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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.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.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 [P0.001], and history of suicide attempts [P = 0.009]). In the multivariable analysis, behavioral addictions (β = 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.Patients with gambling disorder should be carefully assessed for psychiatric comorbidities and interventions should reflect the individual diagnosis.

Background: The term “addiction” encompasses both substance dependence and behavioral addiction and is associated with major societal problems. Measures to combat addiction are currently insufficient in Japan, and further research on addiction is necessary. Methods: Science Council of Japan (SCJ) has three subcommittees – the Addiction Subcommittee, Brain and Mind Subcommittee, and Neuroscience Subcommittee among others. Those three subcommittees are dealing directly or indirectly with addiction problems in Japan. Thus, all authors of this review, members of those subcommittees, collectively recommended what research activities are required in Japan for continuing effort in overcoming addiction problems in Japan. Results: We proposed the following measures. Proposal 1: Understand diversity in addiction and promote related research and education; Proposal 2: Promote personalized measures for patients with addiction disorders; Proposal 3: Foster addiction research personnel; Proposal 4: Develop new guidelines for the rehabilitation of patients with drug dependence; Proposal 5: Establish an institute specializing in addiction research and comprehensively handling information collection, research, countermeasures, treatment, and public relation related to addiction. Conclusion: The opinions of the review are based on the recommendations that were published in 2020 in Japanese by the Addiction Subcommittee, Brain and Mind Subcommittee, and Neuroscience Subcommittee of the SCJ. The authors here are sharing colleagues of Taiwanese Society of Psychiatry with these proposed research activities required to overcome addiction problems in Japan.

Aim The safety and efficacy of nalmefene in Japanese patients with high or very high World Health Organization drinking risk level of alcohol dependence were assessed in a multicenter, randomized, double-blind, placebo-controlled, phase 3 (lead-in) study. Here, the long-term safety and efficacy of nalmefene in an open-label extension of the lead-in study are presented. Methods Patients who completed the 24-week lead-in study were eligible for the extension study, where they were treated with nalmefene 20 mg as needed for 24 weeks. The long-term safety and efficacy of nalmefene 20 mg during the total 48-week period were evaluated. Treatment-emergent adverse events during the study period were recorded and change from baseline in the number of heavy drinking days and total alcohol consumption were calculated. Results Overall, long-term nalmefene 20 mg was well tolerated; the main treatment-emergent adverse events reported in ≥5% of patients included nasopharyngitis (37.2%), nausea (36.5%), somnolence (21.2%), dizziness (16.8%), malaise (14.6%), and vomiting (12.4%). The number of heavy drinking days and total alcohol consumption decreased from baseline to 48 weeks (mixed model for repeated measures, least squares mean ± standard error, -15.09 ± 0.77 days/month and -53.20 ± 2.29 g/day, respectively) during the study. Conclusion This long-term evaluation in Japanese patients with high or very high drinking risk levels of alcohol dependence indicated that nalmefene was safe, well tolerated, and efficacious.

Addiction has become a major worldwide medical, public health, and social problem. Because the prevalence of addiction varies widely geographically, due to differences in ethnicity, culture, education, social environment, and regulation, each country or region needs to understand its current state of addiction and to take appropriate measures, in multidisciplinary collaboration. In order to understand the direction of addiction research in Japan, we analyzed 50 research and development topics and their characteristics, based on an expert questionnaire survey. The topics were placed in five categories, as follows. Category 1: Basic science; all 10 topics were of the Long‐term project and International cooperation types. Category 2: Translational and clinical research; 6 out of 10 topics were of the Long‐term project. Category 3: Fact‐finding surveys; 8 out of 10 topics were of the Japan‐specific type. Category 4: Health system and service; 8 out of 10 topics were of the Japan‐specific type and Short‐term project. Category 5: Study on society, culture, environment, education, and regulation; 7 out of 10 topics were of the Short‐term project (similar to Category 4). As far as we know, this is the first systematic questionnaire survey on the direction of addiction research. The results of this study might support developing a strategy for addiction research, not only in Japan, but also in other countries., Future direction of addiction research was revealed by an expert questionnaire survey in Japan.

