|
Danysz W.
CX-516 Cortex
pharmaceuticals.
Curr Opin Investig Drugs 2002 Jul;3(7):1081-8
"CX-516
is one of a series of AMPA modulators under development by Cortex, in collaboration
with Shire and Servier, for the potential treatment of Alzheimer's disease (AD),
schizophrenia and mild cognitive impairment (MCI) [234221]. By June 2001, CX-516
was in phase II trials for both schizophrenia and attention deficit hyperactivity
disorder (ADHD) [412513]. A phase II trial in fragile X syndrome and autism was
expected to start in May 2002 [449861]. In October 2001, Cortex was awarded a
Phase II SBIR grant of $769,818 from the National Institutes of Mental Health
to investigate the therapeutic potential of AMPAkines in schizophrenia. This award
was to support a phase IIb study of CX-516 as a combination therapy in schizophrenia
patients concomitantly treated with olanzapine. The trial was to enroll 80 patients
and employ a randomized, double-blind, placebo-controlled design in which the
placebo group was to receive olanzapine plus placebo and the active group was
to receive olanzapine plus CX-516 [425982]. In April 2000, Shire and Cortex signed
an option agreement in which Shire was to evaluate CX-516for the treatment of
ADHD. Under the terms of the agreement, Shire would undertake a double-blind,
placebo-controlled evaluation of CX-516 involving ADHD patients. If the study
proved effective, Shire would have the right to convert its option into an exclusive
worldwide license for the AMPAkines for ADHD under a development and licensing
agreement. Should Shire elect to execute this agreement, Shire would bear all
future developmental costs [363618]. By February 2002, Cortex and Servier had
revealed their intention to begin enrolment for an international study of an AMPAkine
compound as a potential treatment for MCI in the near future. Assuming enrollment
proceeded as anticipated, results were expected during the second quarter of 2003
[439301]. By May 2002, phase II trials were underway [450134]. In March 2002,
Cortex was awarded extended funding under the University of California BioSTAR
projectfor the research project: 'Ampakine modulation of brain neurotrophin expression:
a novel therapeutic strategy'. This funding was expected to amount to $193,000
over a two-year period [444872]." [Abstract]
Johnson SA, Simmon VF.
Randomized, double-blind,
placebo-controlled international clinical trial of the Ampakine CX516 in elderly
participants with mild cognitive impairment: a progress report.
J
Mol Neurosci 2002 Aug-Oct;19(1-2):197-200
"This progress report briefly
describes the rationale and study design for the first cross-national clinical
study of a positive AMPA-type glutamate receptor modulator in subjects with mild
cognitive impairment (MCI). The study medication for the double-blind, placebo-controlled
trial, the AMPAKINE CX516, represents a novel pharmacological approach to the
treatment of memory disorders. Previous preclinical and pilot clinical studies
have shown that CX516 has the ability to enhance memory and cognition. Design
of the trial, including outcome measures and inclusion criteria, was aided by
an international panel of experts in the newly emerging field of MCI." [Abstract] Ingvar
M, Ambros-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch
G.
Enhancement by an ampakine of memory encoding in humans.
Exp
Neurol 1997 Aug;146(2):553-9
"Acentrally active drug that enhances AMPA
receptor-mediated currents was tested for its effects on memory in humans. Evidence
for a positive influence on encoding was obtained in four tests: (i) visual associations,
(ii) recognition of odors, (iii) acquisition of a visuospatial maze, and (iv)
location and identity of playing cards. The drug did not improve scores in a task
requiring cued recall of verbal information. The selectivity of drug effects on
memory was confirmed using tests of visual recognition, motor performance, and
general intellectual functioning. These results suggest that positive modulators
of AMPA receptors selectively improve at least some aspects of memory." [Abstract] Lynch
G, Granger R, Ambros-Ingerson J, Davis CM, Kessler M, Schehr R.
Evidence
that a positive modulator of AMPA-type glutamate receptors improves delayed recall
in aged humans.
Exp Neurol 1997 May;145(1):89-92
"Elderly
subjects (65-76 years) were tested for recall of nonsense syllables prior to and
after oral administration of 1-(quinoxalin-6 ylcarbonyl)piperidine (CX516), a
centrally active drug that enhances currents mediated by AMPA-type glutamate receptors.
A significant and positive drug effect was found for delayed (5 min) recall at
75 min posttreatment; average scores for the highest dose group were more than
twofold greater than for the placebo group. The drug had no evident influence
on heart rate or self-assessment of several psychological variables." [Abstract] Lynch
G, Kessler M, Rogers G, Ambros-Ingerson J, Granger R, Schehr RS.
Psychological
effects of a drug that facilitates brain AMPA receptors.
Int
Clin Psychopharmacol 1996 Mar;11(1):13-9
"The effects of 1-(quinoxalin-6-ylcarbonyl)piperidine
(CX516), a centrally active compound that facilitates AMPA receptor-mediated synaptic
responses, were tested in human subjects. Separate tests of delayed recall were
given prior to and nearly 3 h after administration of placebo (n = 12) or drug
(n = 36). Control subjects exhibited poorer performance in the second session
than in the first while subjects given 600-1200 mg of the drug did not. There
were no pre- vs post-treatment differences in immediate recall in either group.
The drug did not reliably affect self-assessment scores for any of several psychological
variables but did disrupt the normally present correlations for within-subject
changes in the variables. These results suggest that AMPA receptor modulators
may (1) improve memory under some circumstances and (2) produce psychological
effects that are subtle or not related to specific mood states." [Abstract] Larson
J, Lieu T, Petchpradub V, LeDuc B, Ngo H, Rogers GA, Lynch G.
Facilitation
of olfactory learning by a modulator of AMPA receptors.
