MacMaster FP, Carrey N, Sparkes S, Kusumakar V.
Proton spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder.
Biol Psychiatry 2003 Jan 15;53(2):184-7
"The frontal-striatal pathway has been previously implicated in the neuropathology of attention-deficit/hyperactivity disorder (ADHD). Hence, we used proton magnetic resonance spectroscopy ((1)H-MRS) to examine metabolite levels in the prefrontal cortex of children with ADHD.Nine age- and gender-matched case-control pairs were examined, ages 7 to 16 years. A long-echo (1)H-MRS scan was acquired from the right prefrontal cortex and left striatum in all subjects. Compounds that can be visualized with (1)H-MRS include N-acetyl-aspartate (NAA), glutamate/glutamine/gamma-aminobutyric acid (Glx), creatine/phosphocreatine (Cr), and choline compounds (Cho).Frontal-striatal glutamatergic resonances were elevated in the children with ADHD as compared to healthy control subjects. No differences were noted in NAA, Cho, or Cr metabolite ratios.These findings suggest that frontal-striatal Glx resonances may be increased in children with ADHD in comparison with healthy control subjects." [Abstract]

Courvoisie H, Hooper SR, Fine C, Kwock L, Castillo M.
Neurometabolic functioning and neuropsychological correlates in children with ADHD-H: preliminary findings.
J Neuropsychiatry Clin Neurosci. 2004 Winter;16(1):63-9.
"Proton magnetic resonance spectroscopy (MRS) and neuropsychological testing were conducted on 8 children with attention-deficit/hyperactivity disorder (ADHD-H), with no learning disabilities or comorbidities and 8 controls. Magnetic resonance spectroscopy revealed increased Glutamate/Glutamine in both frontal areas, and increased N-acetyl aspartate and Choline in the right frontal area of the ADHD-H subjects. Neuropsychological testing revealed few within- and between-group differences. Findings related to frontal lobe dysfunction in ADHD-H subjects were noted. N-acetylasparte/creatine (NAA/Creatine) in the right frontal region, and myoinositol/creatine (Myo inositol/Creatine) in the right and left frontal regions appear to be highly associated with the regulation of sensorimotor, language, and memory and learning functioning in children with ADHD-H." [Abstract]

Carrey N, MacMaster FP, Sparkes SJ, Khan SC, Kusumakar V.
Glutamatergic changes with treatment in attention deficit hyperactivity disorder: a preliminary case series.
J Child Adolesc Psychopharmacol 2002 Winter;12(4):331-6
"Magnetic resonance spectroscopy, a noninvasive neuroimaging method, is a technique with the potential to measure in vivo neurochemical changes to different medication treatments. Symptoms of attention deficit hyperactivity disorder (ADHD) improved in two children treated with methylphenidate and two children treated with atomoxetine, for whom pre- and posttreatment proton magnetic resonance spectroscopy examinations were obtained to assess the relation between the neurochemical profiles in the striatum and prefrontal cortex among symptom severity and response to treatment. In the striatum, a striking decrease in the glutamate/creatine ratio (mean change 56.1%) was observed between 14 and 18 weeks of therapy in all four children with ADHD. In the prefrontal cortex, however, changes in the glutamate/creatine ratio were noted only in subjects receiving atomoxetine, not in those receiving methylphenidate. These data suggest that in vivo magnetic resonance spectroscopy measurement has the potential to assess response to psychopharmacological treatment in children with ADHD." [Abstract]

Carrey N, MacMaster FP, Fogel J, Sparkes S, Waschbusch D, Sullivan S, Schmidt M.
Metabolite changes resulting from treatment in children with ADHD: a 1H-MRS study.
Clin Neuropharmacol. 2003 Jul-Aug; 26(4): 218-21.
"Previously the authors noted an increase in glutamatergic tone in children with attention deficit hyperactivity disorder compared with age- and gender-matched control subjects. In this study they examine the effect of treatment on metabolite concentrations. Fourteen children with attention deficit hyperactivity disorder were investigated medication free and after treatment, using proton magnetic resonance spectroscopy. In the prefrontal cortex and striatum, metabolite peaks of N-acetyl-aspartate, glutamate/glutamine/gamma-aminobutyric acid, creatine/phosphocreatine, and choline compounds were measured, and ratios of the peaks were calculated and compared before and after treatment. The glutamate/glutamine/gamma-aminobutyric acid-to-creatine/phosphocreatine ratio decreased significantly in the striatum. No other metabolites demonstrated any change in response to medication. These findings suggest that glutamate may be involved in treatment response in attention deficit hyperactivity disorder, especially in the striatum." [Abstract]

