Human brain 7Li-MRI following low-dose lithium dietary supplementation in healthy participants.

BACKGROUND: Lithium is an effective mood stabiliser, but its mechanism of action is incompletely defined. Even at very low doses, lithium may have neuroprotective effects, but it is not clear if these relate to brain lithium concentration in vivo. We have developed magnetic resonance imaging (7Li-MRI) methods to detect lithium in the brain following supplementation at a very low dose. METHODS: Lithium orotate supplements were taken by nine healthy adult male subjects (5 mg daily) for up to 28 days, providing 2-7 % of the lithium content of a typical therapeutic lithium carbonate dose. One-dimensional 7Li-images were acquired on a 3.0 T MRI scanner. All subjects were scanned on day 14 or 28; seven were scanned on both, one at baseline and one after 7-days washout. RESULTS: 7Li-MR signal amplitude was broadly stable between days 14 and 28. Two subjects had notably higher 7Li-signal intensities (approximately 2-4×) compared to other study participants. LIMITATIONS: Lithium adherence was self-reported by all participants without formal validation. The coarse spatial resolution necessary for detection of low concentrations of 7Li exhibits imperfect spatial separation of signal from adjacent pixels. CONCLUSIONS: 7Li-MRI performed using a clinical 3T scanner demonstrated detection of lithium in the brain at very low concentration, in the range of approximately 10-60 mM. The methods are suited to studies assessing low dose lithium administration in psychiatric and neurodegenerative disorders, and permit the comparison of different lithium salt preparations at a time of emerging interest in the field.

Kisspeptin modulates gamma-aminobutyric acid levels in the human brain.

Gamma-aminobutyric acid (GABA) is a key inhibitory neurotransmitter that has been implicated in the aetiology of common mood and behavioural disorders. By employing proton magnetic resonance spectroscopy in man, we demonstrate that administration of the reproductive neuropeptide, kisspeptin, robustly decreases GABA levels in the limbic system of the human brain; specifically the anterior cingulate cortex (ACC). This finding defines a novel kisspeptin-activated GABA pathway in man, and provides important mechanistic insights into the mood and behaviour-altering effects of kisspeptin seen in rodents and humans. In addition, this work has therapeutic implications as it identifies GABA-signalling as a potential target for the escalating development of kisspeptin-based therapies for common reproductive disorders of body and mind.

The Effects of Kisspeptin on Brain Response to Food Images and Psychometric Parameters of Appetite in Healthy Men.

CONTEXT: The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans. OBJECTIVE: This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men. DESIGN: A double-blinded, randomized, placebo-controlled, crossover study was conducted. PARTICIPANTS: Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2). INTERVENTION: Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes. MAIN OUTCOME MEASURES: Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle. RESULTS: Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle. CONCLUSIONS: This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism.

Effects of Glucagon-like Peptide-1 on the Reproductive Axis in Healthy Men.

CONTEXT: Glucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans. OBJECTIVE: To investigate the effects of GLP-1 administration on the reproductive axis in humans. DESIGN: Single-blind, randomized, placebo-controlled crossover study. SETTING: Clinical Research Facility, Imperial College Healthcare NHS Trust. PARTICIPANTS: Eighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2). INTERVENTION: Eight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion. MAIN OUTCOME MEASURES: Number of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels. RESULTS: The number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01). CONCLUSIONS: In contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

Rapid-response impulsivity: definitions, measurement issues, and clinical implications.

