Differences between hemispheres and in saccade latency regarding volleyball athletes and non-athletes during saccadic eye movements: an analysis using EEG / Diferenças inter-hemisféricas e na latência sacádica entre atletas de voleibol e não atletas durante movimentos oculares sacádicos: uma análise usando EEG

Abstract Background The saccadic eye movement is responsible for providing focus to a visual object of interest to the retina. In sports like volleyball, identifying relevant targets quickly is essential to a masterful performance. The training improves cortical regions underlying saccadic action, enabling more automated processing in athletes. Objective We investigated changes in the latency during the saccadic eye movement and the absolute theta power on the frontal and prefrontal cortices during the execution of the saccadic eye movement task in volleyball athletes and non-athletes. We hypothesized that the saccade latency and theta power would be lower due to training and perceptual-cognitive enhancement in volleyball players. Methods We recruited 30 healthy volunteers: 15 volleyball athletes (11 men and 4 women; mean age: 15.08 ± 1.06 years) and 15 non-athletes (5 men and 10 women; mean age: 18.00 ± 1.46 years). All tasks were performed simultaneously with electroencephalography signal recording. Results The latency of the saccadic eye movement presented a significant difference between the groups; a shorter time was observed among the athletes, associated with the players' superiority in terms of attention level. During the experiment, the athletes observed a decrease in absolute theta power compared to non-athletes on the electrodes of each frontal and prefrontal area. Conclusion In the present study, we observed the behavior of reaction time and absolute theta power in athletes and non-athletes during a saccadic movement task. Our findings corroborate the premise of cognitive improvement, mainly due to the reduction of saccadic latency and lower beta power, validating the neural efficiency hypothesis.

Resumo Antecedentes O movimento ocular sacádico é responsável por dar foco a um objeto visual de interesse para a retina. Em esportes como o vôlei, identificar alvos relevantes o mais rápido possível é essencial para se ter um desempenho magistral. O treinamento melhora as regiões corticais subjacentes à ação sacádica, e permite um processamento mais automatizado em atletas. Objetivo Investigamos as mudanças na latência durante o movimento ocular sacádico e a potência teta absoluta nos córtices frontal e pré-frontal durante a execução da tarefa de movimento ocular sacádico em atletas e não atletas de voleibol. Nossa hipótese é a de que a latência sacádica e a potência teta seriam menores em atletas devido ao treinamento e ao aprimoramento perceptivo-cognitivo em jogadores de voleibol. Métodos Ao todo, 30 voluntários saudáveis foram recrutados para este estudo: 15 atletas de voleibol (11 homens e 4 mulheres; idade média: 15,08 ± 1,06 anos) e 15 não atletas (5 homens e 10 mulheres; idade média: 18,00 ± 1,46 anos). Todas as tarefas foram realizadas simultaneamente com o registro do sinal eletroencefalográfico. Resultados O resultado da latência do movimento ocular sacádico apresentou diferença significativa entre os grupos, sendo observado menor tempo entre os atletas, associado à superioridade dos jogadores em termos de nível de atenção. Durante o experimento, nos eletrodos de cada área frontal e pré-frontal, observou-se uma diminuição na potência teta absoluta nos atletas em comparação aos não atletas. Conclusão Neste estudo, observou-se o comportamento do tempo de reação e da potência teta absoluta em atletas e não atletas durante uma tarefa de movimento sacádico. Nossos achados corroboram a premissa de melhora cognitiva, principalmente pela redução da latência sacádica e menor potência beta, o que valida a hipótese de eficiência neural.

It's About Time: The Circadian Network as Time-Keeper for Cognitive Functioning, Locomotor Activity and Mental Health.

A variety of organisms including mammals have evolved a 24h, self-sustained timekeeping machinery known as the circadian clock (biological clock), which enables to anticipate, respond, and adapt to environmental influences such as the daily light and dark cycles. Proper functioning of the clock plays a pivotal role in the temporal regulation of a wide range of cellular, physiological, and behavioural processes. The disruption of circadian rhythms was found to be associated with the onset and progression of several pathologies including sleep and mental disorders, cancer, and neurodegeneration. Thus, the role of the circadian clock in health and disease, and its clinical applications, have gained increasing attention, but the exact mechanisms underlying temporal regulation require further work and the integration of evidence from different research fields. In this review, we address the current knowledge regarding the functioning of molecular circuits as generators of circadian rhythms and the essential role of circadian synchrony in a healthy organism. In particular, we discuss the role of circadian regulation in the context of behaviour and cognitive functioning, delineating how the loss of this tight interplay is linked to pathological development with a focus on mental disorders and neurodegeneration. We further describe emerging new aspects on the link between the circadian clock and physical exercise-induced cognitive functioning, and its current usage as circadian activator with a positive impact in delaying the progression of certain pathologies including neurodegeneration and brain-related disorders. Finally, we discuss recent epidemiological evidence pointing to an important role of the circadian clock in mental health.