Kodama T, Honda Y, Watanabe M, Hikosaka K.
Release of neurotransmitters in the monkey frontal cortex is related to level of attention.
Psychiatry Clin Neurosci 2002 Jun;56(3):341-2
"Attention is reported to be maintained by monoamines, acetylcholine and amino acids systems. Changes in the releases of these neurotransmitters during the three stages comprising quiet wake (QW) and two arousal states (AW), which are activated from different sources, were investigated. Norepinephrine releases during AW were significantly higher than that during QW. Conversely, the levels of acetylcholine and serotonin that were released did not change significantly among these three stages. The interesting observation was the dissociation of the increase between glutamate and dopamine releases in the two AW states. The results indicate that attention level is related to the amount of norepinephrine release, and that attention quality is related to the interaction between dopamine and glutamate releases." [Abstract]

Diaz Heijtz R, Kolb B, Forssberg H.
Can a therapeutic dose of amphetamine during pre-adolescence modify the pattern of synaptic organization in the brain?
Eur J Neurosci. 2003 Dec; 18(12): 3394-9.
"Stimulant drugs such as amphetamine have, for many decades, been the drugs of choice in the treatment of children with attention-deficit/hyperactivity disorder. However, little is known about their therapeutic mechanisms or about the consequences of their long-term exposure. In the present study we investigated whether repeated exposure of a low dose of amphetamine (0.5 mg/kg) to juvenile rats could induce long-term morphological alterations in the prefrontal cortex. In addition, to assess possible behavioural consequences of prolonged exposure to this drug, we examined whether changes in the motor response to various dopamine agonists occurred after this treatment. We found that this dose of amphetamine promotes plasma concentrations of amphetamine sulphate in juvenile rats to levels corresponding to the clinical range used for children with attention-deficit/hyperactivity disorder. Amphetamine (0.5 mg/kg; s.c.) was administered twice daily during postnatal days 22-34, and then the brains of the animals were evaluated 2 weeks later. This treatment produced an increase in dendritic length and branches of pyramidal neurons of the medial prefrontal cortex, but not in the nucleus accumbens. These changes were associated with an increase in the expression of calcium/calmodulin-dependent protein kinase II, a highly abundant signalling protein in the postsynaptic densities of excitatory synapses. Interestingly, amphetamine pre-treatment did not alter the motor response to various dopamine agonists, including amphetamine. These data suggest that clinical doses of stimulant drugs may be acting as a trophic support at the glutamatergic synapses, thereby enhancing dopamine-glutamate interactions in the prefrontal cortex." [Abstract]

Crowder JM, Bradford HF.
Inhibitory effects of noradrenaline and dopamine on calcium influx and neurotransmitter glutamate release in mammalian brain slices.
Eur J Pharmacol 1987 Nov 17;143(3):343-52
"Noradrenaline and dopamine (0.1-100 microM) inhibited 45Ca2+ uptake and glutamate release induced by veratrine (25 microM) in cortical and striatal slices but were without effect when added alone. Each parameter was inhibited in a dose-dependent manner by noradrenaline in cortical slices (IC50 = 0.05 microM) and by dopamine in striatal slices (IC50 = 0.08 microM). Noradrenaline (0.01-100 microM) was without influence on veratrine-induced 45Ca2+ influx or glutamate release in the striatal preparation, and likewise dopamine was inactive in cortex slices. The use of adrenoceptor antagonists suggests that the action of noradrenaline is mediated by the alpha 2-receptor which is thought to be adenylate cyclase linked. Dopamine appeared to be acting through the D-2 receptor." [Abstract]

