Exclusive expression of VMAT2 in noradrenergic neurons increases viability of homozygous VMAT2 knockout mice.

The vesicular monoamine transporter 2 (VMAT2) translocates monoamine neurotransmitters from the neuronal cytoplasm into synaptic vesicles. Since VMAT2-/- mice die within a few days of birth, it is difficult to analyze the detailed VMAT2 functions using these mice. In this study, we generated human VMAT2 transgenic mice that expressed VMAT2 in noradrenergic neurons with the aim to rescue the lethality of VMAT2 deletion.

Impaired cliff avoidance reaction in dopamine transporter knockout mice.

Rationale: Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes.

Hyperthermic and lethal effects of methamphetamine: roles of dopamine D1 and D2 receptors.

Both human and animal studies suggest that hyperthermia contributes to the lethal effects of methamphetamine. To elucidate the roles of dopamine D1 and D2 receptors in methamphetamine-induced hyperthermia and lethal effects, we used D1 knockout (D1KO) mice, D2 knockout (D2KO) mice, and wild-type littermates. After the administration (i.

Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter.

The incidence of cancer in patients with schizophrenia has been reported to be lower that in the general population. On the other hand, it is well established that patients with schizophrenia have a hyper-dopaminergic system and dopamine has the ability to inhibit tumor angiogenesis. Therefore, in order to investigate the molecular mechanisms responsible for the lower cancer risk in schizophrenic patients, we used a mouse model of schizophrenia, which shows hyper-dopaminergic transmission in the nerve terminals of dopaminergic neurons.

Altered EphA5 mRNA expression in rat brain with a single methamphetamine treatment.

Methamphetamine is a potent and indirect dopaminergic agonist which can cause chronic brain dysfunctions including drug abuse, drug dependence and drug-induced psychosis. Methamphetamine is known to trigger molecular mechanisms involved in associative learning and memory, and thereby alter patterns of synaptic connectivity. The persistent risk of relapse in methamphetamine abuse, dependence and psychosis may be caused by such alterations in synaptic connectivity.

Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters.

We examined the hyperthermic and lethal toxic effects of methamphetamine in dopamine transporter (DAT) and/or serotonin transporter (SERT) knockout (KO) mice. Methamphetamine (45 mg/kg) caused significant hyperthermia even in the mice with a single DAT gene copy and no SERT copies (DAT+/- SERT-/- mice). Mice with no DAT copies and a single SERT gene copy (DAT-/- SERT+/- mice) showed significant but reduced hyperthermia when compared to wild-type mice after methamphetamine.

Methamphetamine-induced locomotor activity and sensitization in dopamine transporter and vesicular monoamine transporter 2 double mutant mice.

Rationale: The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of methamphetamine (MAP), including acute locomotor effects and behavioral sensitization. However, the relative impact of heterozygous DAT and VMAT2 knockouts (KOs) on the behavioral effects of MAP remains unknown.

Objectives: To evaluate the roles of DAT and VMAT2 in MAP-induced locomotor behavior, we examined locomotor activity and sensitization in heterozygous DAT KO (DAT+/-), heterozygous VMAT2 KO (VMAT2+/-), double heterozygous DAT/VMAT2 KO (DAT+/-VMAT2+/-), and wild-type (WT) mice.

Methamphetamine alters expression of DNA methyltransferase 1 mRNA in rat brain.

Methamphetamine, a potent and indirect dopaminergic agonist, also increases glucocorticoid hormone secretion. Glucocorticoid hormones facilitate behavioral effects of methamphetamine in rodents. Several reports suggest that glucocorticoid hormones modulate expression of DNA (cytosine-5-)-methyltransferase 1 (Dnmt1).

Association analysis of delta-opioid receptor gene polymorphisms in methamphetamine dependence/psychosis.

The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis. DNA samples from Japanese patients with MAP dependence/psychosis were analyzed to find polymorphisms in OPRD1 gene exons and exon-intron boundaries. One novel single nucleotide polymorphism (SNP) in intron 1 and two SNPs in exon 3 were identified.

Psychophysiological differences in identical twins discordant for schizophrenia: a critical index for the onset of schizophrenia.

It has been hypothesized that not only genetic but also environmental factors contribute to the onset of schizophrenia. We therefore conducted psychophysiological studies on a pair of identical twins discordant for schizophrenia, to differentiate non-genetic from genetic indexes possibly associated with this disease. The affected and unaffected twins were 28 year-old females.

Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice.

Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice.

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.

The role of cognitive-motor function in precipitation and inhibition of epileptic seizures.

Purpose: To examine the effects of cognitive-motor function on EEG discharges and the neuropsychological mechanisms of seizure induction in patients sensitive to cognitive-motor tasks.

Methods: Four hundred eighty patients with epilepsies were subjected to cognitive tasking, termed "neuropsychological EEG activation (NPA)." It consisted of reading, speaking, writing, written calculation, mental calculation, and spatial construction.

Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain.

Methamphetamine (MAP), the most frequently abused substance in Japan, causes severe drug dependence and psychosis, similar to schizophrenia. It is suggested that long-term alterations in gene expression is related to MAP-induced brain dysfunction, including dependence and psychosis. DNA (cytosine-5) methyltransferase (Dnmt), a methylating enzyme of cytosine residues on CpG-dinucleotides, plays an important role in X chromosome inactivation, genomic imprinting, and gene expression.

Electroconvulsive shock increases serotonin transporter in the rat frontal cortex.

The antidepressive action of electroconvulsive shock (ECS) is thought to involve the alteration in serotonin (5-HT) neurotransmission, including the increase in 5-HT release and uptake. In our previous study, 5-HT transporter (5-HTT) mRNA expression was decreased after single and repetitive ECS in rat raphe nucleus. In the present study, we investigated the effects of single and repetitive ECS on the protein levels of 5-HTT in the frontal cortex, hippocampus and raphe nucleus of rat brain using quantitative Western blot analysis.

The long-term course of seizure susceptibility in two patients with juvenile myoclonic epilepsy.

We have observed epileptic seizures of juvenile myoclonic epilepsy (JME) to be surprisingly sensitive to higher mental activity. The purpose of the present study was to examine changes over time in seizure susceptibility in two patients with JME who we followed-up for over 20 years. During the period, they were repeatedly subjected to provocative cognitive tasking, that is, to 'neuropsychological EEG activation'.