IntroductionSchizophrenia is believed to be etiologically associated with environmental factors. Poor parental bonding, especially arising from "low care" and "overprotection," may contribute to the prognosis in patients with psychosis. In the present study, we investigated the associations between the aforementioned two different parental bonding types and the prognosis, in terms of the functional recovery, of patients with schizophrenia.MethodsA total of 89 patients with schizophrenia were recruited, and 79 patients were registered for the study. After the parental bonding types and representative childhood adverse events were assessed, specific items on the PANSS were assessed at 0 and 24 weeks of the study period to define the functional prognosis.ResultsAt the end of the 24-week follow-up period, 36% of the patients were judged as showing recovery from schizophrenia. The score for "overprotective attitude," but not that for "low care," was found to be significantly higher in the non-recovery (defined below) group. Exploratory logistic regression analysis identified only "overprotective attitude" of the parents as being predictive of non-recovery. Moreover, a significant negative correlation was found between "low care" and "overprotective attitude" only in the non-recovery group.ConclusionIn the present study, we showed that an overprotective attitude of the parents was associated with non-recovery in patients with schizophrenia.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the I nternational C lassification of D iseases (ICD-10) to categorize disorders and determine treatment fees. However, since the publication of the DSM-III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM-5 is being established, the editorial board of P sychiatry and C linical N eurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM-5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive-Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance-Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty.

AIMS Reducing alcohol consumption is one treatment approach for alcohol-dependent patients. This study compared nalmefene 20 mg and 10 mg with placebo, combined with psychosocial support, in alcohol-dependent Japanese patients with a high or very high drinking risk level (DRL). METHODS This was a multicenter, randomized, double-blind, phase 3 study conducted in alcohol-dependent patients with a high or very high DRL. Patients were randomized to 24 weeks of treatment with as-needed nalmefene 20 mg, 10 mg, or placebo with psychosocial support. The primary endpoint was change in heavy drinking days (HDD) from baseline to week 12. A key secondary endpoint was the change in total alcohol consumption (TAC) from baseline to week 12. RESULTS At week 12, 234, 206, and 154 patients who received placebo, nalmefene 20 mg, and 10 mg were included in the primary endpoint analysis. Compared with placebo, nalmefene was associated with significant reductions in HDD at week 12 (difference in 20 mg group, -4.34 days/month; 95% confidence interval [CI]: -6.05 to -2.62; P

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the I nternational C lassification of D iseases (ICD-10) to categorize disorders and determine treatment fees. However, since the publication of the DSM-III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM-5 is being established, the editorial board of P sychiatry and C linical N eurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM-5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive-Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance-Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty.

The purpose of the present study was to investigate whether brain reward function decreases during withdrawal from nicotine and methamphetamine, and whether decreased reward function is related to aversion during withdrawal from these drugs. For that purpose, male Sprague-Dawley rats were chronically infused subcutaneously with 9 mg/kg per day nicotine, or with 6 mg/kg per day methamphetamine using osmotic minipumps. In an intracranial self-stimulation (ICSS) paradigm, chronic infusion of nicotine and methamphetamine decreased the thresholds for lateral hypothalamic ICSS, whereas their antagonists, mecamylamine and haloperidol increased the ICSS thresholds in the rats treated with nicotine and methamphetamine, respectively. In a conditioned place aversion paradigm, mecamylamine and haloperidol produced place aversion in nicotine- and methamphetamine-infused rats, respectively. Interestingly, elevations in ICSS reward thresholds and place aversion during mecamylamine-precipitated nicotine withdrawal were almost the same in magnitude as those observed during haloperidol-precipitated methamphetamine withdrawal. The present study indicates that 1) brain reward function decreased during nicotine and methamphetamine withdrawal, and 2) a decrease in reward function may reflect the negative affective state (aversion) during withdrawal from nicotine and methamphetamine.

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.

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.

