Posted by CrAzYmEd on May 23, 2010, at 10:59:27 [reposted on May 24, 2010, at 22:42:03 | original URL]
In reply to Re: Also, posted by SLS on May 23, 2010, at 10:54:59
Well, your about to learn more about their potential!
And those are the studies looking at D2/D3 and 5HT1A density:
Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat
G Micheletti, B Lannes, C Haby, E Borrelli, E Kempf, JM Warter, J Zwiller
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Twitter Facebook Linked-inDopamine D2 receptor gene expression was examined in rat striatum after chronic treatment with N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine at 15 mg/kg/day or MK-801 at 0.1, 0.2 and 0.4 mg/kg/day per os, for 50 days). The long-isoform mRNA, as well as the total D2 mRNA expression were induced. No change was noticed in striatal dopamine release or turnover. D2 binding studies carried out in MK-801 chronically treated (0.3 mg/kg/day per os, for 50 days) and control rats revealed an increased receptor density in treated animals without a significant change in receptor affinity. These results suggest that the synthesis of both striatal D2 receptor isoforms is postsynaptically regulated at the transcriptional level, by events triggered by glutamate through the NMDA-type receptor.
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Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.
Author: Mele, A : Cabib, S : Oliverio, A
Citation: Psychopharmacology-(Berl). 1995 Feb; 117(3): 313-7
Abstract: The effects of pretreatment with the non-competitive NMDA antagonist ( )MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day x 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.
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Summary. Behavioral changes have previously been reported following administrations of uncompetitive NMDA receptor antagonists memantine, amantadine and MK-801 for 14 days, at the doses that produce plasma levels comparable to those seen in patients (20, 100 and 0.31 mg/kg/day respectively). Using the same doses, the effect on receptor binding (autoradiography) was studied in rats. [3H]MK-801 binding was increased in the dentate gyrus and CA3 region of the hippocampus (35.2 and 24.3% respectively) following 3 days S.C. infusion of memantine by ALZET minipumps. One daily injection of memantine for 14 days, increased [3H]MK-801 binding in the frontal cortex by 40.3%. The same treatment with amantadine did increase [3H]raclopride binding to dopamine D2 receptors by 13.5%. None of these treatments changed the expression of muscarinic receptors. It is concluded that subchronic blockade of the NMDA receptor by uncompetitive antagonists at moderate (therapeutically-relevant) doses induced only minor changes in NMDA and dopamine D2 receptor expression.
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Decreased striatal dopamine-receptor binding in sporadic ALS: Glutamate hyperactivity?O. J. M. Vogels, MD, PhD, W. J. G. Oyen, MD, PhD, B. G. M. van Engelen, MD, PhD, G. W. A. M. Padberg, MD, PhD and M. W. I. M. Horstink, MD, PhD
From the Departments of Neurology (Drs. Vogels, van Engelen, Padberg, and Horstink) and Nuclear Medicine (Dr. Oyen), University Hospital Nijmegen, the Netherlands.Address correspondence and reprint requests to Dr. O.J.M. Vogels, Department of Neurology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
The pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. The striatum receives massive glutamatergic input. Animal studies suggest that glutamate decreases striatal D2-receptor synthesis. In drug-naďve, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole. Our findings support the glutamatergic excitotoxicity hypothesis in sporadic ALS.
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Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.
