Dopamine and serotonin alterations by Hizikia fusiformis extracts under in vitro cortical primary neuronal cell cultures.

BACKGROUND/OBJECTIVES: Hizikia fusiformis (HF) is a class of brown seaweeds whose active ingredients exert central nervous system protective effects, such as neuroprotection; however, the underlying mechanisms remain unknown. Given that dopamine (DA) and serotonin (5HT) are two major neurotransmitters involved in various psychiatric disorders and neuronal growth in early neurodevelopmental processes, we investigated whether HF extract could modulate the molecular expression associated with DA and 5HT transmission as well as the structural formation of neurons. MATERIALS/METHODS: In vitro cell cultures were prepared from cerebral cortical neurons obtained from CD-1 mice on embryonic day 14. Cultured cells were treated with 0.1, 1.0, or 10.0 µg/mL of HT extract for 24 h, followed by fluorescence immunostaining for DA and 5HT-related receptors and transporters and some neuronal structural formation-associated molecules. RESULTS: HF extract dose-dependently upregulated the expression levels of selective DA and 5HT receptors, and downregulated the levels of DA and 5HT transporters. Moreover, HF extract increased the neurofilament light chain expression. CONCLUSION: These results suggest that HF may modulate DA and 5HT transmission, thereby affecting neurodevelopment.

Distinct Situational Cue Processing in Individuals with Kleptomania: A Preliminary Study.

BACKGROUND: Impulse control disorder has been suggested to meet the criteria of addiction and is often considered a behavioral addiction; however, few studies have examined whether the disorder involves altered responses to situational cues that are associated with symptoms. In this study, we examined behavioral and neural responses to situational cues among individuals with an impulse control disorder: kleptomania. METHODS: Healthy adults and kleptomania patients whose symptoms were characterized by repetitive, uncontrolled shoplifting of sales goods in stores were recruited. Images with and without situational cues (e.g., a grocery store) were presented, and gazing patterns for the images were detected with the eye-tracker. Additionally, prefrontal cortical (PFC) responses were measured using functional near-infrared spectroscopy. PFC activities were further examined while participants were watching video clips in virtual reality with and without situational cues. RESULTS: Among kleptomania patients, the gazing pattern for an image with situational cues was distinct from gazing patterns for other images; such differences were not observed in healthy individuals. Consistent with gazing patterns, PFC local network responses by hemoglobin changes to images and videos with situational cues were substantially different from other images and videos in kleptomania patients, whereas PFC responses were consistent across all image and video presentations in healthy individuals. CONCLUSIONS: These results suggest that kleptomania patients may perceive situational cues associated with their problematic behaviors differently from healthy individuals.

Comparable level of aggression between patients with behavioural addiction and healthy subjects.

Heightened aggression is identified in several psychiatric disorders, including addiction. In this preliminary study with a relatively small number of samples, aggression in subjects diagnosed with behavioural addiction (BA) was implicitly assessed using the point subtraction aggression paradigm (PSAP) test along with measurements of oxy- and deoxyhaemoglobin dynamics in the prefrontal cortex (PFC) during the test using functional near-infrared spectroscopy. Aggression in BA patients was no higher than that of healthy control (CT) subjects in the PSAP test. Although no apparent increase or decrease in haemoglobin concentrations was observed in the PFC of either BA patients or CT subjects, abnormal correlations within the PFC network were present in BA patients. Consistent with comparable aggression between the groups, blood concentrations of the sex hormone testosterone, which has been shown to be associated with aggressiveness, was even lower in BA patients than in CT subjects. In contrast, when a set of questionnaire surveys for the assessment of aggression were administered, BA patients rated themselves as more aggressive than non-BA subjects. Collectively, these results suggest that aggression may not be heightened in BA, but BA patients may overestimate their aggressiveness, raising concerns about the use of questionnaire surveys for assessments of affective traits such as aggression in behavioural addiction.

