Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner.

Previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) enhances cocaine self-administration in a D(1) dopamine receptor-dependent manner. The present study examined the contribution of VTA NMDA, AMPA/kainate, and metabotropic glutamate (mGlu) receptors to this effect. Rats in different groups received three intra-VTA injections, one every third day, of either saline (0.5 microl/side), AMPH (2.5 microg/0.5 microl/side), AMPH+CPP (NMDA receptor antagonist; 10 microM or 100 microM/0.5 microl/side), AMPH+CNQX (AMPA/kainate receptor antagonist; 0.3 mM or 1 mM/0.5 microl/side), AMPH+MCPG (mGlu receptor antagonist; 0.5 mM or 50 mM/0.5 microl/side), or the glutamate receptor antagonists alone. Starting 7-10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) and then tested under a progressive ratio (PR) schedule of reinforcement for 6 consecutive days. As reported previously, VTA AMPH pre-exposed rats worked more and obtained more infusions of cocaine than saline pre-exposed animals. Coadministration of CPP, CNQX, or MCPG with AMPH during pre-exposure dose-dependently blocked this enhancement of cocaine self-administration. Rats pre-exposed to the glutamate receptor antagonists alone did not differ on the test days from the saline pre-exposed controls. These results indicate that, in a manner paralleling the induction of sensitization of the locomotor stimulating effects of AMPH, activation of NMDA, AMPA/kainate, and mGlu receptors during pre-exposure to AMPH in the VTA is necessary for the enhancement of cocaine self-administration to develop.     

The mGlu2/3 receptor agonist LY379268 injected into cortex or thalamus decreases neuronal injury in retrosplenial cortex produced by NMDA receptor antagonist MK-801: possible implications for psychosis

The non-competitive NMDA receptor antagonists, including PCP (phencyclidine), ketamine, and MK-801 (dizocilpine) produce psychosis in humans and injure neurons in retrosplenial cortex in adult rodent brain. This study examined the effects of the metabotropic mGlu2/3 agonist LY379268 and antagonist LY341495 on cortical injury produced by systemic MK-801 (1 mg/kg i.p.) in adult female rats. Systemic injections of mGlu2/3 agonist LY379268, but not mGlu2/3 antagonist LY341495, decreased the injury in the retrosplenial cortex produced by systemic MK-801 as assessed by Hsp70 induction. Bilateral injections of LY379268, but not vehicle, into retrosplenial cortex or bilateral injections of LY379268 into anterior thalamus also decreased the injury in retrosplenial cortex produced by systemic MK-801. The data show that bilateral activation of mGlu2/3 glutamate receptors in cortex or anterior thalamus decreases the neuronal injury in retrosplenial cortex produced by systemic MK-801. Because antipsychotic medications decrease cortical injury produced by NMDA antagonists in rodents and decrease psychosis in humans, mGlu2/3 agonists that decrease cortical injury produced by NMDA antagonists in rodents might be evaluated for decreasing psychosis in people.     

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release.

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.     

Induction of LTD in the adult hippocampus by the synaptic activation of AMPA/kainate and metabotropic glutamate receptors

It has been suggested that the induction of long-term depression (LTD) may be developmentally regulated since LTD can be readily induced by LFS in slices from young but not adult animals. However, we have recently reported that paired pulse low frequency stimulation (PP-LFS) can reliably induce LTD in the CA1 region of adult hippocampal slices. We now describe the role of glutamate receptors in the induction of LTD in adult hippocampus. The induction of LTD was prevented by the combined application of AMPA/kainate and metabotropic glutamate (mGlu) receptor antagonists (CNQX and LY341495). However, LTD was not blocked by the co-application of NMDA and mGlu receptor antagonists nor by the co-application of NMDA and AMPA/kainate receptor antagonists. Taken together, the above results suggest that activation of either AMPA/kainate or mGlu receptors is sufficient to induce LTD. Therefore, these results suggest that PP-LFS can efficiently activate AMPA/kainate and mGlu receptors in order to induce long-lasting synaptic depression in the CA1 region of the adult hippocampus in vitro.     

Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats

The neurobiological mechanism underlying the negative motivational component of withdrawal from acute opiate dependence is far from understood. Our objectives were to determine whether the glutamatergic system is involved in the motivational component of morphine withdrawal in acutely dependent rats and such an involvement is associated with dopaminergic neurotransmission. We examined the effects of various kinds of glutamate receptor antagonists on conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h before. Furthermore, the influence of pretreatment with the dopamine receptor antagonist haloperidol on those effects of glutamate receptor antagonists was also investigated. CPA was attenuated in a dose-dependent manner by all glutamate receptor antagonists examined including the NMDA receptor antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801) and phencyclidine hydrochloride (PCP), AMPA receptor antagonist 1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466), and metabotropic receptor antagonists (+/-)-2-amino-3-phosphonopropionic acid (AP-3) and (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG). The effects of MK-801, GYKI 52466 and MCPG were blocked by haloperidol.These results suggest that the glutamatergic system involving multiple classes of receptors plays a role in the motivational component of withdrawal from acute morphine dependence, and the function of the glutamatergic system would be closely associated with dopaminergic neurotransmission.     

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophrenia-related behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.     

Behavioral and convulsant effects of the (S) enantiomer of the group I metabotropic glutamate receptor agonist 3,5-DHPG in mice

The purpose of the present studies was to investigate the behavioral and convulsant effects produced by the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Administered i.c.v. to mice, (S)-3,5-DHPG produced a behavioral syndrome consisting of scratching and/or facial grooming, tremors, slow forelimb clonus, rearing, and falling that increased over the dose range of 10-400 nmol. The full syndrome, produced by 400 nmol of (S)-3,5-DHPG, was antagonized by the selective mGlu1 receptor antagonist LY456236 but not by the mGlu5 receptor antagonist MPEP or the mGlu2/3 receptor antagonist LY341495. The behaviors induced by the 400 nmol dose were not blocked by the NMDA receptor antagonist MK-801, but were attenuated by the non-NMDA receptor antagonists GYKI 52466 and NBQX, and the Ca2+ mobilization inhibitor dantrolene, but at motor-impairing doses. The scratching behaviors produced by 30 nmol of (S)-3,5-DHPG were antagonized by LY456236 but not by MPEP, LY341495 or MK-801. GYKI 52466 and dantrolene, but not NBQX, inhibited scratching at motor-impairing doses. Both 400 and 30 nmol of (S)-3,5-DHPG produced a generalized seizure as recorded by surface EEG electrodes. LY456236 blocked the seizures produced by 30 nmol but not by 400 nmol; dantrolene was ineffective in blocking seizures produced by either dose. The present findings suggest that (S)-3,5-DHPG produces an increase in excitation that is mediated by mGlu1 and non-NMDA receptors.     

Regulation of the maturation of osteoblasts and osteoclastogenesis by glutamate

Glutamate, an important central excitatory neurotransmitter, is also secreted by osteoblasts and may be involved in the regulation of bone metabolism. Glutamate receptors for N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) are demonstrated in bone cells. Here we investigated the in vivo effects of glutamate by local injection of AMPA, NMDA, and their antagonists into tibia as well as their in vitro effects on the maturation of osteoblasts and formation of osteoclasts. AMPA receptor antagonist CNQX and NMDA receptor antagonist MK-801 significantly inhibited the maturation and mineralization of osteoblasts in high-glutamate α-MEM. On the other hand, AMPA and NMDA up-regulated the mineralized deposition and osteocalcin mRNA expression of primary osteoblasts cultured in glutamate-free DMEM. AMPA and NMDA induced the phosphorylation of extracellular signal-related kinases (ERK) in osteoblasts within 15 min. In addition, NMDA but not AMPA up-regulated the number of osteoclasts while MK801 antagonized this potentiating effect. To explore the action of glutamate agonists on bone formation in animal model, AMPA was locally injected into tibia and it was found that the bone volume in secondary spongiosa significantly increased and co-treatment of CNQX antagonized the enhancing effect of AMPA. These results suggest that glutamate may play a physiological role in regulating the maturation of osteoblasts and osteoclastogenesis. Activation of both AMPA and NMDA receptors regulates the maturation of osteoblasts. NMDA but not AMPA affects receptor for activation of NF-κB ligand (RANKL)-induced osteoclastogenesis.     

