Hisatsugu Miyata

Neurobiological mechanisms of nicotine craving.

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.

Brain regions mediating the discriminative stimulus effects of nicotine in rats.

Abstract: 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 sc) 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 sc), 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.

Medial prefrontal cortex is involved in the discriminative stimulus effects of nicotine in rats.

Abstract  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.

Decreases in Brain Reward Function Reflect Nicotine- and Methamphetamine-Withdrawal Aversion in Rats

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.

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.

Clinical features of nicotine dependence compared with those of alcohol, methamphetamine, and inhalant dependence.

Abstract: 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.

Symptoms of delusion: the effects of discontinuation of low‐dose venlafaxine

Objective:  We report a patient who experienced delusional symptoms during gradual discontinuation of low‐dose venlafaxine and required antipsychotic treatment.

Effectiveness of carbamazepine for benzodiazepine-resistant impulsive aggression in a patient with frontal infarctions.

Abstract  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 patients irritability and agitation gradually decreased. The efficacy of CBZ treatment in this patient suggests a method for controlling benzodiazepine‐resistant impulsive aggression.

Current Viewpoints on DSM-5 in Japan

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.