The Habenula in the Link Between ADHD and Mood Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset, neurodevelopmental disorder, whereas major depressive disorder (MDD) is a mood disorder that typically emerges in adulthood. Accumulating evidence suggests that these seemingly unrelated psychiatric disorders, whose symptoms even appear antithetical [e.g., psychomotor retardation in depression vs. hyperactivity (psychomotor acceleration) in ADHD], are in fact associated with each other. Thus, individuals with ADHD exhibit high comorbidity with MDD later in life. Moreover, genetic studies have shown substantial overlaps of susceptibility genes between ADHD and MDD. Here, we propose a novel and testable hypothesis that the habenula, the epithalamic brain region important for the regulation of monoamine transmission, may be involved in both ADHD and MDD. The hypothesis suggests that an initially hypoactive habenula during childhood in individuals with ADHD may undergo compensatory changes during development, priming the habenula to be hyperactive in response to stress exposure and thereby increasing vulnerability to MDD in adulthood. Moreover, we propose a new perspective on habenular deficits in psychiatric disorders that consider the habenula a neural substrate that could explain multiple psychiatric disorders.

Cognitive and Affective Processes Associated with Social Biases.

BACKGROUND: Our social activities are quite often erroneous and irrational, based on biased judgements and decision-making, known as social biases. However, the cognitive and affective processes that produce such biases remain largely unknown. In this study, we investigated associations between social schemas, such as social judgment and conformity, entailing social biases and psychological measurements relevant to cognitive and affective functions. METHOD: This study recruited 42 healthy adult subjects. A psychological test and a questionnaire were administered to assess biased social judgements by superficial attributes and social conformity by adherence to social norms, respectively, along with additional questionnaires and psychological tests for cognitive and affective measurements, including negative affects, autistic traits, and Theory of Mind (ToM). Associations of social judgment and conformity with cognitive and affective functions were examined using a multiple regression analysis and structural equation modeling. RESULTS: Anxiety and the cognitive realm of ToM were mutually associated with both social judgments and conformity, although social judgements and conformity were still independent processes. Social judgements were also associated with autistic traits and the affective realm of ToM, whereas social conformity was associated with negative affects other than anxiety and an intuitive decision-making style. CONCLUSIONS: These results suggest that ToM and negative affects may play important roles in social judgements and conformity, and the social biases connoted in these social schemas.

Imbalance between dopamine and serotonin caused by neonatal habenula lesion.

Alterations in dopamine (DA) and serotonin (5-HT) transmission have been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). We have previously reported that juvenile rats with neonatal habenula lesion (NHL) exhibit an assortment of behavioral alterations resembling ADHD symptoms. In this study, we investigated the impacts of NHL on DA and 5-HT transmission in mesocorticolimbic regions of rats. Male Sprague-Dawley rats with microinjection of ibotenic acid into the habenula at postnatal day (PND) 7 were subjected for a battery of locomotion test, object exploration test and delay discounting test in the juvenile period (PND28-35), followed by DA and 5-HT brain tissue concentration measurements using high-performance liquid chromatography (HPLC). NHL rats exhibited hyperlocomotion, impulsivity, and attention deficits. NHL induced alterations of tissue DA and 5-HT concentrations only in some mesocorticolimbic regions. However, positive correlations, indicating the balance, between DA and 5-HT observed in control (CTR) rats, were more extensively disrupted across mesocorticolimbic regions in NHL rats. Pharmacological manipulations that modulated both DA and 5-HT systems simultaneously with Astragalus membranaceus (AM) and its active compound formononetin (FOR) normalized the NHL-induced DA and 5-HT imbalance in several brain areas, which consequently improved the behavioral alterations. These results suggest that behavioral alterations caused by NHL may be associated with mesocorticolimbic DA/5-HT imbalance. Drug treatments targeting multiple monoamine systems may be useful to improve the NHL-induced changes.