J
Neurosci 1995 Dec;15(12):8023-30
"The effects of a benzoyl-piperidine
drug (BDP) that facilitates AMPA receptor-mediated synaptic responses were tested
on the acquisition and retention of long-term memory at dosages that had no detectable
effects on a variety of performance measures. BDP-12 produced a dose-dependent
suppression of exploratory activity in rats with statistically reliable effects
occurring at 50 mg/kg (i.p.). The drug had no effects on balance beam performance
at 30 mg/kg but at 45 mg/kg reduced the number of crossings made within a session;
it did not, however, affect the time required to perform a traversal. The performance
of well-trained rats presented with a familiar pair of odors (correct and incorrect)
was not not detectably altered by BDP-12 at 30 mg/kg; however, the number of correct
responses made in a five-trial test was reduced at 45 mg/kg. These results indicate
that the AMPA receptor modulator at 30 mg/kg has little influence on arousal,
motivation, sensori-motor processing, and attention; higher dosages cause a depression
of learned and unlearned prepotent responses. The effects of the lower concentration
were tested on two-odor discrimination learning in rats that had extensive training
on the task. The animals (n = 20) were given three or five acquisition trials
with novel odor pairs immediately after an injection of drug or vehicle and then
tested 1-3 d later for retention in five unrewarded probe trials. Retention performance
was not significantly better than chance 52.6 +/- 4.5% correct) for odors learned
on vehicle injection days but was well above chance for odors learned on drug
injection days (70.6 +/- 4.2% correct). Within-subject comparisons confirmed the
memory enhancing effect of BDP-12 (p < 0.01). Analyses of performance during
five training trials indicated that the rats made more correct responses on days
on which they were given the drug than on days on which they were injected with
vehicle (p < 0.02). Within-subject differences in acquisition were correlated
with differences in retention (r = 0.70). There were no evident effects of the
drug on response latencies during acquisition. These results suggest that AMPA
receptor modulators reduce the amount of training needed for the formation of
long-term memory and do so at dosages which have little effect on variables that
secondarily influence acquisition. Possible reasons for this selectivity are discussed."
[Abstract]
Staubli U, Izrael Z, Xu F.
Remembrance
of odors past: enhancement by central facilitation of AMPA receptors.
Behav
Neurosci 1996 Oct;110(5):1067-73
"Pharmacological facilitation of the
alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptor has
recently been demonstrated to enhance synaptic responses, promote long-term potentiation
(LTP) induction in freely moving rats, and facilitate learning and retention of
information. The present study verifies and extends the behavioral action of allosteric
AMPA receptor modulation by showing that the benzoyl-piperidine compound BDP-12
promotes retention of olfactory and transient spatial memory in a dose-dependent
fashion; is only effective when given before but not after training, consistent
with the hypothesis that glutamatergic facilitation enhances information encoding
by means of action on the machinery involved in LTP induction; and, following
suboptimal training in a paradigm of enduring memory, prolongs the ability of
rats to retain odors by extending the decay of weak memory traces." [Abstract]
Yamada
KA.
Modulating excitatory synaptic neurotransmission: potential treatment
for neurological disease?
Neurobiol Dis 1998 Aug;5(2):67-80
"Excitatory
neurotransmission at many CNS synapses depends upon AMPA-type glutamate receptors.
Derangements in AMPA receptor-mediated synaptic transmission may be a contributing
factor in neurological and neurodegenerative diseases and could be a target for
therapeutic intervention. Drugs that positively modulate AMPA receptors by reducing
AMPA receptor desensitization and/or slowing AMPA receptor deactivation, such
as thiazide derivative (cyclothiazide, diazoxide, IDRA 21) and benzoylpiperidine
derivatives (1-BCP, CX516, aniracetam), facilitate AMPA receptor-mediated processes
and may have beneficial therapeutic effects. For example, AMPA modulators facilitate
long-term potentiation, which may be important for memory storage, and facilitate
memory encoding in behavioral experiments. Thus, AMPA modulators might ameliorate
memory deficits that occur in dementia, such as Alzheimer's disease." [Abstract]
Arai AC, Xia YF, Suzuki E.
Modulation
of AMPA receptor kinetics differentially influences synaptic plasticity in the
hippocampus.
Neuroscience. 2004;123(4):1011-24.
"Prior
studies showed that positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve
the formation of several types of memory in animals and humans. However, these
modulators are highly diverse in their effects on receptor kinetics and synaptic
transmission and thus may differ also in their efficacy to promote changes in
synaptic strength. The present study examined three of these modulators for their
effects on synaptic plasticity in field CA1 of hippocampal slices, two of them
being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine
(CX546) which prominently enhance synaptic transmission yet differ in their relative
impact on amplitude versus duration of the synaptic response. The third drug was
cyclothiazide which potently blocks AMPA receptor desensitization. Effects on
plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation
when using theta-burst stimulation with three instead of four pulses per burst,
(ii) the maximum amount of potentiation under optimal stimulation conditions,
and (iii) the effect on long-term depression (LTD). Both benzamides facilitated
the formation of stable potentiation induced with three-pulse burst stimulation
which is normally ineffective. CX546 in addition increased maximally inducible
potentiation after four-pulse burst stimulation from about 50% to 100%. Burst
response analysis revealed that CX546 greatly prolonged the duration of depolarization
by slowing the decay of the response which thus presumably leads to a more continuous
N-methyl-D-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective
in increasing maximal potentiation in either field or whole-cell recordings. CX546,
but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term
depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant
NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on
currents mediated by these receptors. These results suggest that (1) modulation
of AMPA receptors which increases either response amplitude or duration can facilitate
LTP formation, (2) modulators that effectively slow response deactivation augment
the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have
a minor impact on synaptic plasticity in the hippocampus.Taken together, our data
indicate that AMPA receptor modulators differ substantially in their ability to
enhance synaptic potentiation or depression, depending on their particular influence
on receptor kinetics, and hence that they may also be differentially effective
in influencing higher-order processes such as memory encoding." [Abstract] Arai,
Amy C., Kessler, Markus, Rogers, Gary, Lynch, Gary
Effects of the
Potent Ampakine CX614 on Hippocampal and Recombinant AMPA Receptors: Interactions
with Cyclothiazide and GYKI 52466
Mol Pharmacol 2000 58:
802-813
"R,S-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor up-modulators of the benzamide type ("ampakines") have
previously been shown to enhance excitatory synaptic transmission in vivo and
in vitro and AMPA receptor currents in excised patches. The present study analyzed
the effects of an ampakine (CX614; 2H,3H, 6aH-pyrrolidino[2",1"-3',2']1,3-oxazino[6',5'-5,4]benz
o[e]1, 4-dioxan-10-one) that belongs to a benzoxazine subgroup characterized by
greater structural rigidity and higher potency. CX614 enhanced the size (amplitude
and duration) of field excitatory postsynaptic potentials in hippocampal slices
and autaptically evoked excitatory postsynaptic currents in neuronal cultures
with EC(50) values of 20 to 40 microM. The compound blocked desensitization (EC(50)
= 44 microM) and slowed deactivation of responses to glutamate by a factor of
8.4 in excised patches. Currents through homomeric, recombinant AMPA receptors
were enhanced with EC(50) values that did not differ greatly across GluR1-3 flop
subunits (19-37 microM) but revealed slightly lower potency at corresponding flip
variants. Competition experiments using modulation of [(3)H]fluorowillardiine
binding suggested that CX614 and cyclothiazide share a common binding site but
cyclothiazide seems to bind to an additional site not recognized by the ampakine.