Kamisaki Y, Hamahashi T, Okada CM, Itoh T.
Clonidine inhibition of potassium-evoked release of glutamate and aspartate from rat cortical synaptosomes.
Brain Res 1991 Dec 24;568(1-2):193-8
"Release of endogenous glutamic acid (Glu), aspartic acid (Asp) and gamma-aminobutyric acid (GABA) has been investigated using synaptosomes prepared from rat cerebral cortex. Exposure in superfusion to a depolarizing concentration of KCl (30 mM) evoked 3-, 2- and 2-fold increases in Glu, Asp and GABA release, respectively. More than 70% of Glu and Asp overflow were calcium-dependent, although 67% of the GABA overflow was calcium-independent. Clonidine inhibited the K(+)-evoked overflow of Glu and Asp in a concentration-dependent manner, but the GABA overflow was not inhibited. Clonidine inhibited K(+)-evoked Glu and Asp overflow to 40 and 30% of the control with a potency (IC50) of 11 and 36 nM, respectively. Similarly, norepinephrine inhibited the K(+)-evoked overflow of Glu and Asp, although phenylephrine and isoproterenol showed no effect. Rauwolscine, yohimbine and idazoxan counteracted the effects of clonidine on Glu and Asp overflow. The data suggest that the depolarization-evoked overflow of excitatory amino acids is regulated in an inhibitory fashion by alpha 2 adrenoceptors, which are located on the nerve terminals of Glu and Asp neurons in rat cortex." [Abstract]

Yamamoto BK, Davy S.
Dopaminergic modulation of glutamate release in striatum as measured by microdialysis.
J Neurochem 1992 May;58(5):1736-42
"Glutamate and aspartate are the primary neurotransmitters of projections from motor and premotor cortices to the striatum. Release of glutamate may be modulated by dopamine receptors located on corticostriatal terminals. The present study used microdialysis to investigate the dopaminergic modulation of in vivo striatal glutamate and aspartate release in the striatum of awake-behaving rats. Local perfusion with a depolarizing concentration of K+ through a dialysis probe into the rat striatum produced a significant increase in the release of glutamate, aspartate, and taurine. The D2 agonist LY171555 blocked the K(+)-induced release of glutamate and aspartate, but not taurine, in a concentration-dependent manner. The D1 agonist SKF 38393 did not alter K(+)-induced release of glutamate and taurine, but did significantly decrease aspartate release. Neither agonist had any effect on basal amino acid release. The D2 antagonist (-)-sulpiride reversed the inhibitory effects of LY 171555 on K(+)-induced glutamate release. These results provide in vivo evidence for a functional interaction between dopamine, the D2 receptor, and striatal glutamate release." [Abstract]

Peris J, Dwoskin LP, Zahniser NR.
Biphasic modulation of evoked [3H]D-aspartate release by D-2 dopamine receptors in rat striatal slices.
Synapse 1988;2(4):450-6
"It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fibers via presynaptically located D-2 DA receptors although the evidence presented in the literature has not been conclusive. In the present experiments, the effect of D-2 receptor ligands on K+-stimulated tritium release from rat striatal slices preloaded with the nonmetabolizable glutamate analog [3H]D-aspartate ([3H]ASP was measured. The D-2 receptor antagonist S-sulpiride increased stimulated [3H]ASP release by 75% (EC50 value = 240 nM) and the biologically less-active isomer R-sulpiride, although equally effective, was tenfold less potent. The D-2 receptor agonists pergolide and (+)-4-propyl-9-hydroxynapthoxazine (+PHNO) inhibited [3H]ASP release at nM concentrations; however, this effect was small (20%). This low efficacy of the exogenous agonists was apparently due to competition by high concentrations of endogenous DA since the effect of pergolide was increased in rats whose striatal DA levels were decreased by 97%. These data support the hypothesis that D-2 DA receptors modulate [3H]ASP release in an inhibitory fashion. However, when the agonists were tested at lower concentrations, [3H]ASP release was increased significantly by 20% in control rats and 60% in DA-depleted rats. Both the facilitory and inhibitory effects of pergolide were blocked by 10 microM S-sulpiride, suggesting D-2 receptor mediation. In addition, the facilitory effect of pergolide was blocked by tetrodotoxin (TTX) and by the GABAA antagonist bicuculline, implying mediation of this D-2 effect by an inhibitory GABAergic interneuron. The inhibitory effect of pergolide was decreased by the muscarinic antagonist atropine." [Abstract]