Alterations of amygdala-prefrontal cortical coupling and attention deficit/hyperactivity disorder-like behaviors induced by neonatal habenula lesion: normalization by Ecklonia stolonifera extract and its active compound fucosterol.

Alterations of monoamine transmission in mesocorticolimbic regions have been suggested in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). The habenula is an important brain area in regulation of monoamine transmission. In this study, we investigated behavioral and electrophysiological alterations induced by neonatal habenula lesion (NHL) in rats. In NHL rats, age-dependent behavioral alterations relevant to the ADHD symptoms, such as hyperlocomotion, impulsivity, and attention deficit, were observed. Local field potentials (LFPs) in mesocorticolimbic regions of anesthetized rats were examined with in vivo electrophysiological recordings. Abnormally enhanced synchronization of slow (delta) and fast (gamma) LFP oscillations between the amygdala (AMY) and prefrontal cortex (PFC) was found in juvenile, but not in adult, NHL rats. We further examined the effects of an extract and the active compound from the perennial large brown algae Ecklonia stolonifera (ES), which have previously been demonstrated to modulate monoamine transmission, on these NHL-induced alterations. One week of ES extract treatments normalized the NHL-induced behavioral alterations, whereas the active compound fucosterol improved attention deficit and impulsivity, but not hyperlocomotion, in NHL rats. Consistent with the behavioral effects, ES extract treatments also normalized augmented AMY-PFC coupling. These results suggest that altered limbic-cortical information processing may be involved in ADHD-like behavioral alterations induced by NHL, which could be ameliorated by the natural substance, such as ES that affects monoamine transmission.

Heightened Negative Affects Associated With Neurotic Personality in Behavioral Addiction.

Although studies have demonstrated that negative affects are critical attributes of drug addiction, this has remained less clear in behavioral addiction. In this preliminary study with a relatively small number of samples, we investigated negative affects in patients diagnosed with behavioral addiction, particularly paraphilia and kleptomania. Negative affects were examined using self-rating questionnaire and further evaluated by objective assessments in behavioral addicts and normal subjects. Explicit, self-referential negative affects, such as anxiety, stress, and depression, were higher in behavioral addicts than control subjects. Such self-referential negative affects were, although not entirely, consistent with objective evaluations by others and blood stress hormone concentrations. Further investigation of personality traits in behavioral addicts unveiled that heightened negative affects were associated with stronger neurotic personality in behavioral addicts than normal subjects. These results suggest that behavioral addiction, such as paraphilia and kleptomania, may be characterized by heightened negative affects attributable to stronger neurotic personality.

Monoamine and genome-wide DNA methylation investigation in behavioral addiction.

Behavioral addiction (BA) is characterized by repeated, impulsive and compulsive seeking of specific behaviors, even with consequent negative outcomes. In drug addiction, alterations in biological mechanisms, such as monoamines and epigenetic processes, have been suggested, whereas whether such mechanisms are also altered in BA remains unknown. In this preliminary study with a small sample size, we investigated monoamine concentrations and genome-wide DNA methylation in blood samples from BA patients and control (CT) subjects. Higher dopamine (DA) metabolites and the ratio between DA and its metabolites were observed in the BA group than in the CT group, suggesting increased DA turnover in BA. In the methylation assay, 186 hyper- or hypomethylated CpGs were identified in the BA group compared to the CT group, of which 64 CpGs were further identified to correlate with methylation status in brain tissues with database search. Genes identified with hyper- or hypomethylation were not directly associated with DA transmission, but with cell membrane trafficking and the immune system. Some of the genes were also associated with psychiatric disorders, such as drug addiction, schizophrenia, and autism spectrum disorder. These results suggest that BA may involve alterations in epigenetic regulation of the genes associated with synaptic transmission, including that of monoamines, and neurodevelopment.

Concurrent and Delayed Behavioral and Monoamine Alterations by Excessive Sucrose Intake in Juvenile Mice.

