Tomohiro Abekawa

Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens

We examined effects of a high dose of methamphetamine (MA) (4.02 mg free base/kg, s.c., at 2-h intervals, 4 injections) on extracellular concentrations of monoamines such as dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) and those of glutamate and other several amino acids in rat striatum (ST) and nucleus accumbens (NA) using in vivo microdialysis. Five days after the microdialysis, tissue concentrations of monoamines were measured. The toxic dose of MA markedly increased extracellular concentrations of DA, and decreased those of DOPAC, HVA and 5-HIAA in both ST and NA. Magnitude of the increase in DA release was not different between ST and NA. Extracellular concentrations of glutamate showed a gradual increase in ST, but not in NA, while other amino acids showed no changes in both ST and NA. Tissue concentrations of serotonin (5-HT) and 5-HIAA were decreased to 43-58% of control values in both ST and NA, whereas those of DA, DOPAC and HVA showed 43-54% decrease in ST but no changes in NA. These data suggest that the marked increase of DA release is not directly related to the MA-induced dopaminergic neurotoxicity. The increase in glutamate release found only in ST may be related to the dopaminergic damage in ST. It may be that enhanced release in DA and glutamate act synergistically to cause the dopaminergic neurotoxicity in ST. However, enhancement in glutamate release did not appear to be essential for the MA-induced serotonergic neurotoxicity.

Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine

The present study examined the effects of both competitive (D-CPP-ene) and noncompetitive (MK-801) NMDA antagonists on behavioral sensitization to methamphetamine (MA). Behavioral effects of repeated administration of NMDA antagonists were also examined. Rats treated with MA according to an escalating dose schedule (2.5, 5, 7.5, and 10.0 mg/kg, SC, twice a day on days 1, 3, 5, and 7, respectively) indicated behavioral supersensitivity. Pretreatment with either MK-801 (0.5 mg/kg, IP) or D-CPP-ene (20 mg/kg, IP) prior to MA administration prevented the development of the supersensitivity. Rats treated with MK-801 showed a decrease in the motor activity when subsequently challenged with MK-801 compared with saline-treated rats. Likewise, rats administered with D-CPP-ene showed decreased motor activity when challenged with D-CPP-ene. There was no cross-sensitization nor tolerance between MA and MK-801 or D-CPP-ene. These results suggest that both competitive and noncompetitive NMDA antagonists block sensitization to MA and that repeated administration with NMDA antagonists results in behavioral tolerance.

D1 dopamine receptor activation reduces extracellular glutamate and GABA concentrations in the medial prefrontal cortex.

The present study examined effect of administration of a selective D1 dopamine receptor agonist, SKF38393 on extracellular concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in mPFC, by using in vivo microdialysis. Perfusion with SKF38393 via a dialysis probe reduced concentrations of both Glu and GABA dose-relatedly, and these effects were prevented by co-perfusion with a D1 dopamine receptor antagonist, SCH23390 (40 microM). These results suggested that the dopaminergic hyperactivity may lead to the hypofunction of glutamatergic and GABAergic systems in mPFC via D1 dopamine receptor stimulation.

The role of glutamate in behavioral and neurotoxic effects of methamphetamine.

Studies on the mechanisms of behavioral and neurochemical effects of amphetamine or methamphetamine (MA) have focused on the dopaminergic system. However, recent reports suggest that the glutamatergic system may be involved in the MA effects. Our laboratory has been conducting a series of experiments to further examine the role of glutamate in both behavioral and neurotoxic effects of MA. These studies include (1) behavioral studies on the effect of N-methyl-D-aspartate (NMDA) antagonists on the development of MA-induced behavioral sensitization, (2) neurochemical studies on the effects of NMDA antagonists on MA-induced neurotoxicity, and (3) in vivo microdialysis studies on the effects of MA on glutamate release. In the present paper, the authors comment on an important role of glutamatergic systems in the behavioral and toxic effects of MA.

Effect of NO synthase inhibition on behavioral changes induced by a single administration of methamphetamine

The present study examined the effects of nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME; 10, 30, 60 mg/kg, i.p.) on behavioral changes induced by a single administration of methamphetamine (MA) (3.22 and 0.805 mg free base/kg, s.c.). MA increased locomotion-stereotypy rating scores and motor activity counts measured by an infrared sensor. L-NAME administered prior to MA significantly decreased the level of locomotion stereotypy rating and motor activity induced by MA. An inactive optical isomer, N omega-nitro-D-arginine methyl ester (D-NAME) had no effects on MA-induced behavioral changes. The results suggest that NO synthesis is involved in the full expression of behavioral effects of MA.

Role of the simultaneous enhancement of NMDA and dopamine D1 receptor-mediated neurotransmission in the effects of clozapine on phencyclidine-induced acute increases in glutamate levels in the rat medial prefrontal cortex

