor (nAChR) agonist nicotine are believed, in part, to motivate the excessive cigarette smoking in schizophrenia, a disorder associated with deficits in multiple cognitive domains, including low-level auditory sensory processes and higher-order attention-dependent operations. Objectives: As N-methyl-d-aspartate receptor (NMDAR) hypofunction has been shown to contribute to these cognitive impairments, the primary aims of this healthy volunteer study were to: (a) to shed light on the separate and interactive roles of nAChR and NMDAR systems in the modulation of auditory sensory memory (and sustained attention), as indexed by the auditory event-related brain potential – mismatch negativity (MMN), and (b) to examine how these effects are moderated by a predisposition to auditory hallucinations/delusions (HD). Methods: In a randomized, double-blind, placebo-controlled design involving a low intravenous dose of ketamine (0.04 mg/kg) and a 4 mg dose of nicotine gum, MMN, and performance on a rapid visual information processing (RVIP) task of sustained attention were examined in 24 healthy controls psychometrically stratified as being lower (L-HD, n = 12) or higher (H-HD) for HD propensity. Results: Ketamine significantly slowed MMN, and reduced MMN in H-HD, with amplitude attenuation being blocked by the co-administration of nicotine. Nicotine significantly enhanced response speed [reaction time (RT)] and accuracy (increased % hits and d′ and reduced false alarms) on the RVIP, with improved performance accuracy being prevented when nicotine was administered with ketamine. Both % hits and d′, as well as RT were poorer in H-HD (vs. L-HD) and while hit rate and d′ was increased by nicotine in H-HD, RT was slowed by ketamine in L-HD. Conclusions: Nicotine alleviated ketamine-induced sensory memory impairment and improved attention, particularly in individuals prone to HD.

Craving-Induced EEG Reactivity in Smokers: Effects of Mood Induction, Nicotine Dependence and Gender

Background/Aims: Cigarette craving is a core symptom of smoking withdrawal, which is more intense and more frequently observed in smokers with depressed mood. Using self-reports and electroencephalographic (EEG) indices of frontal hemispheric asymmetry, which has been shown to be sensitive to mood states, the purpose of this study was to investigate the neural basis of cue-elicited cigarette craving, its variation with experimentally induced depressed mood, and with differences in gender and smoker type. Methods: Cigarette-cue reactivity was examined in 11 (5 male) regular and 11 (6 male) light smokers in two sessions involving the induction of neutral or depressed mood. Results: Frontal EEG alpha asymmetry changes reflecting left frontal hypoactivation were evident with cigarette-cue exposure, particularly in female smokers. During cigarette-cue exposure, EEG evidenced both decreases and increases in brain state activation, with the latter activational increments also being influenced by depressed mood. Exposure to the cigarette cue, in addition to increasing withdrawal symptoms, increased cravings and negative affect, these latter effects being more evident in female and regular smokers. Conclusion: These findings, which appear to provide a physiological basis for ‘withdrawal-like’ negative affective experiences during craving, are discussed in relation to theories of drug reinforcement and smoking motivation.

Separate and combined effects of low dose ketamine and nicotine on behavioural and neural correlates of sustained attention

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 (.04mg/kg) of ketamine or placebo, which was accompanied by acute treatment with nicotine (4mg) or placebo gum. Nicotine-enhanced attentional processing was most evident in nonsmokers, with both performance accuracy and P300 amplitude measures. Ketamines 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.

Neural Effects of Nicotine during Auditory Selective Attention in Smokers: An Event-Related Potential Study

Acute nicotine has been found to improve task performance in smokers after smoking abstinence, but the attentional processes mediating these improvements are unclear. Since scalp-recorded event-related potentials (ERPs) have been shown to be sensitive indicators of selective attention, the effects of acutely administered nicotine were examined on ERPs and concomitant behavioural performance measures in an auditory selective attention task. Ten (6 males) overnight smoking-abstinent cigarette smokers received nicotine gum (4 mg) in a randomized, double-blind, placebo-controlled, crossover design. In a dichotic listening task [which required participants to attend and detect (target) deviant stimuli in one ear and to ignore similar stimuli in the other ear] which included ERP recordings and assessment of response speed and accuracy measures, nicotine gum failed to alter behavioural performance or amplitudes of ERP components sensitive to selective attention [reflected in the N100 and negative difference (Nd) component] or to pre-attentive detection of acoustic change [reflected in the mismatch negativity (MMN) component]. However, nicotine did influence the speed of these voluntary selective processes, as reflected by shortened latencies of the early Nd component. The findings are discussed in relation to the stimulus filter theory of smoking, and with respect to nicotine’s actions on involuntary and controlled aspects of selective attention processes.