Our daily diet in the modern society has substantially changed from that in the ancient past. Consequently, new disorders associated with such dietary changes have emerged. For instance, excessive intake of compounds, such as sucrose (SUC), has recently been reported to induce pathological neuronal changes in adults, such as food addiction. It is still largely unclear whether and how excessive intake of such nutrients affects neurodevelopment. We investigated changes in behavior and monoamine signaling caused by excessive, semi-chronic intake of SUC and the non-caloric sweetener saccharin (SAC) in juvenile mice, using a battery of behavioral tests and high-performance liquid chromatography. Both SUC and SAC intake induced behavioral alterations such as altered amphetamine responses, sucrose preference, stress response, and anxiety, but did not affect social behavior and cognitive function such as attention in juvenile and adult mice. Moreover, SUC and SAC also altered dopamine and serotonin transmission in mesocorticolimbic regions. Some of these behavioral and neural alterations were triggered by SAC and SUC but others were distinct between the treatments. Moreover, alterations induced in juvenile mice were also different from those observed in adult mice. These results suggest that excessive SUC and SAC intake during the juvenile period may cause concurrent and delayed behavioral and monoamine signaling alterations in juvenile and adult mice, respectively.

Higher Risk Taking and Impaired Probability Judgment in Behavioral Addiction.

BACKGROUND: Accumulating evidence suggests that deficits in decision-making and judgment may be involved in several psychiatric disorders, including addiction. Behavioral addiction is a conceptually new psychiatric condition, raising a debate of what criteria define behavioral addiction, and several impulse control disorders are equivalently considered as types of behavioral addiction. In this preliminary study with a relatively small sample size, we investigated how decision-making and judgment were compromised in behavioral addiction to further characterize this psychiatric condition. METHOD: Healthy control subjects (n = 31) and patients with kleptomania and paraphilia as behavioral addictions (n = 16) were recruited. A battery of questionnaires for assessments of cognitive biases and economic decision-making were conducted, as was a psychological test for the assessment of the jumping-to-conclusions bias, using functional near-infrared spectroscopy recordings of prefrontal cortical (PFC) activity. RESULTS: Although behavioral addicts exhibited stronger cognitive biases than controls in the questionnaire, the difference was primarily due to lower intelligence in the patients. Behavioral addicts also exhibited higher risk taking and worse performance in economic decision-making, indicating compromised probability judgment, along with diminished PFC activity in the right hemisphere. CONCLUSION: Our study suggests that behavioral addiction may involve impairments of probability judgment associated with attenuated PFC activity, which consequently leads to higher risk taking in decision-making.

Monoamine oxidase polymorphisms in rhesus and Japanese macaques (Macaca mulatta and M. fuscata).

Monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) are enzymes that degrade several monoamines of the central nervous system and have long been implicated in the modulation of social behavior. Macaque monkeys are a suitable model for investigating the role of functional monoamine oxidase polymorphisms in behavior modulation given the high amount of social diversity among the nearly two dozen species. The present study reports allele frequencies for two polymorphisms, MAOA-LPR and MBin2, in samples of rhesus (Macaca mulatta) and Japanese (M. fuscata) macaques. Our results suggest that the two species may differ in high- and low-activity MAOA-LPR allele frequencies. Specifically, 89% of the Japanese macaque alleles in our sample were the low-activity variant, whereas only 41% of the rhesus macaque alleles were of this sort. In our samples, the two species possessed similar allelic variation at the MBin2 locus, with each possessing some species-specific alleles. We also tested for associations between MAOA-LPR genotype and plasma serotonin (5-HT) and dopamine (DA) concentrations in a subset of rhesus macaques, which revealed no association with genotype. Our findings point toward potential differences in the monoaminergic system of two closely related macaque species. Discussion of our results are centered on implications for future investigations that aim to better understand the functionality of monoamine oxidase polymorphisms in the context of primate social behavior.

Atypical Social Rank Recognition in Autism Spectrum Disorder.