Russell VA.
Increased AMPA receptor function in slices containing the prefrontal cortex of spontaneously hypertensive rats.
Metab Brain Dis 2001 Dec;16(3-4):143-9
"Spontaneously hypertensive rats (SHR) are used as a genetic model for attention-deficit hyperactivity disorder (ADHD), since they have behavioral characteristics that mimic the major symptoms of ADHD. We have previously shown that dopaminergic and noradrenergic systems are altered in the prefrontal cortex of SHR compared to normotensive Wistar-Kyoto (WKY) control rats. We also showed that neural circuits that use glutamate as a neurotransmitter increased norepinephrine release from rat prefrontal cortex slices and that glutamate caused significantly greater release of norepinephrine from prefrontal cortex slices of SHR than from those of WKY. The effect of glutamate did not appear to be mediated by NMDA receptors, since NMDA did not exert any effect on norepinephrine release and the NMDA receptor antagonist MK-801 did not reduce the effect of glutamate. In this investigation we show that the stimulatory effect of glutamate is greater in SHR than in WKY and that the effect can be antagonised by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The results suggest that glutamatergic neuron terminals in rat prefrontal cortex establish synaptic contacts with noradrenergic terminals to enhance norepinephrine release by activation of AMPA receptors and that this enhancement is amplified in SHR." [Abstract]

Radisavljevic Z, Cepeda C, Peacock W, Buchwald NA, Levine MS.
Norepinephrine modulates excitatory amino acid-induced responses in developing human and adult rat cerebral cortex.
Int J Dev Neurosci 1994 Jun;12(4):353-61
"These experiments were designed to assess the ability of norepinephrine and its beta-receptor agonist, isoproterenol, to modulate responses induced by activation of excitatory amino acid receptors in brain slices obtained from developing human cortex or adult rat cortex. Human cortical slices were obtained from children undergoing surgery for intractable epilepsy (9 months to 10 yr of age). For comparison, slices were also obtained from rats (2-3 months of age). Iontophoretic application of glutamate, N-methyl-D-aspartate or alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) produced excitatory responses consisting of membrane depolarizations accompanied by action potentials. Iontophoretic or bath application of norepinephrine or isoproterenol enhanced responses evoked by glutamate or N-methyl-D-aspartate. Depolarizations occurred with shorter latencies and their amplitudes increased. Action potential frequency was also increased and responses were of longer duration. In contrast, norepinephrine or isoproterenol had no effect on responses induced by AMPA. The enhancement of responses induced by N-methyl-D-aspartate or glutamate was antagonized by the beta-adrenergic receptor antagonist propranolol. Similar findings were obtained from neurons in humans or rats. These results suggest that norepinephrine, possibly via beta-receptors, potentiates responses mediated by glutamate and N-methyl-D-aspartate receptors without affecting those mediated by AMPA receptors. These effects were observed at all ages studied, indicating that the ability of norepinephrine to modulate excitatory neuronal transmission is well developed in human cortex by 9 months of age." [Abstract]

