Susumu Fukui

Abnormal cerebral perfusion in chronic methamphetamine abusers: A study using 99mTC-HMPAO and spect

1. Cerebral blood flow of nine methamphetamine abusers with technetium-99m-hexamethylpropyleneamine oxime (HMPAO) and single photon emission computed tomography (SPECT) as well as morphological examination with magnetic resonance imaging (MRI) were investigated. 2. Six of these subjects exhibited multiple focal perfusion deficits in cerebral cortices without abnormalities in MRI including cerebral atrophy and/or infarctions. 3. Cerebral perfusion deficits were detected in methamphetamine abusers even after a long abstinence period, suggesting that vascular changes were irreversible to some degree. 4. HMPAO SPECT study appeared to be sensitive to the detection of cerebral perfusion abnormalities in drug abusers.

Induction of heat shock protein (HSP)-70 in posterior cingulate and retrosplenial cortex of rat brain by dizocilpine and phencyclidine: lack of protective effects of s receptor ligands

The role of σ receptors in the induction of heat shock protein (HSP)‐70 by non‐competitive N‐methyl‐Daspartate (NMDA) receptor antagonists (+)‐MK‐801 (dizocilpine) and phencyclidine (PCP) was studied. HSP‐70 is induced in the posterior cingulate and retrosplenial cortex of rat brain 24 hours after a single administration of dizocilpine (1 mg/kg) or PCP (50 mg/kg). The induction of heat shock protein HSP‐70 by dizocilpine or PCP was attenuated partially by pre‐treatment with the antipsychotic drug haloperidol (3 mg/kg, i.p., 15 minutes previously). However, pre‐treatment with high potent and selective σ receptor ligands, 4‐phenyl‐4‐(1‐phenylbutyl)piperidine (4‐PPBP, 3 mg/kg, i.p., 15 minutes previously) and N,N‐dipropyl‐2‐[4‐methoxy‐3‐(2‐phenylethoxy)phenyl]‐ethylamine monohydrochloride) (NE‐100, 3 mg/kg, i.p., 15 minutes previously) did not alter the induction of HSP‐70 by dizocilpine or PCP. These findings suggest that σ receptors may not play a significant role in the induction of HSP‐70 by non‐competitive NMDA receptor antagonists dizocilpine and PCP, and that protective effects of haloperidol on induction of HSP‐70 protein by dizocilpine or PCP may be due to other effect(s) except σ receptors.

The effects of a selective cAMP phosphodiesterase inhibitor, rolipram, on methamphetamine-induced behavior.

The effects of rolipram, a selective cAMP phosphodiesterase inhibitor, on locomotor activity, rearing, and stereotyped behavior (sniffing, repetitive head movements) induced by methamphetamine (MAP) over 1 hour were investigated in rats. Coadministration of rolipram (4 mg/kg IP) significantly attenuated the responses of locomotor activity, rearing and repetitive head movements to MAP (2, 4 or 8 mg/kg IP). Rolipram (0.5, 1, 2, or 4 mg/kg IP) dose-dependently inhibited locomotor hyperactivity and rearing induced by 4 mg/kg of MAP. The rearing was completely inhibited by 4 mg/kg of rolipram, whereas the maximal inhibition of the locomotor hyperactivity was about 50%. However, rolipram did not alter MAP-induced sniffing and repetitive head movements. These results indicate that there is heterogeneity in the response of MAP-induced behavior to rolipram, suggesting that MAP-induced behavioral alteration may be partly regulated by cAMP levels in the brain.

