Natsuko Narita

Interactions of selective serotonin reuptake inhibitors with subtypes of σ receptors in rat brain

The interactions of selective serotonin reuptake inhibitors and tricyclic antidepressants with subtypes of sigma receptors were investigated. The rank order of affinity (Ki values) from competition experiments of [3H](+)-pentazocine binding to sigma 1 sites was: fluvoxamine > sertraline > S(+)-fluoxetine > (+/-)-fluoxetine > citalopram > imipramine > paroxetine > desipramine > R(-)-fluoxetine > (+/-)-norfluoxetine. The Ki values of all drugs for sigma 2 sites were more than 1000 nM. Furthermore, all drugs were more potent at sigma 1 sites than at sigma 2 sites. These findings suggest that sigma receptors (sigma 1 site) may play, in some way, a role in the actions of selective serotonin reuptake inhibitors.

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 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.

Memantine induces heat shock protein HSP70 in the posterior cingulate cortex, retrosplenial cortex and dentate gyrus of rat brain.

High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinsons disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.

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.

Regionally different effects of scopolamine on NMDA antagonist-induced heat shock protein HSP70.

Using immunohistochemical technique, we investigated the regionally different roles of muscarinic receptors in the induction of HSP-70 by NMDA receptor antagonists. The administration of memantine and phencyclidine induced HSP-70 in the retrosplenial cortex of rat brain. Pretreatment with the muscarinic receptor antagonist scopolamine (0.1-1 mg/kg) blocked induction of HSP-70 in layer III of the retrosplenial cortex. However, induction of HSP-70 in layer V was augmented by scopolamine. These results suggest a regional difference in the mechanism of neurotoxicity induced by NMDA receptor antagonists.

Amantadine induces c-fos in rat striatum : reversal with dopamine D1 and NMDA receptor antagonists

Amantadine (1-aminoadamantane) induced Fos expression in the central, dorsal-medial and ventral-medial part of the striatum. The distribution pattern of Fos induced by amantadine was more similar to those seen with dopaminomimetics than with N-methyl-D-aspartate (NMDA) receptor antagonists. Pretreatment with the dopamine D1 receptor antagonist, SCH23390, and the NMDA receptor antagonist, MK-801, blocked amantadine induction of Fos in the striatum. However, amantadine induction of Fos in the striatum was unaffected by the dopamine D2 receptor antagonist, sulpiride. These results suggest that amantadine induction of Fos in the rat striatum is related to dopamine D1 and NMDA receptors.

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.

Lack of neuroprotective effect of σ receptor ligands in the neurotoxicity of p-chloroamphetamine in rat brain

We studied the mechanism of antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan. The pretreatment with potent and selective sigma receptor ligands, 4-phenyl-4-(1-phenylbutyl)piperidine (4-PPBP) and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), did not alter the reduction of 5-hydroxytryptamine and 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the cerebral cortex by repeated administration of p-chloroamphetamine. These results suggest that sigma receptors might not play a significant role in the antagonism of p-chloroamphetamine-induced neurotoxicity by dextromethorphan.

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.