Prevalence and Clinical Significance of Psychiatric Comorbidities With Gambling Disorder in 12 Clinical Settings in Japan.

OBJECTIVES: This study investigated the occurrence rate of psychiatric disorders comorbid with gambling disorder, and their clinical significance in the severity of gambling disorder using a retrospective cross-sectional design. METHODS: The medical records of 359 patients (men/women, 326/33; median age, 37.0 years) with gambling disorder as the primary disorder from 12 treatment facilities specializing in addiction (9 clinics and 3 hospitals) in Japan were studied. We investigated patients' comorbid psychiatric disorders, demographic and clinical characteristics, and the severity of gambling disorder based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. RESULTS: Of all patients, 58.3% had comorbidities (tobacco use disorder, 20.9%; alcohol use disorder, 13.9%; major depressive disorder, 13.1%; behavioral addictions, 13.1%; attention-deficit hyperactivity disorder, 6.1%; etc.). Statistical analysis indicated that as the number of comorbid psychiatric disorders increased, psychosocial problems also increased (e.g., proportion of adverse childhood experiences [ P < 0.001], and history of suicide attempts [ P = 0.009]). In the multivariable analysis, behavioral addictions ( ß = 0.666; t = 3.151) were significantly associated with gambling disorder severity. Specifically, individuals with gambling disorder comorbid with behavioral addictions including kleptomania, excessive buying, and excessive sex-related behavior may present more severe gambling problems than those without behavioral addictions. CONCLUSIONS: Patients with gambling disorder should be carefully assessed for psychiatric comorbidities and interventions should reflect the individual diagnosis.

Learning of efficient behaviour in spatial exploration through observation of behaviour of conspecific in laboratory rats.

Recent studies have suggested that rodent behaviour is influenced by the behaviour of surrounding conspecifics (e.g. emotional contagion and prosocial behaviour). However, little is known about deferred imitation and complex observational learning in rats. The purpose of this study was to reveal whether rats can learn from another rat's experiences. In a maze, observer rats watched the foraging behaviour of other rats (demonstrators) and then foraged in turn. The results showed that demonstrators explored inefficiently, but observers explored more efficiently after observing inefficient exploration by the demonstrators. This observational learning probably involved the acquisition of an efficient strategy through spatial exploration.

Effects of solmach on alcohol hangover model in mice.

Alcohol hangover is an unpleasant state caused by acetaldehyde, which is produced by partial oxidation of ethanol. Treating hangover is important from the viewpoint of preventing excessive drinking. In the present study, we attempted to produce mouse model of alcohol hangover by intraperitoneal pretreatment with cyanamide at 12.5 mg/kg followed by oral ethanol at 1.6 g/kg. The mice showed decrease of spontaneous locomotor activity and food intake. Thus, it is suggested that the hangover model was successively established by co-administration of cyanamide and ethanol. Solmack, a product based on herbal medicine for stomach anda pproved as medical drug, recovered decrease of spontaneous locomotor activity and tended to recover decrease of food intake in the.hangover model mice. Other refreshing drinks did not show such effects, though they contain herbal medicine ingredients to some extent. Our model in mice might be useful to detect effective treatment for alcohol hangover.

DSM-5 from the viewpoint of basic study of dependence and addiction.

In this review, current progress of neurobehavioral research using animal model of dependence and/or addiction is described in light of DSM-5. Although the terms "dependence" and "abuse" are deleted in DSM-5, the concept of dependence and the related animal experiments, drug self-administration, conditioned place preference, and drug discrimination are still useful to predict abuse liability of chemical substances. At the same time, it is necessary to model addictive nature of behavior in animals. Impulsivity, compulsivity, and comorbidity of addiction to other mental disorders are the major topics of such research area. At the same time, basic research aimed at treatment of dependence/addiction has been progressed. For example, a methamphetamine monoclonal antibody, a new chemical acting on DARPP-32 (dopamine and c-AMP-regulated phophoprotein-32), a galanin analogue, oxytocin, and others are included in such attempt. As DSM-5 mentioned the brain reward system as the major site of substance-related and addictive disorders, clinicians would be more interested in biological substrates of dependence/addiction. It is expected that the emergence of new diagnostic criteria promotes mutual communication between basic and clinical researchers.