Gu Q.
Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity.
Neuroscience. 2002;111(4):815-35.
Cortical neuromodulatory transmitter systems refer to those classical neurotransmitters such as acetylcholine and monoamines, which share a number of common features. For instance, their centers are located in subcortical regions and send long projection axons to innervate the cortex. The same transmitter can either excite or inhibit cortical neurons depending on the composition of postsynaptic transmitter receptor subtypes. The overall functions of these transmitters are believed to serve as chemical bases of arousal, attention and motivation. The anatomy and physiology of neuromodulatory transmitter systems and their innervations in the cerebral cortex have been well characterized. In addition, ample evidence is available indicating that neuromodulatory transmitters also play roles in development and plasticity of the cortex. In this article, the anatomical organization and physiological function of each of the following neuromodulatory transmitters, acetylcholine, noradrenaline, serotonin, dopamine, and histamine, in the cortex will be described. The involvement of these transmitters in cortical plasticity will then be discussed. Available data suggest that neuromodulatory transmitters can modulate the excitability of cortical neurons, enhance the signal-to-noise ratio of cortical responses, and modify the threshold for activity-dependent synaptic modifications. Synaptic transmissions of these neuromodulatory transmitters are mediated via numerous subtype receptors, which are linked to multiple signal transduction mechanisms. Among the neuromodulatory transmitter receptor subtypes, cholinergic M(1), noradrenergic beta(1) and serotonergic 5-HT(2C) receptors appear to be more important than other receptor subtypes for cortical plasticity. In general, the contribution of neuromodulatory transmitter systems to cortical plasticity may be made through a facilitation of NMDA receptor-gated processes. [Abstract]

Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.
Neuropsychopharmacology 2002 Nov;27(5):699-711
"The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities." [Abstract]

Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF.
Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine.
J Neurosci 2002 Oct 1;22(19):8771-7
"Norepinephrine strengthens the working memory, behavioral inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic alpha2-adrenoceptors (alpha2-AR). The alpha2-AR agonist guanfacine enhances prefrontal cortical functions in rats, monkeys, and human beings and ameliorates prefrontal cortical deficits in patients with attention deficit hyperactivity disorder. The present study examined the subtype of alpha2-AR underlying these beneficial effects. Because there are no selective alpha2A-AR, alpha2B-AR, or alpha2C-AR agonists or antagonists, genetically altered mice were used to identify the molecular target of the action of guanfacine. Mice with a point mutation of the alpha2A-AR, which serves as a functional knock-out, were compared with wild-type animals and with previously published studies of alpha2C-AR knock-out mice (Tanila et al., 1999). Mice were adapted to handling on a T maze and trained on either a spatial delayed alternation task that is sensitive to prefrontal cortical damage or a spatial discrimination control task with similar motor and motivational demands but no dependence on prefrontal cortex. The effects of guanfacine on performance of the delayed alternation task were assessed in additional groups of wild-type versus alpha2A-AR mutant mice. We observed that functional loss of the alpha2A-AR subtype, unlike knock-out of the alpha2C-AR subtype, weakened performance of the prefrontal cortical task without affecting learning and resulted in loss of the beneficial response to guanfacine. These data demonstrate the importance of alpha2A-AR subtype stimulation for the cognitive functions of the prefrontal cortex and identify the molecular substrate for guanfacine and novel therapeutic interventions." [Abstract]

Golembiowska K, Zylewska A.
Effect of antidepressant drugs on veratridine-evoked glutamate and aspartate release in rat prefrontal cortex.
Pol J Pharmacol 1999 Jan-Feb;51(1):63-70
"In vivo microdialysis in conscious rats was used to evaluate the effect of local application, through a microdialysis probe, of desipramine (DMI), imipramine and citalopram (CIT), on veratridine-evoked glutamate and aspartate release in rat prefrontal cortex (PFCx). All antidepressant drugs (ADs), given at a concentration of 0.1 mM, significantly inhibited glutamate release, while aspartate release was affected only by DMI and CIT. In contrast, local administration of ADs markedly potentiated veratridine-evoked dopamine and noradrenaline release. Perfusion of clonidine, quinpirole and 1-[3-(trifluoro-methyl)phenyl]-piperazine (TFMPP) at 0.1 mM concentration also diminished, evoked release of glutamate and aspartate. The regulation of amino acid release in rat PFCx may be achieved by direct effect of ADs on Na+ channels or indirectly, by involvement of D2/D3, alpha 2 or 5-HT1B heteroceptors activated by the increased level of monoamines in response to the blockade of respective transporters." [Abstract]