Impulsivity is a multifaceted construct that is a core feature of multiple psychiatric conditions and personality disorders. However, progress in understanding and treating impulsivity is limited by a lack of precision and consistency in its definition and assessment. Rapid-response impulsivity (RRI) represents a tendency toward immediate action that occurs with diminished forethought and is out of context with the present demands of the environment. Experts from the International Society for Research on Impulsivity (InSRI) met to discuss and evaluate RRI measures in terms of reliability, sensitivity, and validity, with the goal of helping researchers and clinicians make informed decisions about the use and interpretation of findings from RRI measures. Their recommendations are described in this article. Commonly used clinical and preclinical RRI tasks are described, and considerations are provided to guide task selection. Tasks measuring two conceptually and neurobiologically distinct types of RRI, "refraining from action initiation" (RAI) and "stopping an ongoing action" (SOA) are described. RAI and SOA tasks capture distinct aspects of RRI that may relate to distinct clinical outcomes. The InSRI group recommends that (a) selection of RRI measures should be informed by careful consideration of the strengths, limitations, and practical considerations of the available measures; (b) researchers use both RAI and SOA tasks in RRI studies to allow for direct comparison of RRI types and examination of their associations with clinically relevant measures; and (c) similar considerations be made for human and nonhuman studies in an effort to harmonize and integrate preclinical and clinical research.

Choice impulsivity: Definitions, measurement issues, and clinical implications.

Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, and steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.

Measuring cigarette smoking-induced cortical dopamine release: A [¹¹C]FLB-457 PET study.

Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [(11)C]-FLB-457-binding potential (BPND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BPND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BPND change -12.1±9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [(11)C]FLB-457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response.

Elevation of dopamine induced by cigarette smoking: novel insights from a [11C]-+-PHNO PET study in humans.

Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [(11)C]-(+)-PHNO ([(11)C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [(11)C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [(11)C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [(11)C]-(+)-PHNO binding in D2 and D3-rich areas (-12.0 and -15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [(11)C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.

Neurocognitive endophenotypes in schizophrenia: modulation by nicotinic receptor systems.

Cigarette smoking is the leading preventable cause of death in the Western world, with a considerably higher prevalence observed in schizophrenia compared to the general population. Despite the negative health consequences of smoking heavily, it has been proposed that individuals with schizophrenia may maintain smoking behaviors to remediate symptoms associated with the disorder. Neurocognitive deficits are a core feature of schizophrenia and are present in approximately 80% of patients. Further, these deficits constitute an endophenotype of schizophrenia, as they are stable across disease phases, and are heritable. The neurocognitive deficits that are present in schizophrenia are especially debilitating, since they are associated with poor clinical and functional outcomes and community integration. Interestingly, these deficits may also constitute a vulnerability factor towards the initiation and maintenance of tobacco use. Contributing to the potential shared vulnerability between schizophrenia and tobacco dependence is a dysregulation of the nicotinic acetylcholine receptor (nAChR) system. Pre-clinical evidence has shown that nicotine affects several neurotransmitter systems, including dopamine (DA), glutamate, and γ-aminobutyric acid (GABA), and certain neuropsychological deficits associated with these neurotransmitters (reaction time, spatial working memory, sustained attention, and sensory gating) are improved after nicotine administration in patients with schizophrenia. These positive effects on neurocognition appear to be more pronounced in smokers with schizophrenia, and may be an important mechanism that explains the co-morbidity of schizophrenia and tobacco dependence.

Effect of infusion rate on intravenous nicotine self-administration in rats.

The reinforcing effects of addictive drugs are thought to be more robust when the onset of the drug's effects is fast. It is unclear whether this concept extends to intravenous self-administration (IVSA) of nicotine. We therefore sought to examine the effects of infusion duration on nicotine IVSA in rats. Male Lister hooded rats (n=8) were given daily 1 h limited access to fixed ratio-3 nicotine IVSA (0.03 mg/kg/infusion). Once nicotine IVSA was established, the effect of infusion duration on nicotine seeking was evaluated at a constant unit dose and volume (0.5, 5.0, and 19.6 s compared with the 1-s training infusion duration). Active responses were significantly reduced when the infusion duration was increased (i.e. 5 or 19.6 s compared with 0.5 and 1 s), and the effect was qualitatively similar to saline substitution. The likelihood of maintaining a reliable IVSA in rats was reduced by increasing the infusion duration. The infusion duration therefore represents an important determinant of nicotine reinforcement in rats.

Effects of tobacco smoking on neuropsychological function in schizophrenia in comparison to other psychiatric disorders and non-psychiatric controls.

