Biomedical subjects

B Moghaddam

Publications and source records attributed to B Moghaddam.

At least 37 records · Page 2Linked to original sources

PubMed1996

Excitatory amino acid receptors in the ventral tegmental area regulate dopamine release in the ventral striatum.

The role of excitatory amino acid (EAA) receptors located in the ventral tegmental area (VTA) in tonic and phasic regulation of dopamine release in the ventral striatum was investigated. Microdialysis in conscious rats was used to assess dopamine release primarily from the nucleus accumbens shell region of the ventral striatum while applying EAA antagonists or agonists to the VTA. Infusion of the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (25 and 100 microM) into the VTA did not affect dopamine release in the ventral striatum. In contrast, intra-VTA infusion of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (100 and 500 microM) dose-dependently decreased the striatal release of dopamine. Intra-VTA application of the ionotropic EAA receptor agonists NMDA and AMPA dose-dependently (10 and 100 microM) increased dopamine efflux in the ventral striatum. However, infusion of 50 or 500 microM trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD), a metabotropic EAA receptor agonist, did not significantly affect these levels. These data suggest that NMDA receptors in the VTA exert a tonic excitatory influence on dopamine release in the ventral striatum. Furthermore, dopamine neurotransmission in this region may be enhanced by activation of NMDA and AMPA receptors, but not ACPD-sensitive metabotropic receptors, located in the VTA. These data further suggest that EAA regulation of dopamine release primarily occurs in the VTA as opposed to presynaptically at the terminal level.

Animals↗

PubMed1996

NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine.

The present study was performed to assess the role of excitatory amino acid and dopamine receptors on associative functions of the prefrontal cortex (PFC) of the rat. Spatial delayed alternation was used as a PFC-sensitive cognitive task. In addition, in vivo microdialysis was used to assess the release of dopamine in the PFC. The noncompetitive NMDA antagonists ketamine (10-30 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) dose-dependently impaired the spatial delayed alternation performance compared with the saline-treated control group. Administration of the dopamine antagonists raclopride (0.1 and 0.5 mg/kg), SCH-23390 (0.1 mg/kg), or haloperidol (0.1 mg/kg) was without a significant effect. However, haloperidol and raclopride (but not SCH-23390) reversed the disruptive effect of 30 mg/kg ketamine on spatial delayed alternation performance. Microdialysis studies revealed that this dose of ketamine preferentially increased the release of dopamine in the PFC compared with the striatum. These findings indicate that attenuation of glutamatergic neurotransmission at the NMDA receptor impairs PFC-dependent cognitive functions. Furthermore, activation of dopamine neurotransmission contributes, at least in part, to this impairment.

Animals↗

PubMed1995

Regulation of glutamate efflux by excitatory amino acid receptors: evidence for tonic inhibitory and phasic excitatory regulation.

Several biochemical and electrophysiological studies have proposed the presence of presynaptic receptors that potentiate the release of excitatory amino acids (EAA). However, these studies have utilized exogenous EAA agonists and thus have assessed the autoregulation of EAA release during conditions of receptor hyperstimulation, and not during base line conditions. The aim of the present study was to address the question of whether there is a tonic autoregulation of base line EAA release. It was demonstrated that in the hippocampus and the striatum of freely moving rats, basal outflow of glutamate (Glu) and aspartate (Asp) are increased, in a dose-dependent manner, by local application of the antagonists of N-methyl-D-aspartate (NMDA) or non-NMDA receptors, suggesting that there is an ongoing tonic inhibition of aspartate and Glu outflow by different subtypes of EAA receptors. Subsequently, to investigate the effect EAA receptor-hyperstimulation on Glu outflow, a comprehensive study of the effect of various doses of ionotropic and metabotropic EAA agonists on the extracellular levels of Glu was performed. At high concentrations, agonists of all known subtypes of EAA receptors induced (large) increases in extracellular levels of Glu and in most cases caused behavioral stimulation and/or convulsion. This suggests that during conditions of high agonist availability, such as the massive Glu release thought to occur during pathological conditions, a positive feedback presynaptic mechanism may overcome the autoregulatory mechanism operating during base line conditions.

Animals↗

PubMed1994

Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate.

The hippocampal damage caused by stress has been attributed to an increased glutamatergic tone brought about by secretion of glucocorticoids. Although exposure to stress has been shown to increase the outflow of glutamate, direct involvement of glucocorticoid in this phenomenon has not been examined. The present study demonstrates that adrenalectomy attenuates the stress-induced outflow of glutamate in the hippocampus and prefrontal cortex and that glucocorticoid replacement abolishes this attenuation.