Desensitization of AMPA receptors and AMPA-NMDA receptor interaction: an in vivo cyclic GMP microdialysis study in rat cerebellum.

1. Desensitization is an important characteristic of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type. 2. Stimulation of N-methyl-D-aspartate (NMDA) or AMPA receptors in cerebellum results in increased production of cyclic GMP. We have investigated AMPA receptor desensitization in vivo by monitoring extracellular cyclic GMP during intracerebellar microdialysis in conscious unrestrained adult rats. 3. Local infusion of AMPA (10 to 100 microM) caused dose-related elevations of cyclic GMP levels. The effect of AMPA was prevented by the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) and by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NOARG). 4. In the absence of AMPA, DNQX lowered the basal levels of cyclic GMP whereas the NMDA receptor channel antagonist dizocilpine (MK-801) was ineffective. 5. Cyclothiazide, a blocker of AMPA receptor desensitization, potentiated the cyclic GMP response to exogenous AMPA. Moreover, cyclothiazide (100-300 microM) produced on its own dose-dependent elevations of extracellular cyclic GMP. The cyclothiazide-induced response was prevented not only by DNQX but also by MK-801. 6. While the cyclic GMP response elicited by AMPA was totally insensitive to MK-801, the response produced by AMPA (10 microM) plus cyclothiazide (30 microM) was strongly attenuated by the NMDA receptor antagonist (30 microM). 7. The results suggest that (a) AMPA receptors linked to the NO-cyclic GMP pathway in the cerebellum can undergo desensitization in vivo during exposure to exogenous AMPA; cyclothiazide inhibits such desensitization; (b) AMPA receptors (but not NMDA receptors) are 'tonically' activated and kept in a partly desensitized state by endogenous glutamate; (c) if cyclothiazide is present, activation of AMPA receptors may permit endogenous activation of NMDA receptors.     

Role of AMPA and NMDA receptors in the nucleus accumbens shell in turning behaviour of rats: interaction with dopamine receptors

The role of AMPA and NMDA receptors in the shell of the nucleus accumbens in turning behaviour of rats was investigated. Unilateral injection of the AMPA receptor agonist, AMPA (0.25, 0.4, 0.5 and 1 microg), into the shell of the nucleus accumbens dose-dependently produced contraversive pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping, while injection of AMPA (0.5 microg) into the core produced only a marginal effect. This shell-specific AMPA effect was dose-dependently inhibited by the AMPA receptor antagonist, NBQX (1 and 10 ng), which alone did not produce turning behaviour. The AMPA-induced pivoting was also dose-dependently inhibited by the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.5 microg). Neither MK-801 (0.1, 0.5 and 5 microg) nor the NMDA receptor agonist, NMDA (0.5 and 1 microg), injected unilaterally into the shell, produced turning behaviour. Unilateral injection of a mixture of dopamine D(1) (SKF 38393, 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the shell has been found to elicit contraversive pivoting. The dopamine D(1)/D(2) receptor antagonist, cis-(Z)-flupentixol (1 and 10 microg), injected into the shell, in doses known to block dopamine D(1)/D(2) receptor-mediated pivoting, also significantly inhibited AMPA (0.5 microg)-induced pivoting. Moreover, both NBQX (1 and 10 ng) and MK-801 (0.1 and 0.5 microg), injected into the shell, significantly inhibited dopamine D(1)/D(2) receptor-mediated pivoting. It is therefore concluded that unilateral stimulation of AMPA receptors in the shell of the nucleus accumbens can elicit contraversive pivoting, and that both AMPA and dopamine D(1)/D(2) receptors play a critical role in shell-specific pivoting in contrast to NMDA receptors that at best play only a modulatory role.     

