Hiroshi Fukuzako

Genomewide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p, 14q, and 20p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Proton magnetic resonance spectroscopy of the left medial temporal and frontal lobes in chronic schizophrenia: preliminary report

Proton magnetic resonance spectroscopy (MRS) was performed in 30 medicated schizophrenic patients and 30 normal subjects. Two groups, each containing 15 schizophrenic patients and 15 age-and sex-matched normal subjects, received MRS examinations for different volumes of interest, either the frontal lobe or the medial temporal lobe. Schizophrenic patients showed a decrease in the ratios of N-acetylaspartate (NAA)/choline-containing compounds (Cho) and NAA/creatine-phosphocreatine (Cr). The patients also showed an increase in the ratio of Cho/Cr in the left medial temporal lobe but not in the left frontal lobe. The age at onset of illness correlated positively with the ratios of NAA/Cho and NAA/Cr in the medial temporal lobe. No significant correlation was observed between the ratios of NAA/Cho, NAA/Cr, or Cho/Cr in the left medial temporal and frontal lobes and clinical symptomatology as assessed by the Scale for the Assessment of Negative Symptoms and the Positive and Negative Syndrome Scale.

Reduction in hippocampal formation volume is caused mainly by its shortening in chronic schizophrenia: Assessment by MRI

We performed contiguous, 1 mm thick, magnetic resonance imaging scans in 18 men with chronic schizophrenia and in 18 age-matched healthy subjects to test in living patients the findings of a previous postmortem study. The schizophrenic patients showed bilaterally shortening (left, -6%; right, -9%) and volume reduction (left, -9%; right, -11%) of the hippocampal formation (HF). Volumes of HF correlated positively with HF length in the schizophrenic patients. The reduction in bilateral HF volumes was small after controlling for HF lengths (left, -3%; right, -3%). In schizophrenic patients, significant negative correlations were found bilaterally between the length of HFs and the scores for attention, bizarre behavior, and positive formal thought disorder. The results suggest that the volume reduction seen in the HFs of schizophrenic patients was caused mainly by a shortening of the HF and that these clinical symptoms may be associated with shorter HF length.

Marihuana smoking increases plasma cocaine levels and subjective reports of euphoria in male volunteers

The reasons why individuals use this combination are not entirely clear, however, it has been speculated that marihuana may potentiate cocaines subjective effects. Five male recreational drug users provided informed consent and volunteered to participate in this study. Each subject participated on 3 different days, separated by at least 1 week. Subjects sat in an isolated chamber and were prepared with electrocardiographic (ECG) electrodes for heart rate monitoring and an IV catheter for blood withdrawal. After adapting to the experimental chamber, they smoked a marihuana cigarette containing either 0.004% (placebo), 1.24%, or 2.64% delta 9-tetrahydrocannabinol (THC). Thirty minutes later they received an intranasal dose of 0.9 mg/kg cocaine. On subsequent visits, the marihuana dose was varied on a random basis. Subjects continuously reported changes in their mood state via an instrumental joystick device and filled out visual analog scales. Marihuana-induced tachycardia was increased even more after cocaine. The duration of all marihuana- and cocaine-related positive subjective effects was unchanged when both drugs were given, but marihuana pretreatment significantly reduced the latency to cocaine effects, from 1.87 to 0.53 min, and decreased the duration of dysphoric or bad effects, from 2.1 to 0.5 min. Peak plasma cocaine levels were 122.8 +/- 26.6 ng/ml after placebo marihuana, but pretreatment with the high-dose marihuana resulted in a significant increase in peak cocaine levels (233.8 +/- 19.2 ng/ml) and the apparent bioavailability as determined by area under the curve (AUC) analysis. We conclude that marihuana-induced vasodilation of the nasal mucosa attenuates the vasoconstrictive effects of cocaine and thus increases its absorption.

Phosphorus magnetic resonance spectroscopy in schizophrenia: Correlation between membrane phospholipid metabolism in the temporal lobe and positive symptoms

1. To determine any correlations between phosphorus metabolites in the temporal lobes and clinical symptoms in schizophrenic patients, the authors performed 31phosphorus magnetic resonance spectroscopy in 31 medicated patients and age- and sex- matched normal subjects. 2. Schizophrenic patients demonstrated an increased level of phosphodiesters (PDE) in the temporal lobes bilaterally and a decreased level of beta-adenosine triphosphate (beta-ATP) in the left temporal lobe. 3. A significant positive correlation was observed between the level of PDE in the left temporal lobe and the score of positive symptoms on the Brief Psychiatric Rating Scale. 4. These results suggest that altered membrane phospholipid metabolism in the left temporal lobe is associated with neuroleptic-resistant positive symptoms in schizophrenic patients.