A new clinical evaluation form was developed to compare the clinical features of nicotine dependence with those associated with other abused drugs. A new scoring system for clinical evaluation was developed. The form consisted of five scoring items: subjective effects, liking (of drug), withdrawal syndrome, acute psychic and physical disorders, and social disturbance. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine (cigarette smoking, n = 40), alcohol (n = 39), methamphetamine (n = 31), and inhalants (n = 30), who fulfilled the DSM-IV-TR criteria for drug dependence disregarding the state of "a maladaptive pattern of substance use, leading to clinically significant impairment or distress," and gave written informed consent for participation in the study. Nicotine caused a mild or the least degree of subjective effects, liking, and psychic and physical withdrawal symptoms, without any significant social disturbance or acute disorders. With alcohol, liking, withdrawal syndrome, and acute physical disorders were prominent. Methamphetamine produced the most serious acute psychic disorders, with intensive acute physical disorders and psychic withdrawal symptoms. Inhalants were characterized by an intensive degree of acute psychic disorders. As for social disturbance, alcohol, methamphetamine, and inhalants showed more significant influence than nicotine. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

Nicotine produces core symptoms of substance dependence (craving and withdrawal) without any psychotic symptoms. The psychopharmacological structure of craving is hypothesized to be constituted by three components: the primary reinforcing property of a substance, the secondary reinforcing property of that substance (conditioned aspects of the environment, such as contextual or specific cues associated with substance taking), and the negative affective motivational property during withdrawal (i.e. the desire to avoid the dysphoric withdrawal symptoms elicits craving). Among the three components, the primary reinforcing property of a substance forms the most fundamental factor for establishing substance dependence. Sensitization or reverse tolerance observed in locomotor activity of animals, which had been believed to be a methamphetamine psychosis model, is demonstrated to reflect the establishment of conditioned reinforcement. Finally, non-substance-related addiction such as gambling, internet, and sex is discussed. From the aspect of the above hypothetical psychopharmacological structure of craving, the most significant difference between substance dependence and non-substance-related addiction is that the primary reinforcing property of non-substance reward is relatively intangible in comparison with that of a substance of abuse.

Nicotine induces craving, but the degree of craving is believed to be milder than that with other abused drugs. In this article, the neurobiological mechanisms of craving for nicotine and other drugs are reviewed, focusing especially on three factors that can be involved in the development of craving. The first factor is the affective symptoms of withdrawal, the neural basis of which may involve neuroadaptations (desensitization) within the reward systems. Affective symptoms experienced during withdrawal from nicotine are milder than those experienced in withdrawal from other drugs, probably because of its mode of action on the reward systems, which is similar to that of natural rewards. The second factor is the conditioning process, in which environmental stimuli can gain properties of a secondary reinforcer. Nicotine has weak but reliable conditioning effects, and the brain region mediating those effects of nicotine involves the ventral tegmental area. The third factor is a cognitive (memory) process, but little is known about this area.

Objective: We report a patient who experienced delusional symptoms during gradual discontinuation of low-dose venlafaxine and required antipsychotic treatment. Method: Case report. Results: A 31-year-old woman with major depression had been treated abroad with venlafaxine before returning to Japan. Since venlafaxine is unavailable here, we supplemented her regular venlafaxine dosage of 37.5 mg/day with clomipramine 20 mg/day. After 5 weeks we reduced venlafaxine to 18.75 mg/day and uptitrated clomipramine to 40 mg/day. Four days later she developed delusions of reference, palpitations and nausea. Clomipramine was increased to 60 mg/day, and her symptoms subsided. Eight weeks later her supply of venlafaxine ran out, and within 4 days her condition deteriorated into more severe symptoms that required 4 months’ antipsychotic treatment. Conclusion: We speculate that her symptoms were discontinuation syndrome, including psychotic symptoms and physical symptoms, caused by (i) venlafaxine-clomipramine interaction and/or (ii) the serotonin reuptake inhibitor-like effects of low-dose venlafaxine.

Anticonvulsants have been used for the treatment of impulsive aggression since the 1980s. A 50-year-old man suffered from irritability and agitation after developing a right ipsilateral frontal lobe infarction as a result of Moyamoya disease; these symptoms caused difficulties with his working and interpersonal relationships. The patient had been treated using multiple benzodiazepine agents for 2 years but his symptoms had not improved. However, after treatment with carbamazepine (CBZ; 200 mg) was begun, the patient's irritability and agitation gradually decreased. The efficacy of CBZ treatment in this patient suggests a method for controlling benzodiazepine-resistant impulsive aggression.