Role of glutamate receptors and nitric oxide on the effects of glufosinate ammonium,an organophosphate pesticide,on in vivo dopamine release in rat striatum

The purpose of the present work was to assess the possible role of glutamatergic receptors and nitric oxide (NO) production on effects of glufosinate ammonium (GLA), an organophosphate pesticide structurally related to glutamate, on in vivo striatal dopamine release in awake and freely moving rats. For this, we used antagonists of NMDA (MK-801 and AP5) or AMPA/kainate (CNQX) receptors, or nitric oxide synthase (NOS) inhibitors (l-NAME and 7-NI), to study the effects of GLA on release of dopamine from rat striatum. So, intrastriatal infusion of 10 mM GLA significantly increased dopamine levels (1035 ± 140%, compared with basal levels) and administration of GLA to MK-801 (250 μM) or AP5 (650 μM) pretreated animals, produced increases in dopamine overflow that were ∼40% and ∼90% smaller than those observed in animals not pretreated with MK-801 or AP5. Administration of GLA to CNQX (500 μM) pretreated animals produced an effect that was not significantly different from the one produced in animals not pretreated with CNQX. On the other hand, administration of GLA to l-NAME (100 μM) or 7-NI (100 μM) pretreated animals, produced increases in dopamine overflow that were ∼80% and ∼75% smaller than those observed in animals not pretreated with these inhibitors. In summary, GLA appears to act, at least in part, through an overstimulation of NMDA (and not AMPA/kainate) receptors with possible NO production to induce in vivo dopamine release. Administration of NMDA receptor antagonists and NOS inhibitors partially blocks the release of dopamine from rat striatum.     

Protection from inorganic mercury effects on the in vivo dopamine release by ionotropic glutamate receptor antagonists and nitric oxide synthase inhibitors

The possible role of ionotropics glutamate receptors on the HgCl(2)-induced dopamine (DA) release from rat striatum was investigated by using in vivo brain microdialysis technique after administration of selective NMDA and AMPA/Kainate receptors antagonists dizocilpine (MK-801), D (-)-2-amino-5-phoshonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moreover, we have also studied the effects of nitric oxide synthase (NOS) inhibitors L-nitro-arginine methyl ester (L-NAME) and 7-nitro-indazol (7-NI) on HgCl(2)-induced DA release. Intraestriatal infusion of 1mM HgCl(2) increased striatal DA to 1717.2+/-375.4% respect to basal levels. Infusion of 1mM HgCl(2) in 400 microM MK-801 pre-treated animals produced an increase on striatal DA levels 61% smaller than that induced in non-pre-treated animals. In the case of AP5, this treatment reduced 92% the increase produced by HgCl(2) as compared to non-pre-treated rats. Nevertheless, the administration of CNQX did not produce any effect on HgCl(2)-induced dopamine release. Intrastriatal infusion of 1mM HgCl(2) in 100 microM L-NAME pre-treated animals produced an increase on extracellular DA levels 82% smaller than produced by HgCl(2) alone. In addition, the pre-treatment with 7-NI reduced 90% the increase produced by infusion of HgCl(2) alone in rats. Thus, HgCl(2)-induced DA release could be produced at last in part, by overstimulation of NMDA receptors with NO production, since administration of NMDA receptor antagonists and NOS inhibitors protected against HgCl(2) effects on DA release.     