Effects of D1 and D2 dopamine receptor antagonists on cocaine-induced self-stimulation and locomotor activity in rats

To clarify the involvement of D1 and D2 dopamine systems in intracranial self-stimulation (ICSS) and locomotor activity in rats, we studied the acute effects of cocaine and the interaction between cocaine and dopamine antagonists with respect to these behaviors. Although cocaine (5.0, 10.0, or 20.0 mg/kg) dose-dependently increased locomotor activity, it augmented the rate of ICSS only at 5.0 mg/kg. The failure of high doses of cocaine to augment purpose-oriented behavior such as ICSS may result from its induction of a manic-like state. The D1 dopamine receptor antagonist SCH23390 (0.02, 0.1, or 0.5 mg/kg) or the D2 antagonist nemonapride (0.04, 0.2, or 1.0 mg/kg) significantly decreased cocaine augmentation of ICSS. The higher two doses of either antagonist also produced a significant decrease in cocaine-induced locomotor activity. We therefore suspect that cocaines augmentative effect on those behaviors, especially ICSS, requires activation of both D1 and D2 dopamine receptors.

Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects.

Abstract  To determine whether there are metabolite changes in the left medial temporal and frontal lobes with aging, we performed proton magnetic resonance spectroscopy in 36 normal subjects. The N‐acetylaspartate/creatine‐phosphocreatine ratio in the medial temporal lobe tended to be decreased in subjects over 60 years of age. The ratio decrease in the frontal lobe related to aging was lower than that in the medial temporal lobe. There were no significant differences in the metabolite ratios between males and females. These findings suggest that structures in the medial temporal lobe may be more susceptible to neuronal dysfunction associated with aging than those in the frontal lobe.

Hippocampal volume asymmetry and age at illness onset in males with schizophrenia.

To determine whether there are disturbances of hippocampal volume asymmetry in schizophrenic patients, we obtained contiguous, I-mm-thick magnetic resonance images in 28 males with chronic schizophrenia and in 28 age-matched healthy males. The schizophrenic patients showed a bilateral reduction in volume of the hippocampal formation (HF; left 7.0%; right 8.7%). This reduction was significantly associated with the severity of disorganization syndrome (P < 0.0005). A significant asymmetry in the HF volume was found in the control subjects (P = 0.006), but not in the patients (P = 0.40). There was a significant positive correlation between the asymmetry index and the patient’s age at the onset of schizophrenia (r = 0.46,P = 0.01). Results indicate that a disturbance in the normal asymmetry of the HF may be a characteristic in schizophrenia, particularly in patients with an early onset of the illness.

Neurochemical Investigation of the Schizophrenic Brain by in Vivo Phosphorus Magnetic Resonance Spectroscopy

Abnormal phospholipid metabolisms may play important roles in the pathophysiology of schizophrenia. Phosphorus magnetic resonance spectroscopy (31P-MRS) offers a new method for studying phosphorus-related metabolism in vivo. A decrease in the level of phosphomonoesters (PME) and an increase in the level of phosphodiesters (PDE) has been demonstrated in the prefrontal lobe of neuroleptic-naive schizophrenic patients. Most of the studies in medicated schizophrenic patients have shown decreased PME and/or increased PDE. The decreased PME in the frontal lobe appears to be associated with negative symptoms and poor working memory performance. 1H-decoupled 31P-MRS revealed a reduction in the phosphocholine element of PME and an elevation in the mobile phospholipids of PDE in the prefrontal region of medicated schizophrenic patients. PDE were elevated in the temporal lobes of neuroleptic-naive schizophrenic patients, and this increase was partially normalized by haloperidol administration. Data about the temporal lobes of medicated schizophrenic patients have not been consistent. Except for the reduction in the adenosine triphosphate (ATP) in the basal ganglia and the correlation between the increase in the frontal lobe phosphocreatine (PCr) and negative symptomatology, data related to changes in high-energy phosphates are contradictory. No consensus on the effect of neuroleptics on phosphorus metabolites has been achieved. Methodological problems inherent in 31P-MRS may have contributed to the confusion in understanding available data. Future directions of MRS studies are suggested in the last section of the paper.

c-Fos expression in rat brain after repetitive transcranial magnetic stimulation.

We investigated neuronal response to repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) in terms of c-Fos expression. In rats at postnatal day 49, six rTMS sessions induced widespread nuclear c-Fos-like immunoreactivity in frontal cortex, lateral orbital cortex, striatum, lateral septal nucleus, piriform cortex, dentate gyrus, Ammons horn, cingulate cortex, parietal cortex, thalamus, occipital cortex, and amygdala; this reactivity was greater than with two sessions of rTMS or sham rTMS. ECS produced even stronger c-Fos expression than six sessions of rTMS in all regions except thalamus (no difference) and striatum (stronger with rTMS). Thus, functional modification of neuroanatomic substrates as demonstrated by c-Fos expression may partially differ between rTMS and ECS.