In vivo brain levels of acetylcholine and 5-hydroxytryptamine after oleoylethanolamide or palmitoylethanolamide administrations are mediated by PPARα engagement.

The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that has been linked to the modulation of several physiological functions, including the sleep-wake cycle. The PPARα recognizes as endogenous ligands the lipids oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which in turn, if systemically injected, they exert wake-promoting effects. Moreover, the activation of PPARα by the administration of OEA or PEA increases the extracellular contents of neurotransmitters linked to the control of wakefulness; however, the role of PPARα activated by OEA or PEA on additional biochemicals related to waking regulation, such as acetylcholine (ACh) and 5-hydroxytryptamine (5-HT), has not been fully studied. Here, we have investigated the effects of treatments of OEA or PEA on the contents of ACh and 5-HT by using in vivo microdialysis techniques coupled to HPLC means. For this purpose, OEA or PEA were systemically injected (5, 10 or 30 mg/kg; i.p.), and the levels of ACh and 5-HT were collected from the basal forebrain, a wake-related brain area. These pharmacological treatments significantly increased the contents of ACh and 5-HT as determined by HPLC procedures. Interestingly, PPARα antagonist MK-886 (30 mg/kg; i.p.) injected before the treatments of OEA or PEA blocked these outcomes. Our data suggest that the activation of PPARα by OEA or PEA produces significant changes on ACh and 5-HT levels measured from the basal forebrain and support the conclusion that PPARα is a suitable molecular element involved in the regulation of wake-related neurotransmitters.

The Role of Peroxisome Proliferator-Activated Receptor in Addiction: A Novel Drug Target.

The peroxisome proliferator activated receptors (PPARs) are a superfamily of well-recognized ligand-binding nuclear receptors comprising three isoforms: PPARα, PPARγ, and PPARß/δ. In response to endogenous lipid messengers, PPARs trigger the transcription of genes related to a wider spectrum of physiological phenomena, including fatty acid oxidation, inflammation, adipogenesis, among many others. Thus, the importance of PPARs as putative protective therapy in health issues has increased the interest of studying these nuclear receptors, including the management of neurodegenerative disorders, multiple sclerosis, and likely addiction. In recent years, several pieces of evidence from animal models have demonstrated the promising role of PPARs as a critical element for interventions in addictive behaviors by reducing the reinforcing properties of addictive substances such as alcohol. However, there is a lack of data in the scope and has so far been unexplored the function of PPARs in additional drugs such as cannabis, opioids, methamphetamine, or cocaine. A similar scenario has been found for the management of binge-type eating disorders. Thus, here we review recent advances in understanding the relevance of the PPAR controlling addiction.

A Discussion on Different Approaches for Prescribing Physical Interventions - Four Roads Lead to Rome, but Which One Should We Choose?

It is well recognized that regular physical exercise has positive effects on physical and mental health. To use the beneficial health effects of physical exercise, there are worldwide movements encouraging health care providers to include physical exercise in their care and treatments strategies. However, a crucial point in administering the "exercise polypill" is the dosing and, in turn, the prescription of the physical intervention (PI). In this perspective article, we discuss the advantages and disadvantages of different approaches to prescribe PI. In this context, we also highlight outstanding questions and potential areas of opportunity for further investigations.

The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats.

RATIONALE: The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown. OBJECTIVES: We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression. METHODS: The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments. RESULTS: Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity. CONCLUSIONS: The administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.