Social animals, including humans, structure social groups where social hierarchy exists. Recognizing social rank of other group members is a crucial ability to subsist in such environments. Here we show preliminary evidence with a relatively small number of samples that children with autism spectrum disorder, a neurodevelopmental disorder involving social dysfunction, exhibit atypical, and more robust recognition of social rank than normal children, which may be developed to compensate deficits of the neural systems processing social information.

The effects of Engelhardtia chrysolepis Hance on long-term memory and potential dopamine involvement in mice.

Engelhardtia chrysolepis Hance (ECH) is a perennial plant used in traditional medicine. A major active ingredient of ECH is astilbin (ASB), which has recently been shown to have neuroprotective effects as well as to affect catecholamine neurotransmissions in brain areas such as the prefrontal cortex. In this study, we investigated the effects of ECH and ASB on long-term memory in mice using a battery of behavioral tests. Acute ECH treatments dose-dependently facilitated nonspatial, but not spatial, memory. ECH treatments also upregulated expression of tyrosine hydroxylase, the enzyme mediating catecholamine synthesis, in neuroblastoma cell culture. Acute ASB treatments similarly improved nonspatial memory, whereas chronic ASB treatments improved both nonspatial and spatial memory. In accordance with such behavioral effects, the increased ratio of tissue concentrations of dopamine metabolites over dopamine in striatal regions was observed in mice with chronic ASB treatments. These results suggest that ECH and its active ingredient ASB may facilitate long-term memory by modulating catecholamine transmission.

The Roles of Serotonin in Decision-making under Social Group Conditions.

People in a social group often have to make decisions under conflict, for instance, to conform to the group or obey authority (subjects at higher social rank in the group). The neural mechanisms underlying how social group setting affects decision-making have largely remained unclear. In this study, we designed novel behavioral tests using food access priority and fear conditioning paradigms that captured decision-making under conflict associated with social group environments in mice and examined the roles of serotonin (5-HT) on these processes. Using these behavioral tests, administration of the selective 5-HT reuptake inhibitor, which increased 5-HT transmission, was found to attenuate conflicts in decision-making that may be associated with human cases of social obedience and conformity in mice under group housing. The results suggest that 5-HT plays important roles in the regulation of individual behaviors that organize social group dynamics.

The Effects of Housing Density on Social Interactions and Their Correlations with Serotonin in Rodents and Primates.

Population density has been suggested to affect social interactions of individuals, but the underlying neural mechanisms remain unclear. In contrast, neurotransmission of monoamines such as serotonin (5-HT) and dopamine (DA) has been demonstrated to play important roles in social behaviors. Here, we investigated whether housing density affected social interactions of rodents and non-human primates housed in groups, and its correlations with monoamines. Japanese macaques exhibited higher plasma 5-HT, but not DA, concentrations than rhesus macaques. Similarly, C57BL/6 mice exhibited higher plasma and brain tissue 5-HT concentrations than DBA2 mice. Under crowding, C57BL/6 mice and Japanese macaques exhibited more prominent social avoidance with mates than DBA2 mice and rhesus macaques, respectively. Although DBA2 mice and rhesus macaques in crowding exhibited elevated plasma stress hormones, such stress hormone elevations associated with crowding were absent in C57BL/6 mice and Japanese macaques. Administration of parachlorophenylalanine, which inhibits 5-HT synthesis, increased social interactions and stress hormones in C57BL/6 mice under crowding. These results suggest that, animals with hyperserotonemia may exhibit social avoidance as an adaptive behavioral strategy to mitigate stress associated with crowding environments, which may also be relevant to psychiatric disorder such as autism spectrum disorder.

Dopamine-dependent social information processing in non-human primates.