CX614 did not reverse the effect of GYKI 52466 on responses to brief glutamate
pulses, which indicates that they act through separate sites, a conclusion that
was confirmed in binding experiments. In sum, these results extend prior evidence
that ampakines are effective in enhancing synaptic responses, most likely by slowing
deactivation, and that their effects are exerted through sites that are only in
part shared with other modulators." [Full
Text] Lauterborn JC, Truong GS, Baudry M, Bi X,
Lynch G, Gall CM
Chronic elevation of brain-derived neurotrophic
factor by ampakines.
J Pharmacol Exp Ther. 2003 Oct;307(1):297-305.
Epub 2003 Jul 31.
"The ampakine CX614 positively modulates alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic
acid (AMPA) receptor-gated currents and increases brain-derived neurotrophic factor
(BDNF) expression. In rat hippocampal slice cultures, CX614 rapidly increases
BDNF gene expression but with time, mRNA levels fall despite the continued presence
of active drug. The present study examined this apparent refractory period and
the possibility that spaced ampakine treatments could sustain elevated BDNF protein
levels. In cultured hippocampal slices, CX614, a second ampakine CX546, and the
cholinergic agonist carbachol each increased BDNF mRNA levels with acute (3-h)
treatment. After 4-day pretreatment with CX614, fresh ampakine (CX614 or CX546)
did not induce BDNF mRNA, whereas carbachol did. Western blots confirmed that
after an extended period of ampakine treatment, AMPA receptor protein levels are
indeed reduced, suggesting that with longer treatments receptor down-regulation
mediates ampakine insensitivity. Finally, using a "24-h on/24-h off"
CX614 treatment protocol, the ampakine refractory state was circumvented, BDNF
mRNA was induced with each ampakine application, and elevated BDNF protein levels
were maintained through 5 days in vitro. These results suggest that spaced ampakine
treatments can be used to sustain elevated neurotrophin levels and to test the
utility of this manipulation for neuroprotection by endogenous neurotrophins."
[Abstract]
Lauterborn,
Julie C., Lynch, Gary, Vanderklish, Peter, Arai, Amy, Gall, Christine M.
Positive
Modulation of AMPA Receptors Increases Neurotrophin Expression by Hippocampal
and Cortical Neurons
J. Neurosci. 2000 20: 8-21
"This
study investigated whether positive modulators of AMPA-type glutamate receptors
influence neurotrophin expression by forebrain neurons. Treatments with the ampakine
CX614 markedly and reversibly increased brain-derived neurotrophic factor (BDNF)
mRNA and protein levels in cultured rat entorhinal/hippocampal slices. Acute effects
of CX614 were dose dependent over the range in which the drug increased synchronous
neuronal discharges; threshold concentrations for acute responses had large effects
on mRNA content when applied for 3 d. Comparable results were obtained with a
second, structurally distinct ampakine CX546. Ampakine-induced upregulation was
broadly suppressed by AMPA, but not NMDA, receptor antagonists and by reducing
transmitter release. Antagonism of L-type voltage-sensitive calcium channels blocked
induction in entorhinal cortex but not hippocampus. Prolonged infusions of suprathreshold
ampakine concentrations produced peak BDNF mRNA levels at 12 hr and a return to
baseline levels by 48 hr. In contrast, BDNF protein remained elevated throughout
a 48 hr incubation with the drug. Nerve growth factor mRNA levels also were increased
by ampakines but with a much more rapid return to control levels during chronic
administration. Finally, intraperitoneal injections of CX546 increased hippocampal
BDNF mRNA levels in aged rats and middle-aged mice. The present results provide
evidence of regional differences in mechanisms via which activity regulates neurotrophin
expression. Moreover, these data establish that changes in synaptic potency produce
sufficient network level physiological effects for inducing neurotrophin genes,
indicate that the response becomes refractory during prolonged ampakine exposure,
and raise the possibility of using positive AMPA modulators to regulate neurotrophin
levels in aged brain." [Full
Text] Black MD, Wotanis J, Schilp DE, Hanak SE,
Sorensen SM, Wettstein JG.
Effect of AMPA receptor modulators on
hippocampal and cortical function.
Eur J Pharmacol 2000
Apr 7;394(1):85-90
"Attention has focused on drugs that modulate AMPA
(alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because
of their potential for enhancing memory and treating certain pathologies that
involve glutamatergic neurotransmission. The aim of this study was to compare
and contrast the functionality of positive allosteric modulators of AMPA receptors
in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs
(excitatory postsynaptic potential) in the hippocampus were augmented by CX516
[(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine]
and not by cyclothiazide. Using grease gap electrophysiology, it was found that
the mode of application dramatically altered the effect of the modulators of AMPA-induced
depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516
augmented the response in the frontal cortex. However, in the hippocampus, only
aniracetam and cyclothiazide augmented the response when simultaneously added
to AMPA. Therefore, in addition to regional variations, there appears to be differences
in modulator response dependent upon whether a response is generated endogenously
or exogenously by AMPA." [Abstract]
Arai
A, Lynch G.
The waveform of synaptic transmission at hippocampal
synapses is not determined by AMPA receptor desensitization.
Brain
Res 1998 Jul 20;799(2):230-4
"Relationships between the kinetic properties
of AMPA receptors and the decay phase of fast excitatory transmission were investigated
using modulatory drugs. The benzothiadiazide compound cyclothiazide blocked receptor
desensitization in patches excised from hippocampus but had only a weak influence
on receptor deactivation, i.e., on the decay of responses produced by a 1-ms pulse
of glutamate. The ampakine drug CX516 (BDP-12) produced an opposite pattern of
effects: a fourfold slowing of deactivation with little change in desensitization.
A structurally related drug (CX554 or BDP-20) had prominent effects on both desensitization
and deactivation. The halfwidth of field EPSPs measured in the CA1 region of hippocampal
slices increased 50-100% in the presence of CX516 or CX554 but by less than 15%
at concentrations of cyclothiazide that fully blocked desensitization in patch
experiments. These results indicate that receptor deactivation plays a substantially
greater role than receptor desensitization in determining the duration of synaptic
responses." [Abstract] Brent
D. Holst, Peter W. Vanderklish, Leslie A. Krushel, Wei Zhou, Ronald B. Langdon,
John R. McWhirter, Gerald M. Edelman, and Kathryn L. Crossin
Allosteric
modulation of AMPA-type glutamate receptors increases activity of the promoter
for the neural cell adhesion molecule, N-CAM
PNAS 95: 2597-2602,
1997.
