Trends in Neurosciences
Volume 29, Issue 10, October 2006, Pages 554-562
Journal home page for Trends in Neurosciences

Opinion
Ampakines and the threefold path to cognitive enhancement

https://doi.org/10.1016/j.tins.2006.07.007Get rights and content

Ampakines are the first peripherally administered drugs that increase excitatory monosynaptic responses in the brain. Because of this effect, the compounds improve communication in complex networks, potently facilitate long-term potentiation (LTP) and induce the expression of neurotrophic factors. Ampakines are effective in animal models of neuropsychiatric disorders and have produced positive results in a small number of human studies. Neurobiological considerations and modeling studies suggest that the drugs, in addition to their effects on disturbed behavior, will alter the encoding and organization of information in normal brains. Results from physiological and behavioral studies accord with this prediction. Building on these findings, this article considers how the threefold effects of ampakines will modify, and enhance, cognition.

Introduction

AMPA-type glutamate receptors mediate fast excitatory postsynaptic currents (EPSCs) at the great majority of brain synapses and are widely regarded as an expression mechanism for the memory-related long-term potentiation (LTP) effect. Compounds that freely cross the blood–brain barrier and have sufficient potency to modulate these receptors positively (i.e. ampakines) were first introduced in 1993–1994 1, 2. Ampakines bind to a site on the AMPA receptor but have no agonist or antagonist effects; instead, they stabilize the receptor in its channel-open state following the binding of released transmitter (glutamate). This prolongs current flow through the receptor and thus enhances synaptic responses. Given that excessive glutamate-mediated activity is a cause of seizures and excitotoxic brain damage 3, 4, it was anticipated that positive modulators of AMPA receptors would produce unacceptable side-effects. Unexpectedly, the early ampakines did not cause such effects at doses that both increased excitatory transmission in the hippocampus and noticeably altered behavior. These initial findings were followed by a series of animal studies showing that the drugs accelerate learning 2, 5, 6, 7, reduce age-related memory impairments [8], and suppress symptoms in models of schizophrenia 9, 10, 11, attention-deficit hyperactivity disorder (ADHD) [12] and depression 13, 14. A much more limited body of studies in humans, most using mild versions of ampakines, has found positive effects on memory in the elderly [15] and in psychiatric diseases [16]. Ampakines thus have the potential to act as broad-spectrum therapeutic agents for psychiatric disorders.

Neurobiological studies have identified three routes by which ampakines affect disturbed behavior.

  • (i)

    Deficits in transmission strength within the cortex probably contribute to the cognitive impairments associated with aging [17] and various neuropsychiatric diseases 18, 19; ampakines enhance transmission, without causing noticeable side-effects, and therefore are plausible treatments for such conditions [19].

  • (ii)

    Ampakines, through established mechanisms, both lower the induction threshold and increase the magnitude of LTP [20]. Given the links between LTP and memory 21, 22, 23, these results explain why the drugs accelerate learning.

  • (iii)

    Ampakines enhance the trophic effects of excitatory transmission. Production of brain-derived neurotrophic factor (BDNF) and related proteins is regulated by excitatory input 24, 25 and, consonant with this, their concentrations in the brain are increased by ampakines 26, 27, 28, 29, 30. BDNF exerts potent, acute effects on synaptic plasticity 31, 32, 33, and thus could mediate various behavioral effects associated with ampakines.

Although these three pathways explain the broad effects of ampakines on neuropsychiatric disturbances, it is noteworthy that each one is fully operative in normal brains. This raises the questions of whether ampakines will positively affect intact, in addition to compromised, behaviors, and whether such effects would extend to cognition. Pertinent to these issues, ampakines improved retention scores in complex tasks performed by animals 2, 5, 34, 35 or humans [36]. For example, monkeys required to select a complex target object out of a field of six similar objects had much better scores when tested under the influence of an ampakine [35] and these positive effects became more pronounced as task complexity was increased. Ampakines have also been reported to improve learning of a difficult visuospatial maze by young adult humans [36]. The effects in this instance were not nearly as dramatic as those recorded for rats and monkeys, but this could be because much lower drug concentrations were used in the human studies.

Although these observations indicate that ampakines act as cognition enhancers, they do not specify mechanisms (how does an increase in BDNF affect a particular cognitive activity?) and they are not predictive (which aspects of cognition will be affected?). Missing from the discussion is any consideration of how the drugs affect cortical networks – those structures that lie between the synaptic AMPA receptors targeted by the drugs and observable behavior. Here we will (i) argue that each of the three pathways of ampakine action will produce a characteristic modification to network operations, and (ii) discuss how these effects will both alter and enhance cognition.