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.

This article reviews clinical features and neural mechanisms of nicotine dependence as well as medications for it. The ICD-10 and DSM-IV-TR classifications define nicotine dependence and nicotine withdrawal. The rewarding effects of nicotine have been reported to include a sense of well-being, increased vigilance, relaxation, anxiolytic effects, increased capacity to cope with stressors, and increased ability of learning and memory. These psychopharmacological effects of nicotine may be produced by the ability of nicotine to promote the release of catecholamines, acetylcholine, beta-endorphin, glucocorticoid, and other hormones. As for medications used to treat nicotine dependence, nicotine gum and nicotine patches are used to alleviate nicotine withdrawal, whereas bupropion, varenicline, and rimonabant are used to decrease rewarding effects of nicotine.

The central mechanism mediating the discriminative effects of nicotine was studied using rats. Rats were trained to discriminate subcutaneously administered nicotine at 0.5 mg/kg from saline in a 2-lever operant chamber situation for food reinforcement. 1) Nicotine administered into the lateral ventricle at both 100 micrograms and 120 micrograms substituted for subcutaneously administered nicotine at 0.5 mg/kg. This result indicates that the discriminative effects of nicotine are mediated centrally. 2) Among the drugs, acetylcholine at 0.5-10 micrograms administered into the lateral ventricle and methamphetamine at 5-40 micrograms and dopamine at 1-10 micrograms administered into the nucleus accumbens, none substituted for subcutaneously administered nicotine. These results indicate that the discriminative effects of nicotine differ from those of the above drugs. 3) Nicotine at 100 micrograms administered into the nucleus accumbens almost completely substituted for subcutaneously administered nicotine. In addition, mecamylamine at 180 micrograms administered into the nucleus accumbens attenuated the discriminative effects of subcutaneously administered nicotine. These results suggest that nicotinic receptors in the nucleus accumbens may be involved in the discriminative effects of nicotine. However, further studies are needed, since the nucleus accumbens is regarded not to be a major site of action of nicotine for these effects because of its low susceptibility to nicotine and mecamylamine.

Rationale: Central nicotinic receptors have been reported to be involved in the discriminative stimulus (DS) effects of nicotine. Objectives: The purpose of the present study was to investigate the role of the medial prefrontal cortex (mPFC) and the medial habenular nucleus (mHb) in the DS effects of nicotine. Methods: Substitution tests with nicotine administered into mPFC and mHb were conducted in rats trained to discriminate nicotine (0.5 mg/kg, SC) from saline in a two-lever, food reinforced, operant task. Results: Nicotine (40 µg) administered into mPFC substituted for nicotine (0.5 mg/kg, SC), whereas nicotine administered into mHb did not. Conclusions: Together with our previous study indicating that the nucleus accumbens and the ventral tegmental area are partially involved in the DS effects of nicotine, the present study suggests that mPFC is primarily involved in the DS effects of nicotine.

The role of smoking and nicotine in various neuropsychiatric disorders has been attracting increasing attention. Recently, investigations into the neurobiological properties of brain nicotinic acetylcholine receptors (nAChRs) have led to an improved understanding of their role in the above disorders, alpha4beta2 and alpha7 subunit containing nAChRs are predominantly identified in the brain among all types of nAChRs composed of nine alpha (alpha2 to alpha10) and three beta (beta2 to beta4) subunits. These receptors play important roles in attention, memory, and cognition and participate in the pathogenesis of several neuropsychiatric disorders (schizophrenia, depression, anxiety disorders, Parkinson's and Alzheimer's diseases, attention-deficit hyperactivity disorders, Tourette's syndrome, and autosomal dominant nocturnal frontal lobe epilepsy). For the majority of these disorders, the use of nAChRs agonists may represent either a prophylactic (especially for Parkinson's and Alzheimer's diseases) or a symptomatic treatment. The possible mechanisms underlying these beneficial effects as well as the characteristics and potential therapeutic use of new, subtype-selective nAChRs agonists are presented.