[Behavioral characteristics of nicotine seeking: a role of the nicotine-conditioned effects and other mechanisms].

Nicotine dependence and its neural mechanisms have been well documented by pharmacological, behavioral and neuroscience studies. In this review, we introduce recent new findings in this theme, particularly on the role of nicotine -associated stimuli as non-pharmacological factors affecting maintaining/reinstating nicotine seeking. By using the techniques of drug self-administration and conditioned place preference, nicotine's specific property of forming seeking/taking behavior is well characterized, and the mechanisms of seeking/taking could be partly explained by discrete and/or contextual conditioned stimuli (dCS and cCS). After having the repeated Pavlovian conditioning in the training/conditioning sessions, CSs begin to play a key role for eliciting nicotine seeking behavior, with the activation of mesolimbic dopaminergic systems. In our study, intracranial self- stimulation (ICSS) was used to assess the mesolimbic dopamine activity. The nicotine-associated cCS also activated this neural system, which resulted in decreasing the ICSS threshold approximately 20% in the testing session under the cCS presentation. This finding would support the evidence of CS-induced incentive motivation for nicotine. According to the incentive salience hypothesis, the mesolimbic dopamine reflects the motivation elicited by incentives (CSs), and induces the drug seeking behavior, which is activated through amygdala--nucleus accumbens--medial prefrontal cortex circuit. Additionally, human brain imaging studies have revealed that tobacco- associated stimuli activate not only these regions, but also right temporo-parietal junction of human cortex, which is relevant to the visual attention. In summary, the above evidence shows that nicotine-conditioned stimuli might have powerful incentive salience and regulate nicotine seeking/taking behavior in animals and humans, though stress and nicotine-withdrawal could also enhance nicotine taking in the same way as other dependence -producing mechanisms.

Transcranial direct-current stimulation increases extracellular dopamine levels in the rat striatum.

BACKGROUND: Transcranial direct-current stimulation (tDCS) is a non-invasive procedure that achieves polarity-dependent modulation of neuronal membrane potentials. It has recently been used as a functional intervention technique for the treatment of psychiatric and neurological diseases; however, its neuronal mechanisms have not been fully investigated in vivo. OBJECTIVE/HYPOTHESIS: To investigate whether the application of cathodal or anodal tDCS affects extracellular dopamine and serotonin levels in the rat striatum. METHODS: Stimulation and in vivo microdialysis were carried out under urethane anesthesia, and microdialysis probes were slowly inserted into the striatum. After the collection of baseline fractions in the rat striatum, cathodal or anodal tDCS was applied continuously for 10 min with a current intensity of 800 µA from an electrode placed on the skin of the scalp. Dialysis samples were collected every 10 min until at least 400 min after the onset of stimulation. RESULTS: Following the application of cathodal, but not anodal, tDCS for 10 min, extracellular dopamine levels increased for more than 400 min in the striatum. There were no significant changes in extracellular serotonin levels. CONCLUSION: These findings suggest that tDCS has a direct and/or indirect effect on the dopaminergic system in the rat basal ganglia.

Facilitation of intracranial self-stimulation behavior in rats by environmental stimuli associated with nicotine.

