Nicotine, alcohol, methamphetamine, and inhalant dependence: a comparison of clinical features with the use of a new clinical evaluation form.

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.

[Recent advances in research on nicotine dependence and reward mechanism].

Tobacco/nicotine dependence involves both psychological and physiologic dependence on nicotine. A recent summary of the clinical aspects of nicotine dependence disorders is provided in the ICD-10 of the WHO. There is growing evidence suggesting that nicotine depends on dopamine (DA) for its reinforcing effects. Suppression of DA function using DA-receptor antagonist affects the intravenous self-administration of nicotine, the discriminative properties of nicotine, nicotine-induced intracranial self-stimulation and nicotine-conditioned place preference. The increase inextracellular DA in the nucleus accumbens (NAcc) is a major factor that mediates the self-administration of nicotine. Recently, alpha 7-nicotinic receptors in the ventral tegmental area (VTA) contribute to the acute effects of nicotine on the mesolymbic DA system, reinforcing effects of nicotine and withdrawal symptoms from nicotine. The action of glutamate (Glu) at N-methyl-D-aspartate (NMDA)-sensitive receptors within the VTA is required for nicotine to stimulate DA release in the NAcc. Molecular epidemiological studies have shown that smoking behavior is more strongly influenced by a combination of the serotonin transporter gene and the neuroticism than by either factor alone. Clinically, bupropion, an antidepressant, has been licensed for use in USA to help patients stop smoking. The underlying mechanism is thought to be mediated by increasing the concentration of DA in the NAcc.

[The effects of midazolam on the memory of pain].

The purpose of this study was to evaluate the effects of low dose midazolam (MZ) on memories of spinal puncture. The low doses of MZ were administered to 70 patients (ASA 1-2), of whom 37 patients were premedicated with atropine sulfate 0.5 mg and pethidine hydrochloride i.m. (group P), and 33 patients received no premedication (group N). Double blind randomized trials were conducted with the doses of MZ (0, 0.03, 0.06 mg.kg-1), and MZ was administered i.v. to the patients just prior to spinal puncture. Subjective evaluation of pain was performed with pain score (PS) on postoperative phase, and objective evaluation of pain was performed with the reaction of spinal puncture. Short term memory was impaired mainly after administration of MZ. However, subjective memory of pain almost disappeared, but objective evaluation was not so good. We conclude that MZ induces impairment to recall of pain. However, it might maintain the response to the pain.

Serotonin2A receptor gene polymorphism in mood disorders.

Genes that regulate the serotonin (5-HT) system including 5-HT receptors may be involved in mood disorders. We studied 5-HT2A receptor exons and the adjacent intron regions in 102 patients with mood disorders (71 depressive disorders and 31 bipolar disorders). In 34 mood disorder cases, the gene encoding the 5-HT1A receptor had been sequenced, but no disease-specific polymorphism was found. The substitution of C for T at position 102 in exon 1, which had been reported by Warren et al., was confirmed. The corresponding amino acid, serine, did not change. The allele frequency of C [corrected] at position 102 was significantly higher in patients with depressive disorders than in those with bipolar disorders and healthy control subjects. Furthermore, the mean age of onset in the patients heterozyous for the T and C alleles was lower than that in those homozygous for the C allele. No other polymorphism in the gene was found.

Polymorphisms of dopamine D2-like (D2, D3, and D4) receptors in schizophrenia.

The result of most association studies and linkage analyses have suggested a negative association between schizophrenia and D2-like (D2, D3, and D4) receptor polymorphisms. Although the polymorphisms of the D2-like receptor in themselves may not account for the etiology of schizophrenia, they can contribute to the severity of the symptoms. Thus, we studied the associations between the polymorphisms and their combinations, and the vulnerability of schizophrenics. Fragments of the D2-like receptor genes were amplified by means of the polymerase chain reaction, and the polymorphisms were identified by the restriction fragment length polymorphism and single-stranded conformation polymorphism methods. There were no statistically significant differences in the polymorphisms and their combinations between schizophrenics and controls. Schizophrenics with D4E1(A1/A2), which contains 2 and 1 tandem repeats of a 12-base-pair sequence in exon 1, had a lower total positive symptom score before medication than schizophrenics with D4E1(A1/A1). There was no association between the polymorphisms and negative symptoms.

Intact 5-HT2A receptor exons and the adjoining intron regions in schizophrenia.

Genes that regulate serotonergic (5-HT) systems may underlie the etiology of schizophrenia. In this study the gene encoding the 5-HT2A receptor in schizophrenics and healthy controls was examined. First, we sequenced all exons and the flanking introns of the 5-HT2A receptor gene in 10 schizophrenics and 10 controls. The substitution of C for T at position 102 in exon, which had been reported by Warren et al. (1993), was confirmed. Restriction fragment length polymorphism (RFLP) analysis revealed no association between polymorphism and schizophrenia. There was no association between the polymorphism and subdiagnosis, family history, age of onset, amounts of antipsychotics, or positive and negative symptoms before or after medication. Other polymorphisms in the gene were screened in 100 schizophrenics by the single-strand conformation polymorphism method, but none was found. Our results suggest that an abnormality in the 5-HT2A receptor gene in schizophrenia is unlikely.

