T. Ohmori

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.

Open pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression

Background: Recently, a dopamine hypothesis of depression was put forward, and several studies have demonstrated that direct and indirect dopamine agonists have antidepressant effects. Methods: Using Clinical Global Impressions, we evaluated the efficacy of 4-week treatment of pergolide as an antidepressant adjuvant involving 20 unipolar depressed patients who were refractory to standard treatment with antidepressants. Results: One patients (5%) were very much improved, seven (35%) much improved, four (20%) minimally improved, six (30%) no change or worse, and two (10%) not assessed. There was no significant difference in any clinical factors between the pergolide responder and non-responder group. Limitations: This study was a non-blind open trial, and pergolide was added to tricyclic and heterocyclic antidepressants. Conclusion: Pergolide may be useful as an antidepressant adjuvant, suggesting a potential role for dopamine-2 stimulation in the antidepressant response.

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.

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.

The Role of Benzodiazepine Receptors in the Acquisition and Expression of Behavioral Sensitization to Methamphetamine

The GABA-benzodiazepine neurotransmission has been reported to be implicated in various forms of plasticity such as kindling and learning. In a previous study, we have shown that clonazepam (CZP), a GABA-benzodiazepine agonist, prevents the acquisition of behavioral sensitization to methamphetamine (MA). The present study was conducted to extend this finding by examining the effect of flumazenil (Flu), a GABA-benzodiazepine antagonist on the prevention by CZP. Rats (male Wistar-King rats) treated with MA (1 mg/kg, SC) for 10 days showed significantly enhanced motor activity compared to those treated with saline when tested with MA (1 mg/kg) after a 7-8-day withdrawal, indicating the acquisition of behavioral sensitization. Representing the previous finding, pretreatment with CZP (0.5 mg/kg) prior to MA administration prevented the acquisition of the phenomenon. Pretreatment with Flu (10 mg/kg) prior to MA administration has no influence on the acquisition of sensitization. However, pretreatment with Flu prior to CZP administration reversed the inhibitory effect of CZP. CZP showed no effect on the expression of sensitization in the sensitized rats when given prior to the MA readministration. These results strengthen the suggestion that stimulation of GABA-benzodiazepine receptors plays a role in the acquisition but not in the expression of behavioral sensitization to MA.

Clonazepam Prevents the Development of Sensitization to Methamphetamine

The GABA-benzodiazepine neurotransmission has been implicated in various forms of plasticity such as kindling and learning. The present study examined the effects of clonazepam (CZP), a GABA-benzodiazepine agonist, on the development of behavioral sensitization to methamphetamine (MA). Rats treated with MA (1 mg/kg, S.C.) for 10 days displayed significantly enhanced motor activity when tested with MA (1 mg/kg) after a 7-8-day withdrawal, indicating the development of behavioral sensitization. Pretreatment with CZP (0.5 and 2.0 mg/kg) prior to MA administration prevented the development of the phenomenon. Rats treated with CZP alone showed no difference in the motor activity compared to those treated with saline. These results suggest that stimulation of GABA-benzodiazepine receptors plays a role in the development of behavioral sensitization.

Scopolamine prevents augmentation of stereotypy induced by chronic methamphetamine treatment

Cholinergic neurotransmission has been implicated in various forms of neural plasticity such as kindling and learning. We have previously shown that blockade of muscarinic cholinergic receptors prevents the development of locomotor sensitization to methamphetamine. The present study was conducted to examine whether scopolamine, a muscarinic cholinergic antagonist, would also block augmentation of stereotypy induced by chronic methamphetamine (MA) treatment. Rats treated with MA (2.5 mg/kg, SC) for 10 days indicated significantly enhanced stereotyped behavior when tested with MA (2.5 mg/kg) after a 7-to 8- day withdrawal. Pretreatment with scopolamine (3 mg/kg) prior to MA administration prevented the augmentation of stereotypy. Rats treated with scopolamine alone showed no difference in MA-induced stereotypy compared to those treated with saline. Scopolamine methylbromide, a derivative of scopolamine that does not easily cross the blood-brain barrier, had no effect on the augmentation of stereotypy. These results suggest that stimulation of central muscarinic cholinergic receptors plays a role in the development of sensitization to the stereotypy stimulating effect of methamphetamine.

2008 Neural plasticity in methamphetamine-induced behavioral sensitization

JUNZO MIZUNO, RYUJI MATSUO, YUJI MASUDA, TOSHIFUMI MORIMOTO The rat exhibits various kinds of rhythmical jaw and lip movements, during such as chewing, drinking, and grooming. To examine co-ordination between jaw and lip movements, we compared activities of jaw and orbicularis oris (00) muscles recorded from freely moving rats. The following results were obtained: 1) During chewing, activities of the 00 muscle synchronized with those of the jaw opening muscle. Magnitude of 00 muscle activity decreased with hardness of food, while that of jaw muscles increased. 2) During grooming (licking body surface), activities of the 00 muscle did not synchronized with those of the jaw opening muscle. Magnitude of 00 muscle activity was always greater than that of the jaw opening and closing muscles.