"To study regulation in vivo of the promoter for the neural cell
adhesion molecule, N-CAM, we have used homologous recombination to insert the
bacterial lacZ gene between the transcription and translation initiation sites
of the N-CAM gene. This insertion disrupts the gene and places the expression
of beta-galactosidase under the control of the N-CAM promoter. Animals homozygous
for the disrupted allele did not express N-CAM mRNA or protein, but the pattern
of beta-galactosidase expression in heterozygous and homozygous embryos was similar
to that of N-CAM mRNA in wild-type animals. The homozygotes exhibited many of
the morphological abnormalities observed in previously reported N-CAM knockout
mice, with the exception that hippocampal long-term potentiation in the Schaffer
collaterals was identical in homozygous, heterozygous, and wild-type animals.
Heterozygous mice were used to examine the regulation of the N-CAM promoter in
response to enhanced synaptic transmission. Treatment of the mice with an ampakine,
an allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptors that enhances normal glutamate-mediated synaptic transmission,
increased the expression of beta-galactosidase in vivo as well as in tissue slices
in vitro. Similar treatments also increased the expression of N-CAM mRNA in the
heterozygotes. The effects of ampakine in slices were strongly reduced in the
presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist.
Taken together, these results indicate that facilitation of AMPA receptor-mediated
transmission leads to activation of the N-CAM promoter and provide support for
the hypothesis that N-CAM synthesis is regulated in part by synaptic activity."
[Full Text]
Arai
A, Kessler M, Rogers G, Lynch G.
Effects of a memory-enhancing drug
on DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents
and synaptic transmission in hippocampus.
J Pharmacol Exp
Ther 1996 Aug;278(2):627-38
"The benzoylpiperidine drug BDP-12 (1-(quinoxalin-6-ylcarbonyl)piperidine)
enhances the encoding of transient and stable forms of memory by rats. Results
reported here show that the drug increases fast, excitatory (glutamatergic) synaptic
responses in hippocampal slices by about 50% with an EC50 of 170 microM. Analyses
with polysynaptic responses indicated that the drug has a facilitatory action
at concentrations as low as 12.5 microM. BDP-12 at 1 mM did not change the resting
membrane potential, input resistance or spiking threshold and it did not alter
monosynaptic potentials mediated by gamma-aminobutyric acid (GABA) receptors;
it did, however, enhance disynaptic inhibitory responses. In membrane patches
excised from hippocampal neurons, BDP-12 at moderate concentrations (50 microM)
increased the steady-state currents mediated by DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptors and slowed the rate at which the receptors desensitize,
with a much larger effect on the former; the drug delayed the closing of the AMPA
receptor channel after 1-msec agonist pulses. BDP-12 had no detectable effect
on [3H]AMPA binding affinity. A related and more potent analog produced a different
pattern of results in that it had about equal effects on steady-state currents
and desensitization rates and significantly increased binding to AMPA receptors.
These results indicate that the benzoylpiperidine family of modulators has functionally
distinct subclasses. The findings also establish that BDP-12: 1) enhances synaptic
responses in the same concentration range at which it alters AMPA receptor kinetics,
2) has a lower apparent threshold for effects on complex network operations than
on monosynaptic transmission, 3) does not directly influence inhibitory responses
and 4) is likely to modulate AMPA receptors on interneurons as well as on pyramidal
neurons." [Abstract]
Goff
DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, Johnson SA, Lynch G.
A
placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia.
J Clin Psychopharmacol 2001 Oct;21(5):484-7
"CX516, a positive modulator
of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
receptor, improves performance in tasks requiring learning and memory in animals.
CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding (N =
6) and fixed-dose (N = 13) trials. CX516 was tolerated well and was associated
with moderate to large, between-group effect sizes compared with placebo, representing
improvement in measures of attention and memory. These preliminary results suggest
that CX516 and other "ampakines" hold promise for the treatment of schizophrenia."
[Abstract] Marenco
S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G, Weinberger DR.
Preliminary
experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia:
a case series.
Schizophr Res 2002 Oct 1;57(2-3):221-6
"We
used L-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxasole
propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled
design in a small series of patients with schizophrenia who were partially refractory
to treatment with traditional neuroleptics. The study entailed weekly increments
in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients
were followed with clinical ratings, neuropsychological testing, and were monitored
for adverse events. Four patients received 2 to 4 weeks of CX516, two received
placebo and two withdrew during the placebo phase. Adverse events associated with
drug administration were transient and included leukopenia in one patient and
elevation in liver enzymes in another. No clear improvement in psychosis or in
cognition was observed over the course of the study. CX516 at the doses tested
did not appear to yield dramatic effects as a sole agent, but inference from this
study is limited." [Abstract] Johnson,
Steven A., Luu, Nguyen T., Herbst, Todd A., Knapp, Richard, Lutz, David, Arai,
Amy, Rogers, Gary A., Lynch, Gary
Synergistic Interactions between
Ampakines and Antipsychotic Drugs
J Pharmacol Exp Ther 1999
289: 392-397
"Tests were made for interactions between antipsychotic drugs
and compounds that enhance synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid-type glutamate receptors ("ampakines"). Typical and atypical
antipsychotic drugs decreased methamphetamine-induced hyperactivity in rats; the
effects of near or even subthreshold doses of the antipsychotics were greatly
enhanced by the ampakines. Interactions between the ampakine CX516 and low doses
of different antipsychotics were generally additive and often synergistic. The
ampakine did not exacerbate neuroleptic-induced catalepsy, indicating that the
interaction between the different pharmacological classes was selective. These
results suggest that positive modulators of cortical glutamatergic systems may
be useful adjuncts in treating schizophrenia." [Full
Text] | Lynch
G.
Memory and the brain: unexpected chemistries and a new pharmacology.
Neurobiol
Learn Mem 1998 Jul-Sep;70(1-2):82-100
"Efforts to characterize long-term
potentiation (LTP) and to identify its substrates have led to the discovery of
novel synaptic chemistries, computational algorithms, and, most recently, pharmacologies.