Clozapine (CLZ) can improve both the positive and negative symptoms of treatment-resistant schizophrenia (TRS), which does not respond to typical antipsychotics. This suggests that elucidation of the pharmacological mechanism for CLZ could lead to further clarification of the pathophysiology of TRS. This study examined the effects of CLZ on phencyclidine (PCP)-induced hyperlocomotion and on the acute increases in glutamate levels that occur in the medial prefrontal cortex (mPFC) in order to test the hypothesis that CLZ effect is associated with the simultaneous enhancement of N-methyl-d-aspartate (NMDA) and dopamine D1 receptor-mediated neurotransmission. CLZ effect on PCP-induced hyperlocomotion and increases in glutamate levels were examined by using behavioral rating scores and in vivo microdialysis, respectively. CLZ and haloperidol (HAL) dose-relatedly attenuated PCP-induced hyperlocomotion, and concentration-relatedly blocked PCP-induced acute increases in glutamate levels in the mPFC, with the decrease in saline-induced locomotor activity induced by CLZ being much weaker than that induced by HAL. CLZ also blocked, in a dose-related manner, acute increases in glutamate levels in the mPFC that were induced by local perfusion with a competitive NMDA receptor antagonist, CPP, in this region. Although an enhanced blocking effect of the sub-threshold concentration of NMDA perfusion on PCP-induced acute increases in glutamate levels in the mPFC was noted after co-perfusion with a dopamine D1 receptor agonist, SKF-38393, perfusion with SKF-38393 did not reverse the CLZ blocking of PCP-induced increases in glutamate levels. Therefore, CLZ may block PCP-induced acute increases in glutamate levels in the mPFC by an enhancement of the NMDA receptor-mediated neurotransmission that is not accelerated by an enhanced dopaminergic transmission via dopamine D1 receptors. This blocking effect may partially explain the CLZ-induced attenuation of PCP-induced hyperlocomotion.

Context determines the type of sensitized behaviour: a brief review and a hypothesis on the role of environment in behavioural sensitization.

Behavioural sensitization to psychostimulants may develop context‐dependently in certain circumstances. Animals given a stimulant repeatedly in a test cage but not in other environments may show enhanced drug‐induced behaviour in the test cage. Conditioning mechanisms have been claimed to be responsible for these phenomena. However, several recent findings are not properly accounted for by conditioning. In addition, growing evidence supports the hypothesis that behavioural sensitization reflects neural changes induced by repeated exposure to psychostimulants (the pharmacological hypothesis). However, the pharmacological hypothesis itself fails to account for environmental influences. In this paper, we propose a hypothesis on the role of environment that is complementary to the pharmacological hypothesis. According to our hypothesis, environment does not have a causal role in the development of sensitization, but it modifies the mode of expression of the sensitized behaviour. Sensitization primarily reflects a neuroadaptive change induced by repeated exposure of the neural system to psychostimulants. However, psychostimulants are known to induce different behaviours in different environments. Therefore, repeated administration of a psychostimulant in different environments would result in augmentation of different behaviours. Our hypothesis potentially accommodates various previous observations. We briefly review the literature and present our hypothesis.

Olanzapine and risperidone block a high dose of methamphetamine-induced schizophrenia-like behavioral abnormalities and accompanied apoptosis in the medial prefrontal cortex

This study aims to propose a comprehensive new model for schizophrenia, which shows PPI disruption at baseline state as an endophenotype, the development of cross-sensitization to an NMDA receptor antagonist, MK-801 as a clinical phenotype of the progression into treatment-resistance, and accompanied induction of apoptosis in the medial prefrontal cortex as a critical possibility during the progression. Repeated administration of a high dose of methamphetamine (METH) (2.5 mg/kg), which could increase glutamate levels in the medial prefrontal cortex (mPFC), induced TUNEL-positive cells in this region, accompanied development of behavioral cross-sensitization to MK-801 in response to a challenge injection of MK-801, and PPI disruption at baseline state without a challenge injection. Olanzapine (OLZ) (1.0 mg/kg) and risperidone (RIS) (0.1 mg/kg), which inhibited and remarkably attenuated METH (2.5 mg/kg)-induced increases in glutamate levels, respectively, blocked not only the induction of TUNEL-positive cells in the mPFC but also the accompanied development of above behavioral abnormalities. These findings suggest that repeating the METH-induced glutamate release produces behavioral abnormalities as a clinical phenotype of schizophrenia, accompanied apoptosis as a critical possibility during the progression, and suggest that sufficient dose of olanzapine and risperidone can block the development of these behavioral abnormalities and accompanied apoptosis during the progression.

Effects of nitric oxide synthesis inhibition on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in the rat brain

SummaryWe examined effects of nitric oxide (NO·) synthesis inhibition on methamphetamine (MA)-induced dopaminergic and serotonergic neurotoxicity. The toxic dose of MA (5 mg/kg, sc, X4) significantly decreased contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum (ST), and significantly decreased contents of serotonin (5-HT) in the ST, nucleus accumbens (NA) and medial frontal contex (MFC). Coadministration with a NO· synthase inhibitor, Nω-nitro-L-arginine methyl ester (LNAME) (30 mg/kg, ip, X2), reduced the MA-induced decreases in contents of DA, DOPAC and HVA in the ST, but not reduced the MA-induced decreases in contents of 5-HT in the ST, NA and MFC. These findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO· formation caused by the activation of postsynaptic DA receptor.

Scopolamine prevents the development of sensitization to methamphetamine.

The cholinergic neurotransmission has been implicated in various forms of neural plasticity such as kindling and learning. The present study examined the effects of scopolamine, a muscarinic cholinergic antagonist, on the development of behavioral sensitization to methamphetamine (MA). Rats treated with MA (1 mg/kg, sc) for 10 days indicated significantly enhanced motor activity when tested with MA (0.5 mg/kg) after a 7-8 day withdrawal, indicating the development of behavioral sensitization. Pretreatment with scopolamine (3 mg/kg) prior to MA administration prevented the development of the phenomenon. Rats treated with scopolamine alone showed no difference in the motor activity compared to those treated with saline. These results suggest that stimulation of muscarinic cholinergic receptors plays a role in the development of behavioral sensitization.