Anticonvulsants have been used for the treatment of impulsive aggression since the 1980s. A 50-year-old man suffered from irritability and agitation after developing a right ipsilateral frontal lobe infarction as a result of Moyamoya disease; these symptoms caused difficulties with his working and interpersonal relationships. The patient had been treated using multiple benzodiazepine agents for 2 years but his symptoms had not improved. However, after treatment with carbamazepine (CBZ; 200 mg) was begun, the patient's irritability and agitation gradually decreased. The efficacy of CBZ treatment in this patient suggests a method for controlling benzodiazepine-resistant impulsive aggression.

Nicotine dependence is characterized by weak dependence potential and less ability to produce psychotoxicity and social disturbance. A two-compartment model consisting of "dependence" and "dependence syndrome" was used to clarify clinical features of nicotine dependence. "Dependence" was defined by drug liking. "Dependence syndrome" was defined by a compulsion to take a drug, and drug-induced pathological symptoms (withdrawal syndrome and acute disorders) and social disturbance. Nicotine produced a mild or the least degree of drug liking and withdrawal syndrome, without any significant social disturbance, or acute disorders. Thus, nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome". This review also introduced other current topics of nicotine dependence. First, adolescence is regarded as a risk factor for the development of nicotine dependence, whereas the involvement of gender difference (female) in this respect is controversial. Secondly, many smokers feel difficulties in quitting smoking in spite of the weak dependence potential of nicotine, which is known as the "nicotine paradox". Several working hypotheses have been presented to explain this phenomenon. For example, nicotine has relatively strong conditioning effects and/or dependence liability compared with other drugs of abuse. However, further studies should be carried out to clarify clinical characteristics of the "nicotine paradox".

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical characteristics of nicotine dependence with those associated with other drugs of abuse, using a two-compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of five scoring items: subjective effects, drug liking, withdrawal syndrome, acute psychic and acute physical disorders, and social disturbance. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (cigarette smoking) (n = 114), alcohol (n = 101), methamphetamine (n = 90), inhalants (n = 63), and benzodiazepines (n = 39). All subjects met the DSM-IV-TR criteria for drug dependence. Nicotine produced a mild or the least degree of drug liking and withdrawal syndrome, without any significant social disturbance, or acute disorders. The other four drugs produced more intensive degrees of withdrawal syndrome and acute psychic and physical symptoms, with more significant social disturbance than nicotine. The present study indicated that nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol and methamphetamine dependence, using a two compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of six scoring items: subjective effects, tolerance, drug liking, social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (n = 68), alcohol (n = 62), or methamphetamine (n = 55). All subjects met DSM-IV diagnostic criteria for drug dependence. Nicotine produced a mild degree of drug liking and psychic withdrawal symptoms, but did not cause significant physical withdrawal symptoms, acute psychic or physical disorders or social disturbance. Alcohol and methamphetamine produced a moderate degree of drug liking and significant levels of withdrawal syndrome, acute disorders and social disturbance. Thus, in the present study, nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".

The involvement of cerebral regions in the discriminative stimulus (DS) effects of nicotine was studied using rats. Substitution tests with nicotine administered into the medial prefrontal cortex, nucleus accumbens, and ventral tegmental area, all of which are located on the mesolimbocortical dopaminergic neurons, and into the dorsal hippocampus and medial habenular nucleus, which possess high densities of nicotinic cholinergic receptors, were conducted in rats trained to discriminate nicotine (0.5 mg/kg s.c.) from saline solution in a two-lever, food-reinforced, operant task. Nicotine administered into the medial prefrontal cortex substituted for nicotine (0.5 mg/kg s.c.), whereas nicotine administered into the nucleus accumbens and ventral tegmental area partially substituted for sc injected nicotine. However, nicotine administered into the dorsal hippocampus and medial habenular nucleus did not substitute for sc injected nicotine. These results suggest that the medial prefrontal cortex is primarily involved in the DS effects of nicotine, whereas the nucleus accumbens and ventral tegmental area are partially involved.