Adrenalectomy↗

PubMed1994

Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens.

The effect of systemic ethanol administration on the extracellular levels of glutamate in the hippocampus and nucleus accumbens of conscious rats was assessed using microdialysis. At 0.5 g/kg, ethanol caused a sustained increase in the levels of glutamate in both regions. Following 1.0 g/kg, response was observed in the nucleus accumbens while a trend towards a decrease in glutamate levels occurred in hippocampus. Injection of 2.0 g/kg ethanol decreased these levels in both regions. These findings suggest a relationship between the previously reported biphasic behavioral consequence of ethanol and its effect on glutamatergic neurotransmission.

Animals↗

PubMed1994

Opiate withdrawal increases glutamate and aspartate efflux in the locus coeruleus: an in vivo microdialysis study.

Electrophysiological studies suggest that an increase in excitatory amino acid release may occur in the locus coeruleus during opiate withdrawal. The present study examined directly by microdialysis in anesthetized rats the effect of naltrexone-precipitated opiate withdrawal on the efflux of excitatory amino acids in the locus coeruleus. A withdrawal-induced increase in glutamate and aspartate efflux was found when the microdialysis probe was located in the core of the locus coeruleus; no increase was seen in adjacent regions.

Animals↗

PubMed1994

Preferential activation of dopamine overflow in prefrontal cortex produced by chronic clozapine treatment.

The effect of chronic treatment with clozapine on extracellular dopamine levels in the rat striatum, nucleus accumbens and medial prefrontal cortex (mPFC) was examined using intracerebral microdialysis. Clozapine (20 mg/kg/day x 21 days in drinking water) increased basal dopamine release in the mPFC but had no effect in the striatum or nucleus accumbens. After chronic treatment, an acute dose of clozapine (20 mg/kg i.p.) produced large and long-lasting increases in extracellular dopamine in all three brain regions. The data suggest that chronic clozapine produces a sustained enhancement in dopaminergic tone in the mPFC.

Animals↗

PubMed1994

Glutamatergic antagonists attenuate ability of dopamine uptake blockers to increase extracellular levels of dopamine: implications for tonic influence of glutamate on dopamine release.

Previous in vivo studies reporting a dose-dependent increase in extracellular dopamine (DA) levels by excitatory amino acid (EAA) antagonists have been interpreted to indicate a lack of tonic excitatory effect exerted by these amino acids on striatal DA release. Alternatively, a tonic excitatory influence on DA release may affect a small fraction of DA terminals, so that blockade of this effect does not make a great enough contribution to the extracellular fluid to be detected by microdialysis. To examine this possibility, the effect of EAA antagonists was assessed by microdialysis in the presence of DA uptake blockers. It was found that in the presence of nomifensine or cocaine, antagonists of either NMDA or AMPA/kainate receptors decreased extracellular DA levels in the striatum. These data suggest that EAAs may exert a tonic facilitatory influence on striatal DA release and/or that endogenous EAAs may potentiate the action of DA uptake blockers through mechanisms that are mediated by EAA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1994

Recent basic findings in support of excitatory amino acid hypotheses of schizophrenia.

1. Several clinical and post-mortem tissue findings have suggested a role for excitatory amino acid neuronal systems in the pathophysiology of schizophrenia. 2. These include the ability of NMDA antagonists, phencyclidine and ketamine, to cause both negative and positive symptoms in healthy subjects, and abnormalities in the densities of some types of excitatory amino acid receptors in the postmortem tissue of schizophrenic brains. 3. The present review describes recent basic findings that have examined the involvement of excitatory amino acids in the mechanism of action of antipsychotic drugs. These include studies on the functional links between glutamatergic and dopaminergic systems, effect of acute and chronic antipsychotic drug treatment on excitatory amino acid function, and stress-induced activation of excitatory amino acid release, in particular in the prefrontal cortex.

Antipsychotic Agents↗

PubMed1994

Glutamatergic control of dopamine release during stress in the rat prefrontal cortex.

In vivo microdialysis was used to assess the hypothesis that the stress-induced increase in dopamine release in the prefrontal cortex is mediated by stress-activated glutamate neurotransmission in this region. Local perfusion of an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, blocked the stress-induced increase in dopamine levels, whereas an NMDA receptor antagonist, 2-amino-5-phosphonopentanoic acid, at the dose tested, was not able to alter this response significantly. These data indicate that the effect of stress on dopamine release in the prefrontal cortex is mediated locally by activation of AMPA/kainate receptors, which modulate the release of dopamine in this region.

