Shin-ichiro Tomitaka

Association between novelty seeking and dopamine receptor D4 (DRD4) exon III polymorphism in Japanese subjects

In this study, we investigated the association between dopamine receptor D4 (DRD4) exon III polymorphism and novelty seeking in 69 Japanese women. The group of subjects with long allele (> or =5 repeats) exhibited significantly elevated novelty seeking scores in comparison with subjects lacking the long allele. By contrast, the scores for harm avoidance, reward dependence, and persistence were statistically indistinguishable in the two group of subjects. With regard to the subscales of novelty seeking, the scores for exploratory excitability and extravagance were significantly higher in subjects with the long allele than in subjects lacking the long allele. However, no significant associations with impulsiveness or disorderliness were recognized. Our results suggest that although long alleles of the polymorphic exon III repeats are low in the Japanese population, there is an association between long alleles of DRD4 exon III polymorphism and novelty seeking.

Bilateral blockade of NMDA receptors in anterior thalamus by dizocilpine (MK‐801) injures pyramidal neurons in rat retrosplenial cortex

Non‐competitive N‐methyl‐ d‐aspartate (NMDA) receptor antagonists, ketamine, phencyclidine (PCP) and dizocilpine (MK‐801), produce psychosis in people. In rodents they produce cytoplasmic vacuoles in injured retrosplenial cortical neurons that express HSP70 heat shock protein. This study examined possible circuits and receptors that mediate this neuronal injury. Bilateral, but not unilateral, injection of dizocilpine (5, 10, 15, 20 μg/μL per side) into the anterior thalamus induced HSP70 protein in pyramidal neurons in deep layer III of rat retrosplenial cortex 24 h later. In contrast, bilateral dizocilpine injections (5, 10, 15, 20 μg/μL per side) into the retrosplenial cortex or into the diagonal band of Broca did not induce HSP70. Bilateral injections of muscimol (0.1, 1, 10 μg/μL per side), a GABAA (γ‐aminobutyric acid) agonist, into the anterior thalamus blocked HSP70 induction in the retrosplenial cortex produced by systemic dizocilpine (1 mg/kg). Bilateral thalamic injections of baclofen (0.1, 1, 10 μg/μL per side), a GABAB agonist, were ineffective. Anterograde tracer studies confirmed that neurons in the anterior thalamus project to superficial layer III of the retrosplenial cortex where the dendrites of HSP70‐immunostained neurons in deep layer III reside. Bilateral blockade of NMDA receptors on GABA neurons in the reticular nuclei of the thalamus is proposed to decrease GABA neuronal firing, decrease GABA release and decrease activation of GABAA receptors. This activates thalamic projection neurons that damage retrosplenial cortical neurons presumably via unblocked cortical glutamate α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐4‐propionate (AMPA) and kainate receptors. The increases of blood flow that occur in the thalamus and retrosplenial cortex of people that have psychosis produced by NMDA antagonists could be related to thalamic excitation of the retrosplenial cortex produced by these drugs.

Rolipram, a selective phosphodiesterase type-IV inhibitor, prevents induction of heat shock protein HSP-70 and hsp-70 mRNA in rat retrosplenial cortex by the NMDA receptor antagonist dizocilpine

The non‐competitive NMDA receptor antagonists, such as (+)‐MK‐801 (dizocilpine), cause the expression of heat shock protein HSP‐70 and pathomorphological damage in the retrosplenial cortex of the rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is unknown. The present study was undertaken to examine the role of phosphodiesterase type IV in the expression of heat shock genes induced by dizocilpine. Heat shock protein HSP‐70, which is known as a sensitive marker of neuron injury, was induced in the retrosplenial cortex of the rat brain 24 h after a single administration of dizocilpine (1 mg/kg). Pretreatment with the specific phosphodiesterase type IV inhibitor rolipram (2.5, 5 or 10 mg/kg, 15 rnin before dizocilpine) attenuated the expression of HSP‐70 and hsp‐70 mRNA induced by dizocilpine (1 mg/kg) in a dose‐dependent manner. Furthermore, another phosphodiesterase type IV inhibitor, Ro 20–1724 (5 or 10 mg/kg, 15 min before dizocilpine), and a non‐selective phosphodiesterase inhibitor, 3–isobutyl‐1–methylxanthine (IBMX) (5 or 10 mg/kg, 15 min before dizocilpine), significantly attenuated the expression of HSP‐70 protein and hsp‐70 mRNA induced in the retrosplenial cortex by dizocilpine. However, the induction of the immediate early gene c‐fos and microglial activation in the retrosplenial cortex after administration of dizocilpine was not attenuated by pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine). Moreover, histopathological study indicated that pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine) did not prevent the formation of vacuoles caused by treatment with dizocilpine. The present findings suggest that phosphodiesterase type IV may play a significant role in the expression of HSP‐70 protein and hsp‐70 mRNA in the rat retrosplenial cortex after administration of dizocilpine, and that phosphodiesterase type IV may not play a role in the neurotoxicity of NMDA receptor antagonists such as dizocilpine.