The genes encoding the 5HT1D alpha and 5HT1D beta receptors are unchanged in patients with panic disorder.

To determine the serotonergic function in panic disorder, sequencing of the genes encoding the 5HT1D alpha and 5HT1D beta receptors was carried out. The genes for the 5HT1D alpha and 5HT1D beta receptors were amplified by polymerase chain reaction and sequenced by the dideoxy method. Some patients have both nucleotides C and T at position 1080 in 5HT1D alpha receptor gene; however, both of them code the same amino acid, asparagine. The 5HT1D beta receptor gene had a substitution from GCA276 to GCG276, not only panic disorder but also in controls; however, this substitution does not change the corresponding amino acid, alanine92.

The gene encoding the 5-HT1A receptor is intact in mood disorders.

We studied the 5-HT1A receptor gene in 50 mood disorders and 50 normal volunteers. The 5-HT1A receptor gene was amplified by polymerase chain reaction and sequenced by the dideoxy method. The sequence of the 5-HT1A receptor encodes a protein of 422 amino acids, that is, one amino acid longer than the reported sequence (Kobilka et al. 1987). The DNA sequence at positions 454 to 459 is CGC GCC GCT, not CCG CGT, and the amino acids sequence at these positions is changing from proline arginine to arginine alanine alanine. These differences, however, were observed in both mood disorders and controls. One silent polymorphism, CTG to GTA at position 294, was found. These results suggest that the 5-HT1A receptor gene is intact in mood disorders.

Normal sequences of muscarinic acetylcholine receptors (m1 and m2) in patients with Alzheimer's disease and vascular dementia.

The genes for muscarinic acetylcholine receptors, m1 and m2, were studied in autopsied brains from nine Alzheimer's disease, six vascular dementia and three control. The genes were amplified by the polymerase chain reaction and sequenced by the dideoxy method. Although one DNA polymorphism was found in m1, the deduced amino acid sequences of the muscarinic acetylcholine receptor were unchanged. The amino acid sequences of m1 and m2 in Alzheimer's disease and vascular dementia were intact.

The middle-aged generation is at high risk for suicide in Japan. A comparison between the 1950s and the 1980s.

The suicide rate in Japan was the highest in the world the 10 years after World War II. There were many suicides among young and aged people. Now, Japan has many suicides among middle-aged people, and suicides among elderly people are still remarkable. These findings suggest that middle-aged people in 1980s have a high risk of suicide and that suicide among elderly people will increase in 10-20 years.

Circadian variations in plasma monoamine metabolites level in alcoholic patients: a possible predictor of alcohol withdrawal delirium.

1. Alcohol withdrawal symptoms in 17 alcoholics were classified into two groups according to the severity of their symptoms, and circadian variations in their plasma 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) levels during the alcohol withdrawal and the abstention periods were compared with those in normal controls by two-way ANOVA. 2. Circadian variations in plasma 5HIAA level in alcoholic patients manifested severe alcohol withdrawal symptoms and exhibited phase advances in both the withdrawal and the abstention periods and significantly higher levels in the abstention period. 3. Circadian variation in plasma HVA in the abstention period in alcoholics showed severe withdrawal symptoms demonstrating significantly higher levels compared with normal controls. 4. These findings suggest that the serotonergic and dopaminergic activity may vary depending on the severity of alcohol withdrawal symptoms and the measurement of circadian variations in plasma 5HIAA and HVA levels could possibly be used as a predictor of hardly predictable alcohol withdrawal delirium.

Circadian variation in plasma 5-hydroxyindoleacetic acid level during and after alcohol withdrawal: phase advances in alcoholic patients compared with normal subjects.

Alcohol withdrawal symptoms in 19 male alcoholics were objectively evaluated and classified and circadian variation in their plasma 5-hydroxyindoleacetic acid (5-HIAA) concentrations was determined at 3 different intervals after cessation of drinking. Circadian variations in plasma 5-HIAA level exhibited phase advances in alcoholic patients compared with normal controls and were different depending on the severity of alcohol withdrawal symptoms. Plasma 5-HIAA in patients with delirium tremens showed significantly higher levels during the abstention period, possibly suggesting peculiarity in their serotonergic metabolism.

The effects of beta-blockers and diazepam on heart rate of conscious conditioned rats.

1. Fischer male rats were trained to avoid shock in a shuttle box. After this procedure, a small ECG transmitter was incorporated under the skin of thorax. 2. In saline group, when in the shuttle box heart rate significantly increased, and decreased while exposed to the buzzer. 3. When beta-blocker (carteolol, pindolol, propranolol) was injected, heart rate did not increase after the rat was put in the shuttle box, but decreased after exposed to the buzzer. Change in heart rate was not shown when diazepam was injected. 4. These results indicated that diazepam is more effective than beta-blocker in terms of instability of heart rate in conditioned rats.