2-Amino-5-phosphonovalerate↗

PubMed1994

Preferential activation of cortical dopamine neurotransmission by clozapine: functional significance.

Dopamine projections to the prefrontal cortex are thought to be essential for the proper functioning of this region and are proposed to be involved in negative (deficit) symptomatology of schizophrenia. Our studies in the rodent indicate that clozapine, the most effective antipsychotic drug for the treatment of negative symptoms, causes an increase in the basal output of dopamine neurons projecting to the prefrontal cortex. This finding is in contrast to the effect of clozapine in the basal ganglia and the effect of typical antipsychotic drugs such as haloperidol in the prefrontal cortex. The ability of clozapine to increase dopamine release in the prefrontal cortex and its relatively weak affinity for some types of dopamine receptors suggest that this drug may exert its therapeutic influence in part by increasing dopaminergic function in the prefrontal cortex.

Animals↗

PubMed1993

Actions of clozapine and haloperidol on the extracellular levels of excitatory amino acids in the prefrontal cortex and striatum of conscious rats.

The technique of intracerebral microdialysis was employed to assess the effect of acute clozapine and haloperidol on the extracellular levels of aspartate and glutamate in the striatum and medial prefrontal cortex of conscious rats. Subcutaneous injection of 25 mg/kg clozapine, but not the lower dose of 15 mg/kg, led to a significant increase in both aspartate and glutamate levels over time. The maximum effect was observed two hours after injection. Haloperidol (0.5 and 1 mg/kg s.c.) did not increase the extracellular levels of aspartate and glutamate over time. At all doses tested, both drugs were without a significant effect in the striatum. These data suggest that clozapine may have selective actions on the cortical excitatory amino acid systems.

Animals↗

PubMed1993

In vivo assessment of basal and drug-induced dopamine release in cortical and subcortical regions of the anesthetized primate.

There is an acute interest in studying the functional characteristics of dopamine systems in the cortex of primates. In particular, the prefrontal cortical dopamine projections have received a great deal of attention. This system is essential for proper functioning of the prefrontal cortex, and dysfunction within the system may be involved in some psychiatric and neurological illnesses. In vivo assessments of cortical dopamine in the primate have been scarce. This has been due, in part, to technical difficulties associated with these studies and with quantifying the relatively low levels of dopamine found in cortical regions. In the present study, intracerebral microdialysis was utilized to assess the extracellular concentration of dopamine in cortical and subcortical areas of the pentobarbital-anesthetized rhesus monkey. Basal extracellular dopamine levels were consistently detected in the medial prefrontal cortex, premotor cortex, and caudate-putamen. The basal extracellular concentration of dopamine in the dorsolateral prefrontal cortex was reliably detected in 1 of 4 animals. Intravenous administration of amphetamine (1 mg/kg) enhanced extracellular dopamine levels in the caudate-putamen area by more than 20-fold. In cortical areas, amphetamine's effect was less profound: An increase of 400-500 percent over basal extracellular dopamine levels was observed in each region. These studies demonstrate the feasibility of microdialysis for detecting extracellular fluxes of dopamine in the cortex of nonhuman primates. They further provide direct evidence that the dopamine released within the prefrontal cortex and the premotor cortex of nonhuman primates responds to pharmacological manipulation.

Amphetamine↗

PubMed1993

Depolarization inactivation of dopamine neurons: terminal release characteristics.

The functional consequences of chronic treatment with haloperidol (0.5 mg/kg s.c. for 21-23 days) on striatal extracellular levels of dopamine and excitatory amino acids, aspartate and glutamate, were examined using microdialysis techniques. Our studies indicate that, in both awake and anesthetized animals, chronic haloperidol treatment does not appear to change basal outflow of dopamine and its response to an exogenous antagonist (i.e., a challenge dose of haloperidol). Furthermore, in chronic haloperidol and vehicle-treated animals, extracellular dopamine levels were decreased below our limit of detection following perfusion of tetrodotoxin through the probe, or into the medial forebrain bundle, suggesting that in both groups of animals extracellular dopamine levels are neuronally derived and seemed to depend equally on impulse flow. However, some differences were observed between the vehicle and haloperidol-treated animals: the excitatory action of 30 mM K+ on extracellular dopamine levels was decreased, and extracellular levels of glutamate were significantly increased, in animals treated chronically with haloperidol. The alterations in extracellular glutamate levels suggests that events at the terminal may be involved in maintaining the "normal" extracellular dopamine levels. Furthermore, the decrease in response to stimulation by K+ suggests that chronic haloperidol treatment may decrease the responsivity of the striatal dopamine system to stimuli.