Harkin A, Nowak G, Paul IA.
Noradrenergic lesion antagonizes desipramine-induced adaptation of NMDA receptors.
Eur J Pharmacol 2000 Feb 18;389(2-3):187-92
"Repeated administration of the tricyclic antidepressant, desipramine, for 28 days to mice effected a decrease in the potency of glycine to displace [3H]5,7-dichlorokynurenic acid (5,7-DCKA) in mouse cortical homogenates. Pre-treatment with the noradrenergic neurotoxin DSP-4, while having no effect alone, attenuated the desipramine-induced effect. The present findings support a norepinephrine-dependent adaptation of the NMDA receptor complex in vivo following chronic desipramine treatment. The inter-relationship of norepinephrine and glutamate transmission may provide insight into the mechanism underlying the action of antidepressant drugs." [Abstract]

Li X, Eisenach JC.
alpha2A-adrenoceptor stimulation reduces capsaicin-induced glutamate release from spinal cord synaptosomes.
J Pharmacol Exp Ther 2001 Dec;299(3):939-44
"Glutamate (Glu) is involved in excitatory neurotransmission and nociception and plays an essential role in relaying noxious stimuli in the spinal cord. Intrathecal or epidural injection of alpha2-adrenergic agonists produces potent antinociceptive effects, alters spinal neurotransmitter release, and effectively treats acute nociceptive and chronic neuropathic pain. Although it is generally believed that alpha2-adrenergic receptor stimulation reduces excitatory neurotransmitter release from peripheral afferents, the subtype of receptor causing this effect and its specificity to nociceptive neurotransmission have been inadequately studied. We therefore examined the pharmacology of adrenergic agents to inhibit Glu release in spinal cord from stimulation with capsaicin, a specific agonist for receptors on nociceptive afferents. Capsaicin evoked Glu release in synaptosomes from normal rat dorsal spinal cord in a concentration-dependent manner. Glu release from 30 microM capsaicin was inhibited by adrenergic agonists with a relative potency of clonidine = dexmedetomidine > norepinephrine > ST91 >> phenylephrine = 0, consistent with an action on alpha2A/D subtype receptors. Also consistent with this interpretation was the observation that inhibition of capsaicin-induced Glu release by clonidine or dexmedetomidine was blocked by the alpha2A/D antagonist BRL44408 but not by the alpha2B/C-preferring antagonist ARC239. Similar results were obtained in perfused spinal cord slices. These data suggest that capsaicin-evoked Glu release, likely reflecting stimulation of C fiber terminals, can be inhibited by activation of the alpha2A/D subtype, and this action of adrenergic agonists may reflect in part their efficacy in the treatment of acute pain." [Abstract]

Golembiowska K, Dziubina A.
Involvement of adenosine in the effect of antidepressants on glutamate and aspartate release in the rat prefrontal cortex.
Naunyn Schmiedebergs Arch Pharmacol 2001 Jun;363(6):663-70
"The effect of local administration of amitriptyline (AMI), desipramine (DMI) and citalopram (CIT) on veratridine-evoked glutamate (Glu) and aspartate (Asp) release in the prefrontal cortex of the conscious rat was examined using in vivo reverse microdialysis. The antidepressants (each at 100 microM) significantly reduced Glu and Asp release. The effect of AMI and CIT was attenuated by i.p. administration of the adenosine A1/A2A receptor antagonist caffeine (10 mg/kg), or by local infusion of the adenosine A1 receptor antagonist 8-cyclopentyltheophylline (CPT, 75 microM). Neither caffeine nor CPT influenced the effect of DMI (100 microM). The inhibitory action of DMI at a lower concentration (50 microM) was diminished significantly by CPT, but not caffeine. Perfusion of 5-hydroxytryptamine (5-HT; 100 microM) and the selective agonist of adenosine A1 receptors N6-cyclopentyladenosine (CPA; 50 and 100 microM) also suppressed Glu and Asp release. It is suggested that the blockade of the cellular uptake of adenosine, or indirect enhancement of its release, and subsequent activation of adenosine A1 receptors may be responsible for the inhibitory effect of antidepressants on Glu and Asp release." [Abstract]