Environmental stimuli associated with nicotine act as a trigger for nicotine-seeking behavior and make it difficult to quit smoking. The trigger action might be related to the activity of the mesolimbic dopamine "reward" system. Thus, in the present study, we investigated the effects of nicotine-associated stimuli on reward seeking, assessed by current intensity thresholds of intracranial self-stimulation (ICSS) in rats. Rats were unilaterally implanted with an electrode into the lateral hypothalamus and trained to press a lever to obtain electrical brain stimulation. After stable responses had been established, the rats underwent six conditioning sessions with subcutaneous nicotine at 0.4 mg/kg in particular visual and tactile contexts. The threshold for electrical stimulation was then tested in either the nicotine-conditioned environment or novel environment under saline or nicotine treatment. Nicotine enhanced the responding for ICSS and significantly lowered the threshold in both environments. Under saline treatment, the responding for ICSS was facilitated and the threshold was significantly lower in the nicotine-conditioned environment than in the novel environment. The present results demonstrate that nicotine-conditioned contextual stimuli may affect the mesolimbic dopamine system through ICSS threshold lowering effect.

Photosensitive-polyimide based method for fabricating various neural electrode architectures.

An extensive photosensitive-polyimide (PSPI)-based method for designing and fabricating various neural electrode architectures was developed. The method aims to broaden the design flexibility and expand the fabrication capability for neural electrodes to improve the quality of recorded signals and integrate other functions. After characterizing PSPI's properties for micromachining processes, we successfully designed and fabricated various neural electrodes even on a non-flat substrate using only one PSPI as an insulation material and without the time-consuming dry etching processes. The fabricated neural electrodes were an electrocorticogram (ECoG) electrode, a mesh intracortical electrode with a unique lattice-like mesh structure to fixate neural tissue, and a guide cannula electrode with recording microelectrodes placed on the curved surface of a guide cannula as a microdialysis probe. In vivo neural recordings using anesthetized rats demonstrated that these electrodes can be used to record neural activities repeatedly without any breakage and mechanical failures, which potentially promises stable recordings for long periods of time. These successes make us believe that this PSPI-based fabrication is a powerful method, permitting flexible design, and easy optimization of electrode architectures for a variety of electrophysiological experimental research with improved neural recording performance.

Up-regulation of dopamine D1 receptor in the hippocampus after establishment of conditioned place preference by cocaine.

The hippocampus plays an important role in the formation of contextual memory between the environment and the rewarding effect of abused drugs. The dopaminergic neural transmission in the hippocampus seems to be critical for such memory. Using conditioned place preference in rats, we found that the protein level of the dopamine D(1) receptor and its prerequisite mRNA in the hippocampus increased in animals that showed a clear preference for the environment paired with cocaine. The increase was not a simple reflection of the repeated administration of cocaine. Instead, it is attributable to conditioning, because systematic contingency between drug administration and exposure to a particular environment was necessary for the increase. Furthermore, we found that the mRNA of the dopamine D(1) receptors increased in the granule cell layer of the dentate gyrus. These results suggest that the alteration of dopamine D(1) receptor in the hippocampus, especially in the dentate gyrus, is related to the induction of drug-induced contextual memory. The finding implicates the relevance of the dopaminergic signal transduction in the hippocampus to drug dependence.

A rat model for measuring the effectiveness of transcranial direct current stimulation using fMRI.

Transcranial direct current stimulation (tDCS) is one of the noteworthy noninvasive brain stimulation techniques, but the mechanism of its action remains unclear. With the aim of clarifying the mechanism, we developed a rat model and measured its effectiveness using fMRI. Carbon fiber electrodes were placed on the top of the head over the frontal cortex as the anode and on the neck as the cathode. The stimulus was 400- or 40-µA current applied for 10 min after a baseline recording under an anesthetized condition. The 400-µA stimulation significantly increased signal intensities in the frontal cortex and nucleus accumbens. This suggests anodal tDCS over the frontal cortex induces neuronal activation in the frontal cortex and in its connected brain region.

Structure of rat ultrasonic vocalizations and its relevance to behavior.

Rats are known to emit ultrasonic vocalizations (USVs). These USVs have been hypothesized to hold biological meaning, and the relationship between USVs and behavior has been extensively studied. However, most of these studies looked at specific conditions, such as fear-inducing situations and sexual encounters. In the present experiment, the USVs of pairs of rats in ordinary housing conditions were recorded and their features were examined. Three clusters of USVs in the 25-, 40-, and 60-kHz range were detected, which roughly corresponded to fighting, feeding, and moving, respectively. We analyzed sequential combinations of two or more clusters using a state transition model. The results revealed a more specific correspondence between the USVs and behaviors, suggesting that rat USV may work as a type of communication tool.