Functional interaction of NMDA and group I metabotropic glutamate receptors in negatively reinforced learning in rats

Rationale The role of glutamatergic system in learning and memory has been extensively studied, and especially N-methyl-d-aspartate (NMDA) receptors have been implicated in different learning and memory processes. Less is known, however, about group I metabotropic glutamate (mGlu) receptors in this field. Recent studies indicated that the coactivation of both NMDA and group I mGlu receptors is required for the induction of long-term potentiation (LTP) and learning. Objective The purpose of the study is to evaluate if there is a functional interaction between NMDA and group I mGlu receptors in two different models of aversive learning. Methods Effects of NMDA, mGlu1, and mGlu5 receptor antagonists on acquisition were tested after systemic coadministration of selected ineffective doses in passive avoidance (PA) and fear-potentiated startle (FPS). Results Interaction in aversive learning was investigated using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGlu1, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGlu5, and (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate [(+)MK-801] for NMDA receptors. In PA, the coapplication of MTEP at a dose of 5 mg/kg and (+)MK-801 at a dose of 0.1 mg/kg 30 min before training impaired the acquisition tested 24 h later. Similarly, EMQMCM (2.5 mg/kg) plus (+)MK-801 (0.1 mg/kg), given during the acquisition phase, blocked the acquisition of the PA response. In contrast, neither the combination of MTEP (1.25 mg/kg) nor EMQMCM (5 mg/kg) plus (+)MK-801 (0.05 mg/kg) was effective on the acquisition assessed in the FPS paradigm. Conclusion The findings suggest differences in the interaction of the NMDA and mGlu group I receptor types in aversive instrumental conditioning vs conditioning to a discrete light cue.     

Intrathecal injection of glutamate receptor antagonists/agonist selectively attenuated rat pain-related behaviors induced by the venom of scorpion Buthus martensi Karsch

The present study investigated the involvement of spinal glutamate receptors in the induction and maintenance of the pain-related behaviors induced by the venom of scorpion Buthus martensi Karsch (BmK). (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine hydrogen maleate (MK-801; 40 nmol; a non-competitive NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 40 nmol; a non-NMDA receptor antagonist), dl-amino-3-phosphonopropionic acid (dl-AP3; 100 nmol; a group I metabotropic glutamate receptor antagonist) and 4-aminopyrrolidine-2,4-dicarboxylate (APDC; 100 nmol; a group II metabotropic glutamate receptor agonist) were employed. On intrathecal injection of glutamate receptor antagonists/agonist before BmK venom administration by 10 min, BmK venom-induced spontaneous nociceptive responses could be suppressed by all tested agents. Primary thermal hyperalgesia could be inhibited by MK-801 and dl-AP3, while bilateral mechanical hyperalgesia could be inhibited by CNQX and dl-AP3 and contralateral mechanical hyperalgesia could be inhibited by APDC. On intrathecal injection of glutamate receptor antagonists/agonist after BmK venom injection by 4.5 h, primary thermal hyperalgesia could be partially reversed by all tested agents, while bilateral mechanical hyperalgesia could only be inhibited by APDC. The results suggest that the role of spinal glutamate receptors may be different on the various manifestations of BmK venom-induced pain-related behaviors.     

Studying specific effects of nootropic drugs on glutamate receptors in the rat brain

The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM). The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad rage of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM). Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family.     

Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists.

N-methyl-D-aspartate (NMDA) receptor antagonists can elicit symptoms in humans that resemble those seen in schizophrenic patients. Rodents manifest locomotor and stereotypic behaviors when treated with NMDA receptor antagonists such as phencyclidine (PCP) or dizocilpine maleate (MK-801); these behaviors are usually associated with an activated dopamine system. However, recent evidence suggests that increased glutamatergic transmission mediates the effects of these NMDA receptor antagonists. The role of dopamine in PCP- and MK-801-induced behavior (eg hyperlocomotion) remains unclear. We used dopamine-deficient (DD) mice in which tyrosine hydroxylase is selectively inactivated in dopaminergic neurons to determine whether dopamine is required for the locomotor and molecular effects of PCP and MK-801. DD mice showed a similar increase in locomotor activity and c-fos mRNA induction in the striatum in response to these NMDA receptor antagonists as control mice. Restoration of dopamine signaling in DD mice enhanced their locomotor response to PCP and MK-801. Administration of LY379268, a group II metabotropic glutamate receptor agonist that inhibits glutamate release, blocked PCP- and MK-801-induced hyperlocomotion in both DD and control mice. These results suggest that glutamate, rather than dopamine, is required for the locomotor and molecular effects of NMDA receptor antagonists, but that glutamate and dopamine can act cooperatively.     