Progress has also been made in using LTP to develop a "standard model"
of how unusual, but physiologically plausible, levels of afferent activity create
lasting changes in the operating characteristics of synapses in the cortical telencephalon.
Hypotheses of this type typically distinguish induction, expression, and consolidation
stages in the formation of LTP. Induction involves a sequence consisting of theta-type
rhythmic activity, suppression of inhibitory currents, intense synaptic depolarization,
NMDA receptor activation, and calcium influx into dendritic spines. Calcium-dependent
lipases, kinases, and proteases have been implicated in LTP induction. Regarding
the last group, it has been recently reported that theta pattern stimulation activates
calpain and that translational suppression of the protease blocks potentiation.
It is thus likely that proteolysis is readily driven by synaptic activity and
contributes to structural reorganization. LTP does not interact with treatments
that affect transmitter release, has a markedly differential effect on the currents
mediated by colocalized AMPA vs NMDA synaptic receptors, changes the waveform
of the synaptic current, modifies the effects of drugs that modulate AMPA receptors,
and is sensitive to the subunit composition of those receptors. These results
indicate that LTP is expressed by changes in AMPA receptor operations. LTP is
accompanied by modifications in the anatomy of synapses and spines, something
which accounts for its extreme duration (weeks). As with various types of memory,
LTP requires about 30 min to consolidate (become resistant to disruption). Consolidation
involves adhesion chemistries and, in particular, activation of integrins, a class
of transmembrane receptors that control morphology in numerous cell types. Platelet
activating factor and adenosine may contribute to consolidation by regulating
the engagement of latent integrins. How consolidation stabilizes LTP expression
is a topic of intense investigation but probably involves modifications to one
or more of the following: membrane environment of AMPA receptors; access of regulatory
proteins (e.g., kinases, proteases) to the receptors; receptor clustering; and
space available for receptor insertion. Attempts to enhance LTP have focused on
the induction phase and resulted in a class of centrally active drugs ("ampakines")
that positively modulate AMPA receptors. These compounds promote LTP in vivo and
improve the encoding of variety of memory types in animals. Positive results have
also been obtained in preliminary studies with humans." [Abstract] Lee
HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL.
Regulation of
distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity.
Nature.
2000 Jun 22;405(6789):955-9.
"Bidirectional changes in the efficacy of
neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP)
and long-term depression (LTD), are thought to be mechanisms for information storage
in the brain. LTP and LTD may be mediated by the modulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazloe
proprionic acid) receptor phosphorylation. Here we show that LTP and LTD reversibly
modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary
to the hypothesis that LTP and LTD are the functional inverse of each other, we
find that they are associated with phosphorylation and dephosphorylation, respectively,
of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends
on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates
the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated
synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site
is dephosphorylated. Conversely, LTP induction in naive synapses and depressed
synapses increases phosphorylation of the CaMKII site and the PKA site, respectively.
LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the
history of the synapse. These results indicate that AMPA receptor phosphorylation
is critical for synaptic plasticity, and that identical stimulation conditions
recruit different signal-transduction pathways depending on synaptic history."
[Abstract] Hampson,
Robert E., Rogers, Gary, Lynch, Gary, Deadwyler, Sam A.
Facilitative
Effects of the Ampakine CX516 on Short-Term Memory in Rats: Enhancement of Delayed-Nonmatch-to-Sample
Performance
J. Neurosci. 1998 18: 2740-2747
"Ampakines
are a family of drugs that selectively increase AMPA receptor-gated currents and
improve performance on several behavioral tasks. This report describes evidence
that ampakines cause a cumulative enhancement of performance in a spatial short-term
memory task (Deadwyler et al., 1996). Two groups of rats were trained on a spatial
variant of the delayed-nonmatch-to-sample (DNMS) paradigm. One group (n = 12)
received the ampakine CX516 (Cortex Pharmaceuticals) alternated with vehicle for
17 consecutive days and then only vehicle for an additional 7 d. The second group
(n = 6) received only vehicle injections over the same number of days. CX516 improved
performance within sessions, particularly on trials with delays of 6-35 sec. In
9 of 12 rats, the positive effect of the drug was also present on nondrug days
between CX516 administration and after cessation of CX516 injections. The animals
that received only vehicle injections showed no improvement in DNMS performance
over the entire 32 d of testing. Three of the 12 animals given CX516 did not exhibit
"carryover" effects of the drug to the intervening (vehicle only) test
sessions, but nonetheless exhibited superior performance during the first half
of the session on days in which the ampakine was administered. Evaluation of errors
suggests that the ampakine eliminated the necessity for a shift in response strategy
that produced proactive interference on the following trial. Hippocampal involvement
in these ampakine effects is discussed as a prelude to the second article in the
series (Hampson et al., 1998)." [Full
Text]
Hampson, Robert E., Rogers, Gary, Lynch,
Gary, Deadwyler, Sam A.
Facilitative Effects of the Ampakine CX516
on Short-Term Memory in Rats: Correlations with Hippocampal Neuronal Activity
J.
Neurosci. 1998 18: 2748-2763
"In the companion article (Hampson et al.,
1998), the ampakine CX516 (Cortex Pharmaceuticals) was shown to produce a marked
facilitation of performance of a spatial delayed-nonmatch-to-sample (DNMS) task
in rats. Injections of the drug before each daily session produced a marked and
progressive improvement in performance at longer delays (>5 sec) that persisted
for 7 d after drug treatment was terminated. In most animals (n = 9) the increase
in performance carried over to the intervening vehicle for days, whereas in others
(n = 3) the effects dissipated within the session according to the pharmacological
half-life of CX516. In this article we report firing correlates of simultaneously
recorded cells in the CA1 and CA3 fields of the hippocampus over the period in
which DNMS performance was facilitated by CX516. Sample and Delay period firing
was enhanced by 100-350% under CX516 and increased progressively over days as
did DNMS performance. The firing increases were restricted to correct trials only
and were largest on trials with long delays. Firing in the intertrial interval
was also altered, but in a manner consistent with a previously demonstrated reduction
in between-trial proactive interference by CX516. Finally, in animals in which
the effects of CX516 were restricted to when the drug was actually present (i.e.,
no carryover effects), increased cell firing also paralleled the time course of
the performance increase. Results are discussed with respect to the actions of
ampakines on hippocampal cellular and synaptic processes that underlie DNMS performance."
[Full Text]
Arai
AC, Xia YF, Rogers G, Lynch G, Kessler M.