Dopaminergic drugs alter beta coherence during motor imagery and motor execution in healthy adults / Drogas dopaminérgicas alteram a coerência beta durante a imagética motora e a execução motora em adultos saudáveis

Abstract Background: Motor Imagery (MI) represents the cognitive component of the movement and recruits dopaminergic systems. Objective: To investigate the role of dopaminergic system through the action of methylphenidate and risperidone over beta coherence during execution, action observation and motor imagery. Methods: Electroencephalography (EEG) data were recorded before and after the substance intake. For statistical analysis, a three-way ANOVA was used to identify changes in beta coherence induced by the group, task and the moment variables. Statistical significance was set at p≤0.007. Results: We found a main effect for group for C3/CZ, and a main effect for task for CZ/C4 pairs of electrodes. Furthermore, significant differences were found in the post-drug administration between groups for C3/CZ pair of electrodes, and between task for C4/CZ pair of electrodes. Conclusion: The administration of methylphenidate and risperidone was able to produce electrocortical changes of the cortical central regions, even when featuring antagonistic effects on the dopaminergic pathways. Moreover, the execution task allowed beta-band modulation increase.

Resumo Introdução: A imagética motora (IM) representa o componente cognitivo do movimento e recruta os sistemas dopaminérgicos. Objetivo: Investigar o papel do sistema dopaminérgico por meio da ação do metilfenidato e da risperidona sobre a coerência em beta durante a execução, observação de ação e imagética motora. Métodos: Os dados de eletroencefalografia (EEG) foram registrados antes e depois da ingestão das substâncias. Para a análise estatística, uma ANOVA de três vias foi utilizada para identificar mudanças na coerência beta induzidas pelas variáveis grupo, tarefa e momento. A significância estatística foi estabelecida em p≤0,007. Resultados: Encontramos um efeito principal para o grupo C3/CZ e um efeito principal para a tarefa nos pares de eletrodos CZ/C4. Além disso, diferenças significativas foram encontradas após a administração da droga entre os grupos para o par de eletrodos C3/CZ e entre tarefa para o par de eletrodos C4/CZ. Conclusão: A administração de metilfenidato e risperidona foi capaz de produzir alterações eletrocorticais das regiões somatomotoras, mesmo apresentando efeitos antagônicos nas vias dopaminérgicas. Além disso, a tarefa de execução provocou maior modulação da banda beta.

Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status.

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-ß-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.

Fighting obesity: Non-pharmacological interventions.

The abnormal or excessive fat accumulation that impairs health is one of the criteria that fulfills obesity. According to epidemiological data, obesity has become a worldwide public health problem that in turn would trigger additional pathologies such as cardiorespiratory dysfunctions, cancer, gastrointestinal disturbances, depression, sleep disorders, just to mention a few. Then, the search for a therapeutical intervention aimed to prevent and manage obesity has been the focus of study during the last years. As one can assume, the increased prevalence of obesity has translated to search of efficient pharmaceuticals designed to manage this health issue. However, to further complicate the scenario, scientific literature has described that obesity is the result of interaction between multiple events. Therefore, pharmacological approaches have faced a serious challenge for develop the adequate treatment. Here, we argue that a wide range of non-pharmacological/invasive techniques can be used to manage obesity, such as diets, cognitive behavioral interventions, exercise and transcranial direct current stimulation. Combining these techniques may allow improving quality of life of obese patients.

CRISPR/Cas9, the Powerful New Genome-Editing Tool for Putative Therapeutics in Obesity.

The molecular technology known as clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) is revolutionizing the field of medical research and deepening our understanding of numerous biological processes. The attraction of CRISPR/Cas9 lies in its ability to efficiently edit DNA or modulate gene expression in living eukaryotic cells and organisms, a technology that was once considered either too expensive or scientifically risky. CRISPR/Cas9 has been successfully applied in agriculture to develop the next generation of disease-resistant plants. Now, the capability of gene editing has been translated to the biomedical area, focusing on the future of medicine faced with drug-resistant microbes by selectively targeting genes involved in antibiotic resistance, for example, or finding the ultimate strategy for cancer or HIV. In this regard, it was recently demonstrated that an injection of cancer-fighting CRISPR-modified white blood cells in a patient suffering from metastatic lung cancer could lead to promising results. Researchers and bioethicists are debating questions about the regulation of CRISPR/Cas9 that must be addressed. While legal challenges surround the use of this technique for genetically modifying cell lines in humans, we review the basic understanding of CRISPR/Cas9 and discuss how this technology could represent a candidate for treatment of non-communicable diseases in nutrition, such as obesity.

An Overview of the Clinical Uses, Pharmacology, and Safety of Modafinil.