The role of nitric oxide on glutaminergic modulation of dopaminergic activation.

Biochemical studies have been demonstrated that N-methyl-D-aspartate (NMDA)-evoked dopaminergic (DAergic) activation can be modulated by nitric oxide (NO) systems. Therefore, behavioral study was performed to characterize the role of NO on NMDA modulation of DAergic activation. It is well known that apomorphine induces climbing behaviors in mice by the activation of DAergic receptors. Our previous studies showed that NMDA receptor antagonists reduced apomorphine-induced climbing behaviors. It was reported that nitric oxide synthase (NOS) inhibitors reduced the apomorphine-induced climbing behaviors. In this experiment, NO donor restored the apomorphine-induced climbing behavior, which was inhibited by NMDA receptor antagonist. NOS inhibitor inhibited the apomorphine-induced climbing behavior, which was enhanced by NMDA receptor agonist. These results suggest that DAergic activation is regulated by both NMDA receptors and NO systems, and NO in the down-stream of NMDA receptors play an important role on the glutaminergic NMDA modulation of DAergic function.     

Effect of glutamate receptor antagonists microinjected into the nucleus accumbens on place aversion induced by naloxone in single-dose, morphine-treated rats

It is well established that acute morphine withdrawal can be observed following opioid receptor antagonism in rodents. Glutamate receptor antagonists can attenuate the conditioning place aversion (CPA) induced by naloxone in single-dose, morphine-treated rats. Anatomically, the nucleus accumbens appears to be involved in opiate dependence. In the present study, we examined the effects of various glutamate receptor antagonists in the nucleus accumbens on naloxone-induced CPA in rats. MK-801 (an NMDA receptor antagonist), GYKI52466 (an AMPA receptor antagonist), and MCPG (a metabotropic glutamate receptor antagonist) significantly attenuated naloxone-induced CPA following microinjection into the accumbens. In contrast, none of the agents showed place conditioning ability on their own in either morphine-exposed or na?ve rats. The present study suggests that glutamate receptors in the nucleus accumbens play a key role in the motivational component of withdrawal during acute morphine dependence.     

Differential effects of 7-OH-DPAT and apomorphine on hyperactivity induced by MK-801 (dizocilpine) in rats

Recent experiments from this laboratory demonstrated synergistic locomotor depressant effects of AMPA/kainate receptor blockade and D(2/3) dopamine (DA) receptor stimulation. This study explored functional interactions between DA and glutamate (Glu) systems using the NMDA receptor antagonist MK-801 and the DA receptor agonists 7-OH-DPAT and apomorphine. Using photocell locomotor activity boxes, systemic effects of MK-801 in combination with 7-OH-DPAT (0.03 mgkg(-1) SC, n=8) or a pre-synaptically effective dose of apomorphine (0.05 mgkg(-1) SC, n=6) were measured in male Sprague-Dawley rats. Effects of bilateral applications of MK-801 and 7-OH-DPAT into the nucleus accumbens (NAS) shell subregion were also investigated (n=7). When given alone, MK-801 (0.13 mgkg(-1) or 0.66 microg intra-NAS shell) increased horizontal locomotor activity, while 7-OH-DPAT (0.03 mgkg(-1)) or apomorphine (0.05 mgkg(-1)) decreased this measure. Co-administration of 7-OH-DPAT (systemically or into the NAS shell) completely blocked MK-801 induced hyperactivity. In contrast, MK-801 and apomorphine demonstrated additive effects. Stimulation of D(3) DA receptors may therefore block the hyperactivity induced by NMDA receptor antagonism, and the NAS shell is an important site for this interaction. The differential effects of the DA agonists on hyperactivity induced by NMDA receptor blockade support the proposal that 7-OH-DPAT may induce hypoactivity by stimulation of postsynaptic D(3) DA receptors.     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.