Hippocampal theta rhythm and drug-related reward-seeking behavior: an analysis of cocaine-induced conditioned place preference in rats.

Drug cravings are elicited by environmental stimuli associated with the rewarding effects of drugs. As an animal model of such associative learning, conditioned place preference (CPP) is widely used. Since the hippocampus is closely related to reward memory and the hippocampal local field potential (LFP), and in particular the theta rhythm is known to be associated with bodily movements, the theta rhythm might be one of the key neural substrates. On the basis of this assumption, we recorded the behaviors and hippocampal LFP of eight rats during cocaine-induced acquisition and expression of CPP. The earliest appearance of phase-locked theta activity was observed before the rats entered the cocaine-paired environment after conditioning; after entrance, the theta disappeared. This phase-locked theta was stronger when the rats stayed for a long time in the cocaine-paired environment. Our observation suggested that the phase-locked hippocampal theta rhythm is related to the approaching behavior of the rat caused by reward memory. Thus, the role of the hippocampus in drug craving should be emphasized further.

Big losses lead to irrational decision-making in gambling situations: relationship between deliberation and impulsivity.

In gambling situations, we found a paradoxical reinforcing effect of high-risk decision-making after repeated big monetary losses. The computerized version of the Iowa Gambling Task (Bechara et al., 2000), which contained six big loss cards in deck B', was conducted on normal healthy college students. The results indicated that the total number of selections from deck A' and deck B' decreased across trials. However, there was no decrease in selections from deck B'. Detailed analysis of the card selections revealed that some people persisted in selecting from the "risky" deck B' as the number of big losses increased. This tendency was prominent in self-rated deliberative people. However, they were implicitly impulsive, as revealed by the matching familiar figure test. These results suggest that the gap between explicit deliberation and implicit impulsivity drew them into pathological gambling.

[Decision making and the Iowa Gambling Task: relevance to dependence study].

The Iowa Gambling Task (IGT) is an experimental tool to study decision making. In this task, participants choose a card from four decks of cards. Each card indicates either gain or loss of money. Participants are instructed to earn as much money as possible. Two of the four decks are "risky", containing cards with bigger gains and losses than the other two decks. The sustained selection of the risky decks ends up in overall loss. Therefore, the choice behavior becomes "cautious" in healthy participants during the task. However, patients with lesions in the prefrontal cortex and substance abusers persist on the risky decks. This tendency is interpreted to reflect impulsivity. Thus, the task has been used to detect impulsiveness in certain neurological/psychiatric disorders. Our recent study found that even in health participants, some people persisted in selecting from the risky deck as the number of big losses increased. This tendency was prominent in self-rated deliberative people. However, they were implicitly impulsive, as revealed by the matching familiar figure test. These results suggest that the gap between explicit deliberation and implicit impulsivity drew them into risky decision making. In this article we introduce theoretical backgrounds, practical procedure, and several applicative studies from the IGT literatures and suggest the usefulness of the IGT in dependence and addiction study.

A new behavioral test for assessment of drug effects on attentional performance and its validity in cynomolgus monkeys.

The assessment of drug effects on attention is important in non-clinical pharmacology, for both evaluation of safety and therapeutic efficacy of medicinal products. In the present study, we have developed a two-lever choice behavioral test to assess drug effects on attentional performance in monkeys. In each trial of this experiment, one of two lamps in front of a monkey was randomly illuminated for a brief period of time and the monkey was required to press a lever beneath the lamp 30 times to obtain a food reward. The percentage of correct responses, response latency of correct choice responses and response speed were measured. Using this test, we examined the effects of three sedative drugs, diazepam (0.25, 1 and 4 mg/kg, i.g.), ethanol (0.5, 1 and 2 g/kg, i.g.), and pentobarbital (0.25, 1 and 4 mg/kg, i.v.). Diazepam and pentobarbital lengthened response latency without significantly affecting the percentage of correct responses, response and response speed, suggesting selective disruptive effects on attentional performance. In contrast, ethanol at the high dose tested caused deterioration in all three measurements, which is thought to reflect a general sedative effect including motor impairment as reflected by lengthening response speed. It is suggested that the present behavioral test method could detect drug effects on attentional performance in monkeys and could be a useful tool for safety assessment in drug development.