RATIONALE: Dopamine (DA) is a neurotransmitter whose roles have been suggested in various aspects of brain functions. Recent studies in rodents have reported its roles in social function. However, how DA is involved in social information processing in primates has largely remained unclear. OBJECTIVES: We investigated prefrontal cortical (PFC) activities associated with social vs. nonsocial visual stimulus processing. METHODS: Near-infrared spectroscopy (NIRS) was applied to Japanese macaques, along with pharmacological manipulations of DA transmission, while they were gazing at social and nonsocial visual stimuli. RESULTS: Oxygenated (oxy-Hb) and deoxygenated (deoxy-Hb) hemoglobin changes as well as functional connectivity based on such Hb changes within the PFC network which were distinct between social and nonsocial stimuli were observed. Administration of both D1 and D2 receptor antagonists affected the Hb changes associated with social stimuli, whereas D1, but not D2, receptor antagonist affected the Hb changes associated with nonsocial stimuli. CONCLUSIONS: These results suggest that mesocortical DA transmission in the PFC plays significant roles in social information processing, which involves both D1 and D2 receptor activation, in nonhuman primates. However, D1 and D2 receptor signaling in the PFC mediates different aspects of social vs. nonsocial information processing.

Histamine H3 receptor antagonists ameliorate attention deficit/hyperactivity disorder-like behavioral changes caused by neonatal habenula lesion.

A partial agonist and a full antagonist of the histamine H3 receptor have been suggested to have therapeutic effects on cognitive deficits in psychiatric disorders. We have previously shown that neonatal habenula lesion (NHL) induces behavioral deficits that resemble the symptoms of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the effects of three H3 antagonists on ADHD-like behavioral changes caused by NHL in rats. Behavioral tests and administration of the H3 receptor antagonists were performed in juvenile rats with NHL. H3 antagonist administration to juvenile rats dose dependently improved NHL-induced hyperlocomotion, impulsive behavior, and attention deficit. These results suggest that histamine H3 antagonists may be used as alternative therapeutic drugs for the treatment of ADHD.

Dopamine-dependent visual attention preference to social stimuli in nonhuman primates.

RATIONALE: Dopamine (DA) plays a central role in reward processing. Accumulating evidence suggests that social interaction and social stimuli have rewarding properties that activate the DA reward circuits. However, few studies have attempted to investigate how DA is involved in the processing of social stimuli. OBJECTIVES: In this study, we investigated the effects of pharmacological manipulations of DA D1 and D2 receptors on social vs. nonsocial visual attention preference in macaques. METHODS: Japanese macaques were subjected to behavioral tests in which visual attention toward social (monkey faces with and without affective expressions) and nonsocial stimuli was examined, with D1 and D2 antagonist administration. RESULTS: The macaques exhibited significantly longer durations of gazing toward the images with social cues than did those with nonsocial cues. Both D1 and D2 antagonist administration decreased duration of gazing toward the social images with and without affective valences. In addition, although D1 antagonist administration increased the duration of gazing toward the nonsocial images, D2 antagonism had no effect. CONCLUSIONS: These results suggest that both D1 and D2 receptors may have roles in the processing of social signals but through separate mechanisms.

The Roles of Dopamine D2 Receptor in the Social Hierarchy of Rodents and Primates.

Dopamine (DA) plays significant roles in regulation of social behavior. In social groups of humans and other animals, social hierarchy exists, which is determined by several behavioral characteristics such as aggression and impulsivity as well as social affiliations. In this study, we investigated the effects of pharmacological blockade of DA D2 receptor on social hierarchy of Japanese macaque and mouse social groups. We found acute administration of the D2 antagonist, sulpiride, in socially housed Japanese macaques attenuated social dominance when the drug was given to high social class macaques. A similar attenuation of social dominance was observed in high social class mice with D2 antagonist administration. In contrast, D2 antagonist administration in low social class macaque resulted in more stable social hierarchy of the group, whereas such effect was not observed in mouse social group. These results suggest that D2 receptor signaling may play important roles in establishment and maintenance of social hierarchy in social groups of several species of animals.