Benzamide-type AMPA receptor
modulators form two subfamilies with distinct modes of action.
J Pharmacol Exp Ther 2002 Dec;303(3):1075-85
"CX516 (BDP-12) and CX546,
two first-generation benzamide-type AMPA receptor modulators, were compared with
regard to their influence on AMPA receptor-mediated currents, autaptic responses
in cultured hippocampal neurons, hippocampal excitatory postsynaptic currents,
synaptic field potentials, and agonist binding. The two drugs exhibited comparable
potencies in most tests but differed in their efficacy and in their relative impact
on various response parameters. CX546 greatly prolonged the duration of synaptic
responses, and it slowed 10-fold the deactivation of excised-patch currents following
1-ms pulses of glutamate. The effects of CX516 on those measures were, by comparison,
small; however, the drug was equally or more efficacious than CX546 in increasing
the amplitude of synaptic responses. This double dissociation suggests that amplitude
and duration of synaptic responses are governed by different aspects of receptor
kinetics, which are differentially modified by the two drugs. These effects can
be reproduced in receptor simulations if one assumes that CX516 preferentially
accelerates channel opening while CX546 slows channel closing. In binding tests,
CX546 caused an approximately 2-fold increase in the affinity for radiolabeled
agonists, whereas CX516 was ineffective. More importantly, even millimolar concentrations
of CX516 did not influence the dose-response relation for CX546, suggesting the
possibility that they bind to different sites. Taken together, the evidence suggests
that benzamide modulators from the Ampakine family form two subgroups with different
modes and sites of action. Of these, CX516-type drugs may have the greater therapeutic
utility because of their limited efficacy in prolonging synaptic responses and
in attenuating receptor desensitization." [Abstract] Nagarajan
N, Quast C, Boxall AR, Shahid M, Rosenmund C.
Mechanism and impact
of allosteric AMPA receptor modulation by the ampakine CX546.
Neuropharmacology
2001 Nov;41(6):650-63
"Glutamate release at central synapses is transduced
into a characteristic fast postsynaptic response by AMPA receptor gating and agonist
affinity. The effect of two classes of modulators of AMPA receptor desensitization,
the benzothiadiazides (cyclothiazide and IDRA 21) and the benzoylpiperidines (CX516
and CX546), were studied on gating kinetics of recombinant, native AMPA receptors
and on synaptic currents. CX546 reduced the degree of desensitization more potently
than CX516 or IDRA 21, but not as efficiently as cyclothiazide. In presence of
CX516/CX546, desensitization of GluR2(flip) receptors was inhibited more than
of GluR1(flip), whereas they had no effect upon response shape or conductance.
CX546 increased agonist affinity threefold on nondesensitizing AMPA receptors
by slowing agonist unbinding. Analysis of modulatory action suggests that, in
contrast to cyclothiazide or IDRA 21, the Ampakine CX546 binds specifically to
the agonist bound nondesensitized receptor, most likely acting by destabilizing
the desensitized receptor conformation. All modulators tested showed higher efficiency
on native receptors as compared to homomeric receptors. At the glutamatergic synapse,
evoked synaptic amplitudes were weakly potentiated, while EPSC decay was slowed
by nearly a factor of three in the presence of CX546 or cyclothiazide. In the
presence of CX546, the current induced by short pulses of glutamate from recombinant
GluR2 receptors decayed with a time course that was approximately twentyfold faster
than EPSCs. The unique properties of CX546 may be beneficial for therapeutical
use." [Abstract]
Suppiramaniam
V, Bahr BA, Sinnarajah S, Owens K, Rogers G, Yilma S, Vodyanoy V.
Member
of the Ampakine class of memory enhancers prolongs the single channel open time
of reconstituted AMPA receptors.
Synapse 2001 May;40(2):154-8
"Ampakines
are small benzamide compounds that allosterically produce the positive modulation
of AMPA receptors and improve performance on a variety of behavioral tasks. To
test if the native synaptic membrane is necessary for the effects of such positive
modulators, the mechanism of action of the Ampakine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine
(CX509) was investigated in isolated rat brain AMPA receptors reconstituted in
lipid bilayers. The drug increased the open time of AMPA-induced single channel
current fluctuations with an EC(50) of 4 microM. The action of CX509 was highly
selective since it had no effect on the amplitude or close time of channel events.
The open time effect had a maximum enhancement of 70-fold and the modulated currents
were blocked by CNQX. It is concluded that the synaptic membrane environment is
not necessary for Ampakine effects. In fact, CX509 was about 100 times more potent
on the reconstituted AMPA receptors than on receptors in their native membrane.
These findings indicate that centrally active Ampakines modulate specific kinetic
properties of AMPA currents. They also raise the possibility that AMPA receptors
are regulated by factors present in situ, thus explaining the more efficient modulatory
effects of CX509 when acting on receptors removed from their synaptic location."
[Abstract] Davis
CM, Moskovitz B, Nguyen MA, Tran BB, Arai A, Lynch G, Granger R.
A
profile of the behavioral changes produced by facilitation of AMPA-type glutamate
receptors.
Psychopharmacology (Berl) 1997 Sep;133(2):161-7
"A
newly developed group of benzoylpiperidine drugs that enhance AMPA-receptor-gated
currents ("ampakines") has been shown to improve memory encoding in
rats across a variety of experimental paradigms. The present experiments were
intended to i) provide a partial profile of the behavioral changes produced by
ampakines, ii) test if two ampakines (BDP-12 and BDP-20) that differ significantly
in their effects on AMPA receptor kinetics produce similar behavioral profiles,
and iii) determine if physiological potency is reflected in behavioral potency.
BDP-20 reduced two measures of exploratory activity in aged rats but increased
speed of performance in a radial maze; the drug also caused substantially improved
retention of spatial information. These results are similar to those obtained
with BDP-12, an analog that differs from BDP-20 in its effects on ligand binding
to the AMPA receptor and on the physiological responses of the receptors to glutamate.
BDP-20 was approximately ten-fold more potent in behavioral effects than BDP-12,
which agrees with the relative potencies of the two drugs as assessed with excised
patches and excitatory synaptic responses. These findings indicate that ampakines,
though differing in their effects on AMPA-receptor-mediated responses, have similar
effects at the behavioral level." [Abstract] Munirathinam
S, Rogers G, Bahr BA.
Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid-type glutamate receptors elicits neuroprotection after trimethyltin exposure
in hippocampus.