Induction of Fos protein by 3,4‐ methylenedioxymethamphetamine (Ecstasy) in rat brain: regional differences in pharmacological manipulation

Psychostimulant drugs have been reported to increase the expression of some immediate‐early genes in the brain. In the present study, immunohistochemical techniques were used to assess the pattern of Fos protein produced by 3,4‐methylenedioxymethamphetamine (MDMA) in several brain regions. Furthermore, we also studied the role of the dopamine D and D receptors and the N‐methyl‐ D‐aspartate (NMDA) receptor in the induction of Fos protein by MDMA. A single administration of MDMA (5, 10 or 20 mg/kg) caused marked induction of Fos‐immunoreactivity in several regions including frontal cortex, striatum and olfactory tubercle of rat brain, in a dose‐dependent manner. However, in the hippocampus and cerebellum, there were few or no Fos immunoreactive cells induced by MDMA. Furthermore, the induction of Fos protein in the striatum and olfactory tubercle after administration of MDMA (10 mg/kg) was blocked by pre‐treatment with the dopamine D receptor antagonist SCH 23390 (1 mg/kg) or the NMDA receptor antagonist dizocilpine (1 mg/kg), but not by the dopamine D receptor antagonist (‐)‐sulpiride (100 mg/kg). However, the induction of Fos protein in the frontal cortex and hippocampus by MDMA was unaltered by pretreatment with SCH 23390 (1 mg/kg) or (‐)‐sulpiride (100 mg/kg). These results suggest that MDMA induces the expression of Fos protein in several regions of rat brain, and that the expression of Fos protein by MDMA in the striatum and olfactory tubercle appears to be mediated at least in part by the dopamine D and NMDA receptors.

Fluoxetine prevents PCP- and MK801-induced HSP70 expression in injured limbic cortical neurons of rats

BACKGROUND N-Methyl-D-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP) and dizocilpine (MK801), cause schizophrenialike psychosis in humans, and produce vacuolated neurons in the cingulate and retrosplenial cortices of the rat brain. Since psychotically depressed patients and schizophrenic depressed patients may require treatment with selective serotonin reuptake inhibitors (SSRIs), it is of interest to examine the relationship between SSRIs and NMDA antagonist neurotoxicity. METHODS The neurotoxicity of PCP and MK801 was assessed using heat shock protein (HSP70) immunocytochemistry and HSP70 Western blots because HSP70 is expressed in the injured, vacuolated neurons. Female rats were given fluoxetine (0, 5, 10, and 20 mg/kg IP) followed 1 hour later by MK801 (1 mg/kg IP) or PCP (50 mg/kg IP). RESULTS Pretreatment with fluoxetine (20 mg/kg IP) 1 hour before MK801 prevented the induction of HSP70 by MK801 in the cingulate and retrosplenial cortices. Pretreatment with fluoxetine (10 or 20 mg/kg IP) 1 hour before PCP also prevented the HSP70 induction by PCP. CONCLUSIONS Fluoxetine prevents the neurotoxicity of NMDA receptor antagonists in rat brain. This suggests the possibility that SSRIs could modulate psychosis, and may provide a model for examining the link between the hallucinogenic properties of PCP and lysergic acid diethylamide.

YM90K, a selective‐amino‐3‐hydroxy5‐methyl‐4‐isoxazole propionate (AMPA) receptor antagonist, prevents induction of heat shock protein HSP ‐70 and hsp ‐70 mRNA in rat retrosplenial cortex by phencyclidine

Abstract The non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist such as an abused drug phencyclidine (PCP) causes the induction of heat shock protein HSP‐70, a sensitive marker of neuronal injury, in the retrosplenial cortex of rat brain. The present study was undertaken to examine the role of a ‐amino‐3‐ hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptor in the expression of heat shock protein HSP‐70 and hsp‐70 mRNA in the retrosplenial cortex by PCP. Administration of PCP (50 mg/kg, i.p.) caused the induction of heat shock protein HSP‐70 in the retrosplenial cortex of rat brain, whereas no HSP‐70 immunoreactivity was detected in the vehicle‐treated group. Pretreatment with a potent and selective AMPA receptor antagonist YM90K (1, 3 or 10 mg/kg, i.p; 15 min) inhibited in a dose dependent manner, the induction of heat shock protein HSP‐70 by PCP (50 mg/kg). Furthermore, administration of PCP (50 mg/kg, i.p) caused marked expression of hsp‐70 mRNA in the retrosplenial cortex of rat brain, whereas the expression of hsp‐70 mRNA was NOT found in the vehicle‐treated group. Pretreatment with YM90K (1, 3 or 10 mg/kg, i p; 15 min) also inhibited the expression of hsp‐70 mRNA by PCP (50 mg/kg), in a dose‐dependent manner. These results suggest that AMPA receptor may play a role in the expression of heat shock protein HSP‐70 and heat shock gene hsp‐70 mRNA in the retrosplenial cortex of rat brain by non‐competitive NMDA receptor antagonists such as PCP.

In vivo regulation of serotonin 5-HT2A receptors in rat brain by subchronic administration of sigma receptor ligand NE-100.

In the present study, we examined the effect of the novel sigma receptor ligand NE-100 on 5-hydroxytryptamine-2A (5-HT2A) receptor binding in rat brain using an in vivo approach. Rats received intraperitoneal injections of either vehicle (1 ml/kg) or NE-100 (3 mg/kg) twice daily for 14 days. The in vivo binding of [3H]RP 62203, a selective 5-HT2A receptor radioligand, to 5-HT2A receptors in the rat brain was examined at 1, 3 or 7 days after final treatment. The specific binding of [3H]RP 62203 in the frontal cortex, parietal cortex and occipital cortex 1 day after subchronic administration of NE-100 was significantly increased as compared to animals treated with vehicle. In contrast, specific binding in the frontal cortex and parietal cortex 3 days after subchronic administration of NE-100 was significantly decreased as compared with the vehicle treated group. Seven days after the last injection of NE-100 or vehicle, there were no significant differences between the NE-100 and vehicle treated groups in [3H]RP 62203 binding in all the regions examined except for the hippocampus. These findings indicate that subchronic treatment with NE-100 may regulate the in vivo binding characteristics of 5-HT2A receptors in the cerebral cortex of rat brain.