Modafinil (MOD) is a wakefulness-inducing compound prescribed for treatment of excessive daytime sleepiness as a consequence of sleep disturbances such as shift work sleep disorder, obstructive sleep apnea, restless leg syndrome, or narcolepsy. While providing effective results in patients with sleepiness, MOD also produces positive outcomes in the management of fatigue associated with different conditions including depression, cancer, or tiredness in military personnel. Although there is clear evidence of the stimulant effects of MOD, current data also show that administration of this drug apparently induces positive neurobiological effects, such as improvement in memory. However, serious concerns have been raised since some reports have suggested MOD dependence. Taken together, these findings highlight the need to characterize the changes induced by MOD which have been observed in several neurobiological functions. Moreover, further work should follow up on the likely long-term effects of this drug if used for treatment of drowsiness and tiredness. Here, we review and summarize recent findings of the medical uses of MOD in the management of sleepiness and fatigue associated with depression or cancer as well as exhaustion in military personnel. We also discuss the available literature related with the cognitive enhancing properties of this stimulant, as well as what is known and unknown about MOD addiction.

Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation.

The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep-wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The injection of CBD or MOD increased alertness during sleep rebound period after TSD. However, AA-5-HT blocked this effect by allowing animals to display an enhancement in sleep across sleep rebound period. Overall, our findings provide evidence that AA-5-HT is an important modulator of sleep, sleep homeostasis and neurotransmitter contents.

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis.

The endocannabinoid system comprises receptors (CB1 and CB2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/kg; ip; separately each one) into rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD) while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking.

Alpha power oscillation in the frontal cortex under Bromazepam and Modafinil effects / Oscilações da potência alfa no córtex frontal sob influência do Bromazepam e Modafinil

ABSTRACTObjective Our aim was to investigate and compare the neuromodulatory effects of bromazepam (6 mg) and modafinil (200 mg) during a sensorimotor task analyzing the changes produced in the absolute alpha power.Method The sample was composed of 15 healthy individuals exposed to three experimental conditions: placebo, modafinil and bromazepam. EEG data were recorded before, during and after the execution of the task. A three-way ANOVA was applied, in order to compare the absolute alpha power among the factors: Group (control, bromazepam and modafinil) Condition (Pre and Post-drug ingestion) and Moment (pre and post-stimulus).Results Interaction was found between the group and condition factors for Fp1, F4 and F3. We observed a main effect of moment and condition for the Fp2, F8 and Fz electrodes.Conclusion We concluded that drugs may interfere in sensorimotor processes, such as in the performance of tasks carried out in an unpredictable scenario.

RESUMOObjetivo Investigar e comparar os efeitos neuromoduladores do bromazepam (6mg) e modafinil (200mg), durante a prática de uma tarefa sensoriomotora, analisando as modificações produzidas na potência absoluta de alfa.Método A amostra foi composta por 15 indivíduos saudáveis, expostos a três condições experimentais: Placebo, modafinil e bromazepam. Dados eletroencefalográficos foram registrados antes, durante e após a execução da tarefa motora. Um ANOVA three-way foi aplicado para comparar a potência absoluta de alfa nos fatores Grupo (controle, bromazepam e modafinil), Condição (Pré e Pós ingestão da droga) e Momento (Pré e Pós estimulo).Resultados Verificou-se interação entre os fatores grupo e condição para os eletrodos Fp1, F4 e F3. Observamos um efeito principal para momento e condição nos eletrodos Fp2, F8 e Fz.Conclusão Concluímos que as drogas, podem interferir em processos sensoriomotores, como no desempenho de tarefas executadas em um cenário imprevisível.

Physical activity interventions in schools for improving lifestyle in European countries.

BACKGROUND: In the last decades, children's and adolescents' obesity and overweight have increased in European Countries. Unhealthy eating habits and sedentary lifestyle have been recognized to determine such an epidemic. Schools represent an ideal setting to modify harmful behaviors, and physical activity could be regarded as a potential way to avoid the metabolic risks related to obesity. Methods : A systematic review of the literature was carried out to summarize the evidence of school-based interventions aimed to promote, enhance and implement physical activity in European schools. Only randomized controlled trials were included, carried out in Europe from January 2000 to April 2014, universally delivered and targeting pupils aged between 3 and 18 years old. Results : Forty-seven studies were retrieved based either on multicomponent interventions or solely physical activity programs. Most aimed to prevent obesity and cardiovascular risks among youths. While few studies showed a decrease in BMI, positive results were achieved on other outcomes, such as metabolic parameters and physical fitness. Conclusion : Physical activity in schools should be regarded as a simple, non-expensive and enjoyable way to reach all the children and adolescents with adequate doses of moderate to vigorous physical activity.

Nicotine dependence is characterized by disordered reward processing in a network driving motivation.