Toxicol Appl Pharmacol 2002 Dec 1;185(2):111-8
"The
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic
receptors have been linked to survival signaling, especially when the receptors
are allosterically modulated by members of the Ampakine family. While increased
glutamatergic communication through AMPA receptors has been shown to protect against
toxic conditions that target hippocampal subfield CA1, protection in other subfields
has not been shown. Accordingly, positive modulation of AMPA receptors by Ampakine
compounds CX727 and CX516 was tested for effects on trimethyltin (TMT) neurotoxicity
in rat hippocampal slice cultures. TMT was applied for 4 h followed by a rapid
washout and antagonistic quenching of AMPA and N-methyl-D-aspartate (NMDA) receptors.
After a 24-h period, the TMT-exposed slices exhibited increased levels of calpain-mediated
spectrin breakdown as well as synaptic deterioration. TMT selectively targeted
CA3 pyramidal neurons and dentate gyrus (DG) granule cells as evidenced by degeneration
and neuronal loss. The cytoskeletal and synaptic damage was reduced when Ampakine
modulation was initiated during the postinsult period. Furthermore, the extent
of protection was comparable to that produced by the NMDA receptor antagonist
AP5. The above results were substantiated by histological experiments, revealing
that Ampakine treatment prevented TMT-induced cell loss in CA3 and DG. These results
indicate that AMPA receptor signals are part of cellular repair responses following
exposure to an environmental toxin." [Abstract] Dicou
E, Rangon CM, Guimiot F, Spedding M, Gressens P.
Positive allosteric
modulators of AMPA receptors are neuroprotective against lesions induced by an
NMDA agonist in neonatal mouse brain.
Brain Res 2003 Apr
25;970(1-2):221-5
"Four positive modulators of AMPA-type glutamate receptors
(cyclothiazide, CX614, LY404187 and S18986-1) given in acute or chronic manner
exerted a neuroprotective effect in lesions induced in postnatal day 5 (P5) mice
by intracerebral injection of ibotenate, an NMDA agonist. The neuroprotective
effects were mediated via the MAPK pathway since coinjection of the MEK inhibitor,
PD98059, blocked the neuroprotective effects. Administration of CX614 to neonatal
mice was followed by upregulation of hippocampal and cortical BDNF expression."
[Abstract] Bahr
BA, Bendiske J, Brown QB, Munirathinam S, Caba E, Rudin M, Urwyler S, Sauter A,
Rogers G.
Survival signaling and selective neuroprotection through
glutamatergic transmission.
Exp Neurol 2002 Mar;174(1):37-47
"In
the brain, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors
mediate glutamatergic neurotransmission and, when intensely activated, can induce
excitotoxic cell death. In addition to their ionotropic properties, however, AMPA
receptors have been functionally coupled to a variety of signal transduction events
involving Src-family kinases, G-proteins, and the mitogen-activated protein kinase
(MAPK). In the present study, we tested whether AMPA receptors are linked to appropriate
signaling events in order to prevent neuronal injury and/or enhance recovery.
AMPA stimulation in hippocampal slice cultures caused the selective activation
of MAPK through the upstream activator MAPK kinase (MEK). Inhibition of either
component of the AMPA receptor--MAPK pathway potentiated cellular damage due to
serum deprivation, suggesting that this pathway facilitates compensatory signals
in response to injury. Correspondingly, positive modulation of AMPA receptors
with the Ampakine 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) enhanced MAPK
activation and reduced the extent of synaptic and neuronal degeneration resulting
from excitotoxic episodes. CX516 was neuroprotective when infused into slices
either before or after the insult. The Ampakine derivative also elicited neuroprotection
in an in vivo model of excitotoxicity as evidenced by reduction in lesion size
and preservation of two different types of neurons. Interestingly, the AMPA receptor--MAPK
pathway selectively protects against excitotoxicity since enhancing the pathway
did not protect against the nonexcitotoxic, slow pathology initiated by lysosomal
dysfunction. The results indicate that glutamatergic communication is important
for cellular maintenance and that AMPA receptors activate survival signals to
counterpoise their own excitotoxic potential." [Abstract] Knapp
RJ, Goldenberg R, Shuck C, Cecil A, Watkins J, Miller C, Crites G, Malatynska
E.
Antidepressant activity of memory-enhancing drugs in the reduction
of submissive behavior model.
Eur J Pharmacol 2002 Apr 5;440(1):27-35
"The
present study tests the activity of nootropic drugs in a behavioral test linked
to depression. This test measures the reduction of submissive behavior in a competition
test as the relative success of two food-restricted rats to gain access to a feeder.
Nootropic drugs tested include piracetam (2-oxo-1-pyrrolidineacetamide), aniracetam
(1-(4-methoxybenzoyl)-2-pyrrolidinone), the Ampakine, Ampalex, 1-(quinoxalin-6-ylcarbonyl)piperidine,
and analogs were compared to the antidepressants, fluoxetine ((+/-)-N-methyl-gamma-(4-[trifluoromethyl]phenoxy)-benzenepropanamine)
and desimpramine (5H-dibenz[b,f]azepine-5-propanamine, 10,11-dihydro-N-methyl-,
monohydrochloride), while the anxiolytic diazepam (7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one)
served as a control. Drugs were given intraperitoneally for 3 weeks. The antidepressant
and nootropic drugs reduced submissive behavior over time. The effect was dose
dependent as measured for fluoxetine and Ampakines. The reduction of submissive
behavior by Ampakines gradually faded after cessation of treatment and had a more
rapid onset of activity (during the 1st week of treatment) than fluoxetine (after
2 weeks). The results suggest that Ampakines may have antidepressant activity.
The potential of depression treatment with memory-enhancing drugs is hypothesized
and the link between cognition and depression is discussed." [Abstract] Baumbarger,
Polly J., Muhlhauser, Mark, Zhai, Jin, Yang, Charles R., Nisenbaum, Eric S.
Positive
Modulation of alpha -Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA)
Receptors in Prefrontal Cortical Pyramidal Neurons by a Novel Allosteric Potentiator
J
Pharmacol Exp Ther 2001 298: 86-102
"Positive modulators of glutamate
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors can
enhance cognitive function in several species. The present experiments compared
the actions of a novel biarylpropylsulfonamide compound, LY404187, with the prototypical
benzoylpiperidine, 1-(quinoxalin-6-ylcarbonyl)-piperidine (CX516), on AMPA receptors
of prefrontal cortex (PFC) pyramidal neurons. LY404187 (0.03-10 microM) selectively
enhanced glutamate-evoked currents through AMPA receptor/channels of acutely isolated
pyramidal neurons with considerably greater potency (EC50 = 1.3 +/- 0.3 microM)
and efficacy (Emax = 45.3 +/- 8.0-fold increase) than did CX516 (EC50 = 2.8 +/-
0.9 mM; Emax = 4.8 +/- 1.4-fold increase). Both LY404187 and CX516 increased the
potency of the glutamate concentration-response profile by 6- and 3-fold, respectively.