Fredriksson A, Archer T.
Hyperactivity following postnatal NMDA antagonist treatment: reversal by D-amphetamine.
Neurotox Res. 2003;5(7):549-64.
"Three experiments were performed to study the effects of neonatal administration of glutamate receptor antagonists, on either Day 11 (dizocilpine = MK-801, 3 x 0.5 mg/kg, s.c., injected at 0800, 1600 and 2400 h) or Day 10 (Ketamine, 1 x 50 mg/kg, s.c., or Ethanol-Low, 1 x 2.5 mg/kg, or, Ethanol-High, 2 x 2.5 mg/kg, s.c., with 2-h interval) to male mice pups, on spontaneous motor behavior, habituation to a novel situation and D-amphetamine-induced activity in the adult animals. Mice administered MK-801 showed initial hypoactivity followed by hyperactivity over the later (20-40 and 40-60 min) periods of testing. Mice administered Ketamine and Ethanol-High similarly displayed an initial hypoactivity followed by hyperactivity over the later time (20-60 min) of testing. Habituation to the novel activity test chambers was reduced drastically in the MK-801 mice compared with vehicle-treated mice. Similarly, mice administered Ketamine and Ethanol-High displayed too drastically reduced habituation behavior. The low dose of D-amphetamine (0.25 mg/kg) reduced the hyperactivity of neonatal MK-801-treated mice, particularly from 30-60 min onwards, and elevated the activity level of the vehicle-treated mice. Similarly, the low dose of D-amphetamine (0.25 mg/kg) reduced the hyperactivity of neonatally Ketamine-treated and Ethanol-High-treated mice, particularly from 30-60 min onwards, and elevated the activity level of the respective vehicle-treated mice. Fluoro-jade staining per mm(2) regional brain tissue of MK-801 mice pups expressed as percent of vehicle mice pups showed also that the extensiveness of staining was markedly greater in the parietal cortex, hippocampus, frontal cortex, and lesser so in the laterodorsal thalamus. Ketamine-treated mice showed cell degeneration mainly in the parietal cortex, whereas the Ethanol-High mice showed marked cell degeneration in both the parietal and laterodorsal cortex. The present findings that encompass a pattern of regional neuronal degeneration, disruptions of spontaneous motor activity, habituation deficits and reversal of hyperactivity by a low dose of D-amphetamine suggest a model of Attention Deficit Hyperactivity Disorder that underlines the intimate role of N-methyl-D-aspartate (NMDA) receptors in the developing brain." [Abstract]

Lehohla M, Kellaway L, Russell VA.
NMDA receptor function in the prefrontal cortex of a rat model for attention-deficit hyperactivity disorder.
Metab Brain Dis. 2004 Jun;19(1-2):35-42.
"The spontaneously hypertensive rat (SHR) is an accepted model for attention-deficit hyperactivity disorder (ADHD) since it displays the major symptoms of ADHD (hyperactivity, impulsivity, and poor performance in tasks that require sustained attention). We have previously shown that glutamate activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors released significantly more norepinephrine from SHR prefrontal cortex slices than control Wistar-Kyoto (WKY) rats. The aim of this study was to determine whether N-methyl-D-aspartate (NMDA) receptor function is disturbed in the prefrontal cortex of SHR. Prefrontal cortex slices were incubated with 45Ca2+ in the presence or absence of 100 microM NMDA for 2 min. Activation of NMDA receptors stimulated significantly less Ca2+ uptake into prefrontal cortex slices of SHR than control WKY (2.8 +/- 0.17 vs. 3.7 +/- 0.38 nmol/mg protein, respectively, P < 0.05). Basal Ca2+ uptake into SHR slices was not significantly different from WKY. These findings are consistent with suggestions that the intracellular concentration of calcium is elevated and therefore the concentration gradient that drives calcium into the cell is decreased in SHR compared to WKY. Impaired NMDA receptor function in the prefrontal cortex of SHR could give rise to impaired cognition and an inability to sustain attention." [Abstract]