Psychosocial withdrawal characteristics of nicotine compared with alcohol and caffeine.

The purpose of the present study was to observe the psychosocial characteristics of withdrawal from cigarette smoking in comparison with those from caffeine (CAF) and alcoholic (ALC) beverage withdrawal. Twenty-seven healthy volunteers at a medial level of dependence on both cigarettes (nicotine, NCT) and either CAF or ALC, as judged by the DSM-IV-TR criteria for substance dependence, participated in this study. The participants were required to abstain from smoking and either CAF or ALC for 7 days, each one after another, with a 7-day interval. The order of abstinence was counterbalanced among the participants. Psychosocial parameters, including a desire for substances, social activity function, well-being, withdrawal symptoms, and vital signs, were assessed during the withdrawal periods. The study protocol was approved by the Jikei University Review Board. The results indicated that there were no differences in the maximum level of desire for a substance and the influence on social activity function between NCT and other substances during the withdrawal periods. As for withdrawal symptoms, NCT caused a more intensive degree of irritability than CAF or ALC, and a more intensive degree of difficulty concentrating and restlessness than did withdrawal from ALC. However, the subjective well-being questionnaire indicated no differences in these symptoms between NCT and other substances. The present results suggest that there are no significant differences in psychosocial manifestations regarding the difficulty in abstaining from NCT, CAF, and ALC.

Prepulse inhibition of acoustic startle in Japanese patients with chronic schizophrenia.

Prepulse inhibition (PPI) of acoustic startle reflex has been suggested as a neurophysiologic measure of information processing abnormalities in schizophrenia. However, there has been little information on PPI and related measures in Asian patients with schizophrenia. We examined startle response to acoustic stimuli, its habituation, and PPI in 20 Japanese patients with chronic schizophrenia under antipsychotic medication and 16 healthy controls matched for age and sex. We measured PPI with 115 dB of pulse (40 ms), 82, 86, or 90 dB of prepulse (20 ms) and 30, 60, or 120 ms of lead interval (LI). The startle response to pulse alone trials was significantly smaller in schizophrenics than in controls, which may be due, at least in part, to medication. There was no significant difference in habituation of startle response during the test session between the two groups. PPI differed significantly between the two groups when LI was 120 ms. No significant relationship was found on startle response or PPI with age of onset, number of previous admission, medication dosages, or symptom scores assessed with the Positive and Negative Syndrome Scale (PANSS). Our results confirm impaired PPI in chronic schizophrenia patients compared with controls in Japanese.

Effects of ifenprodil on the discriminative stimulus effects of cocaine in rhesus monkeys.

Ifenprodil is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which prefers NR2B-containing NMDA receptors to NR2A-containing NMDA receptors. It has been reported that ifenprodil suppresses morphine-induced place preference in mice. In this study, the effects of ifenprodil on the discriminative stimulus effects of cocaine were examined in rhesus monkeys. Five monkeys were trained to discriminate cocaine at 0.25 or 0.5 mg/kg im from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio schedule of food reinforcement. A single dose of cocaine (0.06-0.5 mg/kg) produced a dose-dependent increase in cocaine-appropriate response, and training doses produced 100% cocaine-lever response in each monkey. Pretreatment with ifenprodil (1 or 2 mg/kg, i.v.) blocked the cocaine-appropriate response when low doses of cocaine were used. The results suggest that NR2B-containing NMDA receptor-mediated mechanisms modulate the discriminative stimulus effects of cocaine in rhesus monkeys.