BACKGROUND AND OBJECTIVES: Compared to the general population cigarette smoking prevalence is elevated in psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). These disorders are also associated with neurocognitive impairments. Cigarette smoking is associated with improved cognition in SZ. The effects of smoking on cognition in BD and MDD are less well studied. METHODS: We used a cross-sectional design to study neuropsychological performance in these disorders as a function of smoking status. Subjects (N = 108) were SZ smokers (n = 32), SZ non-smokers (n = 15), BD smokers (n = 10), BD non-smokers (n = 6), MDD smokers (n = 6), MDD non-smokers (n = 10), control smokers (n = 12), and control non-smokers (n = 17). Participants completed a neuropsychological battery; smokers were non-deprived. RESULTS: SZ subjects performed significantly worse than controls in select domains, while BD and MDD subjects did not differ from controls. Three verbal memory outcomes were improved in SZ smokers compared with non-smokers; smoking status did not alter performance in BD or MDD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These data suggest that smoking is associated with neurocognitive improvements in SZ, but not BD or MDD. Our data may suggest specificity of cigarette-smoking modulation of neurocognitive deficits in SZ.

Brain stimulation methods to treat tobacco addiction.

BACKGROUND: Tobacco smoking is the leading cause of preventable deaths worldwide, but many smokers are simply unable to quit. Psychosocial and pharmaceutical treatments have shown modest results on smoking cessation rates, but there is an urgent need to develop treatments with greater efficacy. Brain stimulation methods are gaining increasing interest as possible addiction therapeutics. OBJECTIVES: The purpose of this paper is to review the studies that have evaluated brain stimulation techniques on tobacco addiction, and discuss future directions for research in this novel area of addiction interventions. METHODS: Electronic and manual literature searches identified fifteen studies that administered repetitive transcranial magnetic stimulation (rTMS), cranial electrostimulation (CES), transcranial direct current stimulation (tDCS) or deep brain stimulation (DBS). RESULTS: rTMS was found to be the most well studied method with respect to tobacco addiction. Results indicate that rTMS and tDCS targeted to the dorsolateral prefrontal cortex (DLPFC) were the most efficacious in reducing tobacco cravings, an effect that may be mediated through the brain reward system involved in tobacco addiction. While rTMS was shown to reduce consumption of cigarettes, as yet no brain stimulation technique has been shown to significantly increase abstinence rates. It is possible that the therapeutic effects of rTMS and tDCS may be improved by optimization of stimulation parameters and increasing the duration of treatment. CONCLUSION: Although further studies are needed to confirm the ability of brain stimulation methods to treat tobacco addiction, this review indicates that rTMS and tDCS both represent potentially novel treatment modalities.

Reproducibility of the nicotine metabolite ratio in cigarette smokers.

BACKGROUND: The nicotine metabolite ratio (NMR or 3-hydroxycotinine/cotinine) has been used to phenotype CYP2A6-mediated nicotine metabolism. Our objectives were to analyze (i) the stability of NMR in plasma, saliva, and blood in various storage conditions, (ii) the relationship between NMRs derived from blood, plasma, saliva, and urine, and (iii) the reproducibility of plasma NMR in ad libitum cigarette smokers. METHODS: We analyzed data from four clinical studies. In studies 1 and 2, we assessed NMR stability in saliva and plasma samples at room temperature (~22°C) over 14 days and in blood at 4°C for up to 72 hours. In studies 2 and 3, we used Bland-Altman analysis to assess agreement between blood, plasma, saliva, and urine NMRs. In study 4, plasma NMR was measured on six occasions over 44 weeks in 43 ad libitum smokers. RESULTS: Reliability coefficients for stability tests of NMR in plasma and saliva at room temperature were 0.97 and 0.98, respectively, and 0.92 for blood at 4°C. Blood NMR agreed consistently with saliva and plasma NMRs but showed more variability in relation to urine NMR. The reliability coefficient for repeated plasma NMR measurements in smokers was 0.85. CONCLUSION: The NMR is stable in blood, plasma, and saliva at the conditions tested. Blood, plasma, and saliva NMRs are similar whereas urine NMR is a good proxy for these NMR measures. Plasma NMR was reproducible over time in smokers. IMPACT: One measurement may reliably estimate a smoker's NMR for use as an estimate of the rate of nicotine metabolism.