Rapid perfusion experiments demonstrated that LY404187 produced a marked suppression
in the magnitude but no change in the kinetics of receptor desensitization; whereas
CX516 produced little change in the degree and a modest deceleration of the desensitization
process. In PFC slices, both spontaneous and stimulus-evoked AMPA receptor-mediated
excitatory postsynaptic potentials were enhanced by nanomolar concentrations of
LY404187. Voltage-sensitive N-methyl-D-aspartate (NMDA) receptor-dependent synaptic
responses also were indirectly augmented as a consequence of greater postsynaptic
depolarization. Consistent with the in vitro data, LY404187 was 1000-fold more
potent than CX516 in enhancing the probability of discharge of PFC neurons in
response to stimulation of glutamatergic afferents from hippocampus in vivo. This
potentiation by LY404187 was reduced by both selective AMPA (LY300168, 1 mg/kg,
i.v.) and NMDA (LY235959, 5 mg/kg, i.v.) receptor antagonists. Collectively, these
results demonstrate that LY404187 is an extremely potent and centrally active
potentiator of native AMPA receptors and has a unique mechanism of action. The
therapeutic implications of AMPA receptor potentiators are discussed." [Full
Text]
Kessler M, Mutneja MS, Rogers G, Lynch
G.
Regional preferences of AMPA receptor modulators determined through
agonist binding autoradiography.
Brain Res 1998 Feb 2;783(1):121-6
"Autoradiographic
techniques were used to test if positive modulators of AMPA-type glutamate receptors
have regionally differentiated effects on ligand binding. Cyclothiazide, a drug
with ten fold greater effects on 'flip' than 'flop' splice variants of the receptors,
had unequal effects across the subdivisions of hippocampus; i.e., it reduced [3H]AMPA
binding in field CA3 with an EC50 of 24 microM and in field CA1 and dentate gyrus
with EC50s between 60 and 100 microM. The EC50 for the drug's influence on binding
was also significantly lower in the superficial than in the deeper layers of the
neocortex, though these differences were not as pronounced as those in the hippocampus.
The ampakine CX614, a compound with a modest preference for flop variants, had
a slightly lower EC50 for its effects on [3H]AMPA binding in CA1 than in CA3.
This result was confirmed with [3H]fluorowillardiine binding. The effects of the
ampakine in neocortex tended to be greater in the deeper than superficial layers
but this did not reach statistical significance. These results indicate that differential
effects of modulators on AMPA receptor subunits are reflected in their relative
potency across brain subdivisions. This raises the possibility that subclasses
of positive modulators will exhibit a measurable degree of selectivity in their
physiological and behavioral influences." [Abstract] Palmer
LC, Hess US, Larson J, Rogers GA, Gall CM, Lynch G.
Comparison of
the effects of an ampakine with those of methamphetamine on aggregate neuronal
activity in cortex versus striatum.
Brain Res Mol Brain
Res 1997 Jun;46(1-2):127-35
"The present study used in situ hybridization
to c-fos mRNA to compare the effects of an 'ampakine' (a positive modulator of
AMPA type glutamate receptors) with those of methamphetamine on the balance of
aggregate neuronal activity in the cortex versus striatum. Methamphetamine (n
= 11) induced a marked increase in c-fos mRNA in the dorsomedial quadrant of the
striatum and a 21% smaller, but still reliable, increase in the ventrolateral
quadrant. The drug also elevated c-fos mRNA levels in the ventral and medial segments
of the orbitofrontal cortex but had no detectable effects in motor and somatosensory
neocortices. The ampakine (n = 11) caused a near inverse pattern of changes; i.e.
a sizable increase in somatosensory labeling and a significant decrease in striatal
labeling with statistically insignificant effects in motor and orbitofrontal cortex.
Within-rat cortical and striatal values were correlated in both the vehicle (n
= 11) and ampakine groups, and appropriate comparisons established that the ampakine
caused 27-55% increases in the ratio of cortical to striatal labeling. These results
are in accord with the idea that facilitation of glutamatergic transmission has
'network level' effects that are opposite in nature to those resulting from enhanced
dopaminergic transmission. The potential relevance of ampakines alone or in conjunction
with dopamine antagonists for the treatment of schizophrenia is discussed."
[Abstract] Hess
US, Whalen SP, Sandoval LM, Lynch G, Gall CM.
Ampakines reduce methamphetamine-driven
rotation and activate neocortex in a regionally selective fashion.
Neuroscience.
2003;121(2):509-21.
"It has been proposed that glutamatergic and dopaminergic
systems are functionally opposed in their regulation of striatal output. The present
study tested the effects of drugs that enhance AMPA-receptor-mediated glutamatergic
transmission (ampakines) for their effects on dopamine-related alterations in
cortical activity and locomotor behavior. Rats with unilateral 6-hydroxydopamine
lesions of the ascending nigro-striatal dopamine system were sensitized to methamphetamine
and then tested for methamphetamine-induced circling behavior in the presence
and absence of ampakines CX546 and CX614. Both ampakines produced rapid, dose-dependent
reductions in circling that were evident within 15 min and sustained through 1
h of behavioral testing. In situ hybridization maps of c-fos mRNA expression showed
that in the intact hemisphere, ampakine cotreatment markedly increased c-fos expression
in parietal, sensori-motor neocortex above that found in rats treated with methamphetamine
alone. Ampakine cotreatment did not augment c-fos expression in frontal, sensori-motor
cortex or striatum. Still larger ampakine-elicited effects were obtained in parietal
cortex of the dopamine-depleted hemisphere where labeling densities were increased
by approximately 60% above values found in methamphetamine-alone rats. With these
effects, the hemispheric asymmetry of cortical activation was less pronounced
in the ampakine-cotreatment group as compared with the methamphetamine-alone group.
These results indicate that positive modulation of AMPA-type glutamate receptors
1) can offset behavioral disturbances arising from sensitized dopamine receptors
and 2) increases aggregate neuronal activity in a regionally selective manner
that is probably dependent upon behavioral demands." [Abstract] |
