MacMaster FP, Carrey N, Sparkes S, Kusumakar V.
spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder.
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]
H, Hooper SR, Fine C, Kwock L, Castillo M.
and neuropsychological correlates in children with ADHD-H: preliminary findings.
Neuropsychiatry Clin Neurosci. 2004 Winter;16(1):63-9.
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]
N, MacMaster FP, Sparkes SJ, Khan SC, Kusumakar V.
changes with treatment in attention deficit hyperactivity disorder: a preliminary
J Child Adolesc Psychopharmacol 2002 Winter;12(4):331-6
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]
N, MacMaster FP, Fogel J, Sparkes S, Waschbusch D, Sullivan S, Schmidt M.
changes resulting from treatment in children with ADHD: a 1H-MRS study.
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]
T, Honda Y, Watanabe M, Hikosaka K.
Release of neurotransmitters
in the monkey frontal cortex is related to level of attention.
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.
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]
JM, Bradford HF.
Inhibitory effects of noradrenaline and dopamine
on calcium influx and neurotransmitter glutamate release in mammalian brain slices.
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
Y, Hamahashi T, Okada CM, Itoh T.
Clonidine inhibition of potassium-evoked
release of glutamate and aspartate from rat cortical synaptosomes.
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]
BK, Davy S.
Dopaminergic modulation of glutamate release in striatum
as measured by microdialysis.
J Neurochem 1992 May;58(5):1736-42
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
J, Dwoskin LP, Zahniser NR.
Biphasic modulation of evoked [3H]D-aspartate
release by D-2 dopamine receptors in rat striatal slices.
"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
Increased AMPA receptor function in slices containing the prefrontal
cortex of spontaneously hypertensive rats.
Metab Brain Dis
"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."
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]
Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity.
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.
increases extracellular levels of norepinephrine and dopamine in prefrontal cortex
of rat: a potential mechanism for efficacy in attention deficit/hyperactivity
Neuropsychopharmacology 2002 Nov;27(5):699-711
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]
JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF.
of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive
enhancement by guanfacine.
J Neurosci 2002 Oct 1;22(19):8771-7
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
Pol J Pharmacol 1999 Jan-Feb;51(1):63-70
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.
lesion antagonizes desipramine-induced adaptation of NMDA receptors.
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]
X, Eisenach JC.
alpha2A-adrenoceptor stimulation reduces capsaicin-induced
glutamate release from spinal cord synaptosomes.
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]
K, Dziubina A.
Involvement of adenosine in the effect of antidepressants
on glutamate and aspartate release in the rat prefrontal cortex.
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]
A, Archer T.
Hyperactivity following postnatal NMDA antagonist treatment:
reversal by D-amphetamine.
Neurotox Res. 2003;5(7):549-64.
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
M, Kellaway L, Russell VA.
NMDA receptor function in the prefrontal
cortex of a rat model for attention-deficit hyperactivity disorder.
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]