Translating the smoking cessation properties of the antidepressant nortriptyline using reinforcing, discriminative and aversive stimulus effects of nicotine in rats.

RATIONALE: The antidepressant nortriptyline is a second-line pharmacotherapy for smoking cessation. Given that there is limited preclinical data available on the effects of nortriptyline on responses to nicotine, the present study sought to evaluate its effects on the reinforcing, discriminative stimulus (DS) and aversive effects of nicotine in male hooded Lister rats. METHODS: The effects of nortriptyline (0, 1, 3 and 10 mg/kg, i.p.) on responding under the control of a second order schedule of nicotine (0.03 mg/kg per infusion) intravenous self-administration (IVSA; n = 7), food-maintained responding (n = 6), discrimination of nicotine (0.2 mg/kg, s.c.) from saline in a two-lever procedure controlled by a fixed ratio and variable interval schedule of food reinforcement (n = 12) and on the development of nicotine- and lithium-induced conditioned taste aversions (CTA) (n = 8 per dose of nortriptyline) were examined. RESULTS: Nortriptyline (3 mg/kg) reduced responding for nicotine in the drug-free interval in which behaviour was supported by nicotine-associated cues and subsequent intervals in which nicotine was available; however, food-maintained responding was also reduced at the same dose. Nortriptyline (3 mg/kg) blocked the development of a nicotine-induced CTA but not a lithium-induced CTA, indicating that these effects are unlikely to be due to non-specific effects of nortriptyline on taste perception or learning. Lastly, nortriptyline had no effect on the DS properties of nicotine. CONCLUSIONS: Nortriptyline appears to attenuate the reinforcing and aversive stimulus properties of nicotine, which may mediate its anti-smoking effects. However, the results should be interpreted with caution, as non-specific effects of nortriptyline may have contributed to these findings.

Effects of cigarette smoking status on delay discounting in schizophrenia and healthy controls.

BACKGROUND: Delay discounting is a measure of future-oriented decision-making and impulsivity. Cigarette smoking is associated with rapid discounting of the value of delayed outcomes. In schizophrenia, however, cigarette smoking improves certain neurocognitive impairments associated with the disorder which may explain the high smoking rates in this population. This study examined the relationship between cigarette smoking and delay discounting in schizophrenia and control participants. METHODS: A total of N=130 participants, including those with schizophrenia (n=68) and healthy controls (n=62) were assessed on the Kirby Delay Discounting Task and compared across smoking status (smokers; non-smokers) and smoking history (current, former; never smokers). RESULTS: Smokers exhibited higher discounting rates (i.e., were more impulsive) than non-smokers of the same diagnostic group. Current and former smokers with schizophrenia exhibited similar and significantly higher discounting rates than never smokers, suggesting that in schizophrenia delay discounting is a trait-dependent phenomenon independent of current cigarette smoking. Consistent with previous studies, there was a trend for higher discounting rates in control current smokers compared to control former and never smokers. CONCLUSIONS: Smokers with and without schizophrenia have higher rates of delay discounting than non-smokers. However, in schizophrenia, rapid delay discounting appears to be a trait associated with having ever been a smoker (i.e., current and former smoking).

A review of neurobiological vulnerability factors and treatment implications for comorbid tobacco dependence in schizophrenia.

There is converging evidence that certain subpopulations of smokers, such as smokers with a serious mental illness like schizophrenia (SCZ), are more likely to become addicted to tobacco and are less likely to quit smoking. This review focuses on the unique risk factors that may increase vulnerability to the initiation and maintenance of nicotine addiction in persons with schizophrenia and other psychotic disorders and also reviews the latest approaches to treating nicotine addiction and schizophrenia based on our neurobiological understanding of central nicotinic receptor systems and related neurotransmitters. In addition, suggestions for future lines of research to better understand reasons for the comorbidity of nicotine addiction in schizophrenia are discussed.