Effects of a small dose of triazolam on P300 and resting EEG

The aim of the present study was to clarify whether cognitive impairments caused by benzodiazepines (BDZs) are a consequence of their specific direct effects on cognitive function or whether they are explained as secondary effects of increased sleepiness. Ten healthy men (mean age, 33.9 years) participated in two experimental sessions in a randomized cross-over, double-blind study: in one session subjects were given a placebo and in the other they were given 0.125 mg triazolam (TRZ). Each experimental session was conducted on 1 day. After a pre-drug EEG recording and an event-related potential (ERP) recording, under an oddball paradigm, subjects took the TRZ or placebo orally at 1000 hours. Thereafter, EEG and ERP recording sessions, following the same procedure as the pre-drug sessions, were conducted at 1, 2, 4, 6 and 8 h after drug administration. The EEG and ERP recordings from Cz and Pz referred to the bilaterally linked ear electrodes were used. We found that P300 latency was significantly prolonged in TRZ condition at 2 h (Pz) and 4 h (Cz and Pz) after TRZ, and that the P300 amplitude was significantly reduced at 2 h (Cz and Pz) and 4 h (Pz) after TRZ, compared to the same times after placebo. The absolute power values for the theta (4–7 Hz), alpha 1 (8–9 Hz), and alpha 2 (10–12 Hz) bands did not differ at any measurement time between the treatments. Only the beta band (13–19 Hz) power value was significantly elevated after the TRZ administration (versus placebo). No significant sedative effects were detected in subjective measurements. These results indicate that a single oral dose of 0.125 mg TRZ caused cortical changes without distinct general sedation or subjective sleepiness.

Quantitative in vivo analysis of benzodiazepine binding sites in the human brain using positron emission tomography

Central-type benzodiazepine binding sites were characterized in a single normal human subject, using positron emission tomography (PET) and the radiolabelled benzodiazepine antagonist, carbon-11 labelled flumazenil ([11C] Ro 15-1788). The subject was scanned using tracer alone and tracer plus 4 different concentrations of unlabelled Ro 15-1788, including one concentration of unlabelled Ro 15-1788, chosen to produce maximum displacement of [11C] Ro 15-1788 from specific binding sites. Concentrations of free, unmetabolized [11C] Ro 15-1788 in plasma were estimated using a simple extraction and ultrafiltration method. Radioactivity in the regional exchangeable pool in brain was estimated under non-saturation conditions from the ratio of radioactivity in brain to plasma, under saturation conditions and the kinetics of free ligand in plasma. The specific binding was, then, estimated by the difference between the total radioactivity in brain and exchangeable pool radioactivity. Scatchard analyses were performed to yield Bmax and Kd values under pseudo-equilibrium conditions, which was observed as an increase of specific binding/free with reduction in specific binding. In cerebral cortex and cerebellum, the Bmax values were about 62-73 nmol/l and the Kd values were 3.6-6 nM in the estimation of free ligand in plasma and 12-15 nM in the estimation of exchangeable pool in brain, as free in brain.

Dopamine D2 and serotonin S2 receptors in susceptibility to methamphetamine psychosis detected by positron emission tomography

Positron emission tomography (PET) was used to assess the role of dopamine D2 receptors in the striatum and serotonin S2 receptors in the frontal cortex in the susceptibility to methamphetamine-induced psychosis. Subjects were six men who had previously experienced methamphetamine psychosis (methamphetamine subjects) and 10 age- and sex-matched control subjects. The radiotracer used was 11C-N-methylspiperone. Although binding availability, assessed by dynamic analysis, in the two regions did not differ between the two groups, the ratio of binding availability in the striatum to that in the frontal cortex significantly decreased in the methamphetamine subjects as compared with the control subjects. These findings suggest that an imbalance in the activity of these two receptors may be related to the susceptibility to methamphetamine psychosis.

Induction of heat shock protein HSP-70 in rat retrosplenial cortex following administration of dextromethorphan.

Dextromethorphan, a non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptor, is one of the most widely used non-opioid cough suppressants, and it is generally considered to be a safe drug. In this study, we have examined whether dextromethorphan is neurotoxic to rat cerebrocortical neurons. Induction of heat shock protein HSP-70, an indicator of cellular stress, was observed in the posterior cingulate and retrosplenial cortex of rat brain after a single administration of dextromethorphan (75 mg/kg). Furthermore, administration of dextromethorphan (75 mg/kg) caused vacuolization in the same regions. These results suggest that high doses of dextromethorphan could cause neuronal injury in the cerebrocortical neurons.