Rogóz Z, Dlaboga D, Dziedzicka-Wasylewska M.Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. rogoz@if-pan.krakow.pl
In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptors, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either drug alone given. Since it has been suggested that dopamine receptors, among others, may play a role in anti-immobility effect of IMI, in the present study we examined the effect of AMA (10 mg/kg) and IMI (5 and 10 mg/kg) given separately or jointly, as a single dose or repeatedly (twice daily for 14 days) on the dopamine D2 and D3 receptors in the rat brain, using receptor autoradiography. Following repeated administration of AMA alone or given in combination with IMI (5 mg/kg), the binding of [3H]quinpirole (dopamine D2/D3 receptors agonist) was increased, and similar changes were observed at the level of mRNA encoding dopamine D2 receptors. We used [3H]7-OH-DPAT to selectively label the dopamine D3 receptors. This experiment has shown that AMA given repeatedly did not induce statistically significant changes in the D3 receptor binding, while IMI at both used doses, increased the [3H]7-OH-DPAT binding, and this effect was still observed after repeated joint administration of AMA with both doses of IMI. However, using both radioligands, we did not observe any synergistic or even additive effects in the binding studies after joint administration of AMA and IMI. Nevertheless, we can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain, and this effect may explain their synergistic action observed in the behavioral studies involving dopaminergic transmission.Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
Nair VD, Savelli JE, Mishra RK.Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
The expression of dopamine D2 receptor mRNA was studied in rat brain following micro-injection of a competitive N-methyl D-aspartate (NMDA) receptor antagonist at the prefrontal cortex. Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with a competitive NMDA receptor antagonist ( /-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). The levels of mRNA for NMDA-R1 and dopamine D2 receptors were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and D2 receptor density was quantified by [3H]spiperone binding in the cortex and striatum of these animals. In the prefrontal cortex, the levels of NMDA-R1 receptor mRNA showed significant decrease in CPP-treated animals compared to control animals. However, NMDA-R1 mRNA levels in striatum remained unchanged in any of the experimental groups. The D2 receptor mRNA levels and [3H]spiroperidol binding in prefrontal cortical membranes showed no significant difference between the CPP-treated and control groups of animals. In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP. The increase in D2 mRNA level was correlated with an increase in the D2 receptor binding sites in the striatal membranes. These results suggest a possible interaction between prefrontal cortical NMDA receptors and striatal dopamine receptors.
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J Mol Neurosci. 1998 Oct;11(2):121-6.
Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
Nair VD, Savelli JE, Mishra RK.Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
The expression of dopamine D2 receptor mRNA was studied in rat brain following micro-injection of a competitive N-methyl D-aspartate (NMDA) receptor antagonist at the prefrontal cortex. Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with a competitive NMDA receptor antagonist ( /-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). The levels of mRNA for NMDA-R1 and dopamine D2 receptors were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and D2 receptor density was quantified by [3H]spiperone binding in the cortex and striatum of these animals. In the prefrontal cortex, the levels of NMDA-R1 receptor mRNA showed significant decrease in CPP-treated animals compared to control animals. However, NMDA-R1 mRNA levels in striatum remained unchanged in any of the experimental groups. The D2 receptor mRNA levels and [3H]spiroperidol binding in prefrontal cortical membranes showed no significant difference between the CPP-treated and control groups of animals. In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP. The increase in D2 mRNA level was correlated with an increase in the D2 receptor binding sites in the striatal membranes. These results suggest a possible interaction between prefrontal cortical NMDA receptors and striatal dopamine receptors.
And about 5HT1A:
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Single doses of MK-801, a non-competitive antagonist of NMDA receptors, increase the number of 5-HT1A serotonin receptors in the rat brainK. Wdzony*, M. Ma
kowiak, A. Czyrak, K. Fijał and B. Michalska
Institute of Pharmacology, Polish Academy of Sciences, 12 Smtna Street, PL-31-343 Kraków, Poland
Accepted 22 January 1997. Available online 22 July 1997.
Abstract
In the present study, we investigated the impact of MK-801, a non-competitive NMDA receptor antagonist, on the density of serotonergic receptors of the 5-HT1A subtype and on the metabolism of serotonin in various regions of the rat brain containing terminals and cell bodies of serotonergic neurons. The binding of [3H]8-OH-DPAT to 5-HT1A serotonin receptors was increased after MK-801 (0.4 mg/kg) as was shown by autoradiographic studies in the frontal, cingulate and part of enthorinal cortex, subregions of the hippocampus and raphe nuclei. The above receptor changes were observed at 2 h and, in some brain regions, at 24 h after MK-801. In saturation binding studies, an increase in the Bmax value in the rat hippocampus was found after MK-801 (0.4 mg/kg) while no changes being noted in the Kd value. MK-801 (0.4 mg/kg) increased the concentration of the serotonin metabolite 5-HIAA in the prefrontal cortex and hippocampus, respectively, at 2 and 3 or 3 h after administration, being without effect on the level of serotonin. In the dorsal raphe nucleus, MK-801 (0.4 mg/kg) decreased the level of serotonin without affecting the level 5-HIAA (0.5 h after administration) or increased the level of 5-HIAA without altering the concentration of serotonin (3 h after administration). It is concluded that single administration of MK-801 may alter the density of serotonergic 5-HT1A receptors and in consequence influence the function of the central nervous system associated with activation of 5-HT1A receptors.
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