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol, methamphetamine, and inhalant dependence. The clinical evaluation form consisted of six scoring items: subjective effects, tolerance, liking (of drug), social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine ( n = 25), alcohol ( n = 36), methamphetamine ( n = 11), and inhalants ( n = 6). All subjects met the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnostic criteria for drug dependence, as defined by the Work Group for the chapter "Substance-Related Disorders": M. A. Schuckit, J. E. Helzer, L. B. Cottler, T. Crowley, P. E. Nathan, & G. E. Woody. Nicotine produced subjective effects, tolerance, liking, and psychic withdrawal symptoms, all of which were mild in degree. However, nicotine did not produce social disturbance, physical withdrawal symptoms, or acute psychic or acute physical disorders. With alcohol, acute psychic and acute physical disorders were prominent, and alcohol also produced a moderate degree of influence on various other items that were evaluated. Methamphetamine produced the most serious acute psychic and acute physical disorders with intensive subjective effects. Inhalants were characterized by an intensive degree of acute psychic disorders and subjective effects with mild withdrawal syndrome. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

Since the nucleus accumbens has been hypothesized to centrally mediate the discriminative effects of psychomotor stimulants, the discriminative effects of methamphetamine (MA) as well as dopamine (DA) and noradrenaline (NA) were observed by intracerebral administration of these drugs into the nucleus accumbens in rats discriminating subcutaneous MA from saline. These rats were trained and maintained to discriminate between MA at 0.5 mg/kg, s.c. and saline under a fixed ratio 10 schedule for food reinforcement in a 2-lever operant chamber situation. Guide cannulae were implanted bilaterally into the nucleus accumbens. In the substitution tests, the drug was administered into the nucleus accumbens. MA at 10 micrograms per rat substituted for subcutaneous MA in 4 out of 5 rats but neither DA at 10-40 micrograms per rat (n = 7) nor NA at 10-40 micrograms per rat (n = 4) substituted for subcutaneous MA. On the other hand, the same drugs administered into the nucleus accumbens induced increased spontaneous motor activity as also observed in six other untrained rats. MA, DA or NA alone each at 10 micrograms per rat increased spontaneous motor activity. The discriminative effects of MA are considered to be mediated in the nucleus accumbens of rats. Although DA or NA alone administered into the nucleus accumbens showed similar increasing motor activity effects as those of MA, the discriminative effects of exogenous DA or NA alone administered into the same brain area were different from those of MA in the present experimental condition.

In a 2-lever operant chamber situation for food reinforcement, the effects of nicotine, arecoline and physostigmine on delayed discrimination responses in rats treated with ethylcholine mustard aziridinium ion (AF64A) were investigated. AF64A at 6 nmol, i.c.v., decreased the percentage of correct choices (% CR) at the delay time of 4 sec, and this effect depended on the delay time. On the other hand, AF64A at the same dose shortened the latency (LAT: the period from the end of the delay time to the initiation of lever-pressing responses) at the delay time of 16 sec, but this effect didn't depend on the delay time. Nicotine at 0.25 mg/kg, s.c., improved the decrease of % CR; and at 0.13-0.5 mg/kg, s.c., it shortened LAT at the delay time of 4 sec in rats treated with AF64A. Arecoline at 4 mg/kg, s.c., and physostigmine at 0.06-0.5 mg/kg, s.c., extended LAT, but both drugs showed no effects on % CR at the delay time of 4 sec in rats treated with AF64A. These results suggest that the present procedure might be useful for the evaluation of drug effects on memory in rats, and nicotine improved the delayed discrimination disruption induced by AF64A.

Delayed discrimination experiments were conducted to examine drug effects on memory in rats. Three kinds of experimental situations: a Y-maze, an operant chamber with two retractable levers, and an operant chamber with two fixed levers were used. A discriminative stimulus light either on the left or the right side of a stimulus panel was presented for a brief period in each situation. After a certain delay time following extinguishment of the light, a choice response to the previously lighted side was termed as a correct choice. Scopolamine at 0.015-0.06 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0 sec in the Y-maze situation and in trials with longer delay times in the operant chamber situations. Nicotine at 0.06-1 mg/kg, s.c., decreased the correct choice ratio in trials with a delay time of 0-4 sec in the Y-maze situation, a delay time of 4 sec in the retractable-lever operant chamber situation, and a delay time of 0.1 sec in the fixed-lever operant chamber situation. Using this delayed discrimination procedure, drug effects on the relationship between delay time and correct choice ratio were observed. From these results, the present procedure was found to be useful for the evaluation of drug effects on memory in rats.