Anesthesia, General↗

PubMed1993

Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia.

The technique of intracerebral microdialysis was used to assess the effect of stress on the extracellular concentrations of excitatory amino acids, glutamate and aspartate, in the rat medial prefrontal cortex, hippocampus, striatum, and nucleus accumbens. A 20-min restraint procedure led to an increase in extracellular glutamate in all regions tested. The increase in glutamate levels was significantly higher in the prefrontal cortex than that observed in other regions. With the exception of the striatum, extracellular levels of aspartate were increased in all regions. Furthermore, the increase in aspartate levels was significantly higher in prefrontal cortex compared to hippocampus and nucleus accumbens. Local perfusion of tetrodotoxin during the restraint procedure significantly decreased the stress-induced increase in extracellular excitatory amino acids. In order to ensure that the above results were not an artifact of restraint not associated with stress (e.g., decreased mobility), we also examined the effect of swimming stress on the extracellular levels of excitatory amino acids in selected regions, i.e., striatum and medial prefrontal cortex. Both regions displayed a significant increase in extracellular levels of aspartate and glutamate following 20 min of swimming in room temperature water. This study provides direct evidence that stress increases the neuronal release of excitatory amino acids in a regionally selective manner. The implications of the present findings for stress-induced catecholamine release and/or hippocampal degeneration are discussed.

Animals↗

PubMed1993

Distinct actions of endogenous excitatory amino acids on the outflow of dopamine in the nucleus accumbens.

Intracerebral microdialysis was utilized to assess the effect of endogenous excitatory amino acids (EAA), l-glutamate (GLU) and l-aspartate (ASP), on the extracellular levels of dopamine in the rat nucleus accumbens. Both ASP and GLU produced a release response at a concentration range of 1 to 10 mM. GLU was generally less efficacious in increasing dopamine outflow; at 5 and 10 mM, the maximum effect exerted by GLU was significantly less than that observed with ASP. The specific N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic (AP5) acid was more effective in attenuating the actions of 5 and 10 mM ASP than the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). On the other hand, the stimulatory actions of 5 and 10 mM GLU were more effectively decreased with CNQX when compared with AP5. Perfusion of tetrodotoxin before application of either GLU or ASP blocked the excitatory effect of these amino acids on dopamine overflow. These results suggest that in the nucleus accumbens, ASP and GLU may increase dopamine release through distinct mechanisms and that their stimulatory action is dependent on axonal impulse flow.

Amino Acids↗

PubMed1992

Tonic inhibition of striatal dopamine transmission: effects of benzodiazepine and GABAA receptor antagonists on extracellular dopamine levels.

At present, it is unclear whether ligands which bind at the benzodiazepine/GABA receptor complex play a tonic modulatory role with regard to striatal dopamine (DA) transmission. The present study was designed to examine the effects of Ro15-1788, a benzodiazepine (BZ) receptor antagonist, and SR 95531, a GABAA receptor antagonist, on striatal extracellular DA (DA[e]) concentrations in anesthetized and awake rats using the technique of in vivo microdialysis. Local administration of Ro15-1788 resulted in a dose-dependent increase in DA[e] in both anesthetized and awake animals. The Ro15-1788-induced increase in DA[e] was blocked by coadministration of the BZ agonist diazepam, as well as GABA. Local administration of SR 95531 also resulted in a dose-dependent alteration in striatal DA levels in both anesthetized and awake animals. The SR 95531-induced increase in DA was blocked by coadministration of GABA. The results suggest that GABA may play a tonic inhibitory role with regard to striatal DA transmission.

Animals↗

PubMed1991

Do endogenous excitatory amino acids influence striatal dopamine release?

In vivo microdialysis techniques were used to examine whether endogenous excitatory amino acids exert a tonic facilitatory influence on striatal dopamine release. Local application of NMDA and non-NMDA antagonists at 10 microM was without an effect on basal dopamine release while 100 microM and 1 mM of these drugs significantly enhanced the release. Our findings do not support the idea that excitatory amino acids have a tonic excitatory effect on striatal dopamine release.

Amino Acids↗