BACKGROUND: Drug addiction is characterized by an unhealthy priority for drug consumption with a compulsive, uncontrolled drug-intake pattern due to a disordered motivational system. However, only some individuals become addicted, whereas others maintain regular but controlled drug use. Whether the transition occurs might depend on how individuals process drug relative to nondrug reward. METHODS: We applied functional magnetic resonance imaging to measure mesocorticolimbic activity to stimuli predicting monetary or cigarette reward, together with behavioral assessment of subsequent motivation to obtain the respective reward on a trial-by-trial basis, in 21 nicotine-dependent and 21 nondependent, occasional smokers. RESULTS: Occasional smokers showed increased reactivity of the mesocorticolimbic system to stimuli predicting monetary reward relative to cigarette reward and subsequently spent more effort to obtain money. In the group of dependent smokers, we found equivalent anticipatory activity and subsequent instrumental response rates for both reward types. Additionally, anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain reward. CONCLUSIONS: This imbalance in the incentive salience of drug relative to nondrug reward-predicting cues, in a network that drives motivation to obtain reward, could represent a central mechanism of drug addiction.

Serotonin transporter promoter polymorphism and dopaminergic sensitivity in alcoholics.

The central serotonin (5-HT) system plays an important role in the rewarding and addictive properties of alcohol by a direct activation of the mesolimbic dopamine (DA) system. An insertion/deletion (L/S) promoter polymorphism (5-HTTLPR) of the 5-HT transporter (5-HHT) gene (SLC6A4) has been shown to influence transcriptional activity. It is predicted that reduced transynaptic 5-HT neurotransmission in alcoholics with the L/L genotype of 5-HTTLPR would result in a change in DA function compared to the S/S genotype. Thus the present study has tested whether dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. Dopaminergic sensitivity, 5-HTTLPR genotype and smoking status were assessed in 121 alcoholics. Dopaminergic sensitivity as an indicator of the functional state of the dopaminergic system was measured by the amount of growth hormone (GH) secretion after subcutaneous administration of apomorphine (APO, 0.01 mg/kg). 5-HTTLPR genotype was significantly associated with dopaminergic sensitivity (P = 0.004) explaining 9.2% of the variance of GH response. Subjects homozygous for the L allele (with high 5-HTT expression) showed the lowest GH response, whereas those homozygous for the S allele (with low 5-HTT expression) showed the highest GH response (this was intermediate in heterozygous participants). Furthermore smoking was associated with a significantly reduced GH response (P = 0.006). Our findings indicate that the postsynaptic dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. It is hypothesized that the reduction of sensitivity of the central DA receptors in alcoholics with the L/L genotype might be due to their higher vulnerability to the neurotoxic effects of chronic alcohol consumption than the S carriers.

Neuroendocrinological and neuropsychological correlates of dopaminergic function in nicotine dependence.

RATIONALE: There is multiple evidence that nicotine--as with ethanol and other drugs of abuse--stimulates dopamine release in the ventral striatum as a central part of the brain reward circuits. Chronic nicotine exposure leads to changes in these dopaminergic reward circuits. During nicotine withdrawal, an impaired dopaminergic function has been reported. On the behavioral level, this seems to result in motivational disturbances in abstaining smokers. OBJECTIVES: To investigate the impact of smoking on dopaminergic function in humans both on a neuroendocrinological and on a neuropsychological level. METHODS: Thirty-seven healthy smokers were assessed whilst smoking (test 1) and after abstaining overnight for 12 h (test 2). A control group of 18 non-smokers was also examined twice. Severity of nicotine dependence, incentive motivation, digit span and verbal fluency were assessed. The sensitivity of central dopamine (DA) D2 receptors was assessed with the apomorphine-induced growth hormone (GH) secretion. RESULTS: ANOVA revealed that GH response was significantly lower in smokers than in non-smokers (P=0.04). The GH response was significantly inversely correlated with severity of nicotine dependence (r=-0.39). Neuropsychological performance was not influenced by smoking status. After overnight abstinence from nicotine GH response, digit span and verbal fluency were not affected, whereas incentive motivation was significantly impaired in smokers (P=0.04). CONCLUSIONS: Smoking is significantly associated with a reduced sensitivity of central DA D2 receptors. This alteration of dopaminergic sensitivity is stable even after 12 h of abstinence from nicotine. Therefore, the hypothesis that the motivational impairment during withdrawal from nicotine is associated with an altered sensitivity of central DA D2 receptors cannot be supported.