Section snippets

Effects of ampakines on glutamate receptors and synaptic transmission

The original ampakines were benzamide compounds that with further synthesis and testing evolved into two subgroups 1, 2. Subsequent work by different groups resulted in three additional, chemically distinct families of small molecule (300–500 Da) modulators: pyridothiadiazines [37], biarylpropylsulfonamides [38] and 5′-alkyl-benzothiadiazides [39]. Compounds from each of these groups, all of which are referred to here as ampakines, have positive effects in animal models of learning [40],

The first path to cognitive enhancement: increase transmission to expand cortical networks

Repeated assembly (and disassembly) of complex functional networks, which are largely composed of glutamatergic neurons, is the only explanation so far advanced for how the cortex carries out the computations that underlie cognition. Limits on the size of such networks, and thus on the complexity of cognitive operations, can reasonably be assumed to reflect the reliability of transmission at individual synapses. According to this argument, the nonlinearities built into the generation of a

The second path: facilitate LTP to accelerate learning

The NMDA-type glutamate receptors that trigger LTP are normally voltage blocked and depend on depolarization produced by the colocalized AMPA receptors for activation. Because the pertinent channels are relatively slow to open, this dependency extends to both the duration and the amplitude of the AMPA receptor-mediated currents. According to a recent report [54], ampakine variants that only increase response amplitude (deactivation drugs, as already mentioned) simply lower the threshold for

The third path: upregulate BDNF to improve memory consolidation

Multiple lines of work indicate that the excitatory inputs to cortical neurons regulate the expression of BDNF and nerve growth factor (NGF) 61, 62. Consonant with this, ampakines induce BDNF expression in vitro and in vivo 27, 28, 42 and do so without causing evident disturbances to ongoing behavior. BDNF applied to slices potently facilitates the induction of LTP 32, 63 and experiments using selective antagonists indicate that endogenous BDNF, which is released by the theta-burst stimulation

Concluding remarks

Ampakines have large effects on polysynaptic EPSCs and selectively increase aggregate cortical activity associated with complex tasks in rats and monkeys. This accords with the idea that the drugs provide a means for obviating the limits on network size that are imposed by probabilistic transmission failures. The expectation that this would lead to new cognitive capacities remains to be formally tested. As expected from their positive effects on LTP, ampakines accelerate learning across diverse

Acknowledgements

Research supported, in part, by grants NS0518237 and NS45260 from NINDS.

References (75)

  • B. Legutko

    Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator

    Neuropharmacology

    (2001)
  • M. Ingvar

    Enhancement by an ampakine of memory encoding in humans

    Exp. Neurol.

    (1997)
  • D. Phillips

    5′-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity

    Bioorg. Med. Chem.

    (2002)
  • C. Lebrun

    Effects of S 18986-1, a novel cognitive enhancer, on memory performances in an object recognition task in rats

    Eur. J. Pharmacol.

    (2000)
  • G.R. Jordan

    Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography

    Neuropharmacology

    (2005)
  • E. Dicou

    Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain

    Brain Res.

    (2003)
  • A. Arai

    Effects of a centrally active benzoylpiperidine drug on AMPA receptor kinetics

    Neuroscience

    (1996)
  • A. Arai et al.

    The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization

    Brain Res.

    (1998)
  • J. Sirvio

    Effects of pharmacologically facilitating glutamatergic transmission in the trisynaptic intrahippocampal circuit

    Neuroscience

    (1996)
  • G. Lynch

    Glutamate-based therapeutic approaches: ampakines

    Curr. Opin. Pharmacol.

    (2006)
  • U.S. Hess

    Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion

    Neuroscience

    (2003)
  • A.C. Arai

    Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus

    Neuroscience

    (2004)
  • G. Lynch

    AMPA receptor modulators as cognitive enhancers

    Curr. Opin. Pharmacol.

    (2004)
  • C. Gall

    Regulation of brain neurotrophin expression by physiological activity

    Trends Pharmacol. Sci.

    (1992)
  • G. Barrionuevo

    The effects of repetitive low frequency stimulation on control and ‘potentiated’ synaptic responses in the hippocampus

    Life Sci.

    (1980)
  • A. Arai

    The effects of adenosine on the development of long-term potentiation

    Neurosci. Lett.

    (1990)
  • J. Larson

    Reversal of LTP by theta frequency stimulation

    Brain Res.

    (1993)
  • G. Buzsaki

    Hippocampal sharp waves: their origin and significance

    Brain Res.

    (1986)
  • U. Ungerstedt et al.

    Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system

    Brain Res.

    (1970)
  • R. Granger

    A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning-dependent task

    Synapse

    (1993)
  • U. Staubli

    Facilitation of glutamate receptors enhances memory

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • M.P. Mattson

    Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders

    Neuromol. Med.

    (2003)
  • J. Larson

    Facilitation of olfactory learning by a modulator of AMPA receptors

    J. Neurosci.

    (1995)
  • M.T. Rogan

    AMPA receptor facilitation accelerates fear learning without altering the level of conditioned fear acquired

    J. Neurosci.

    (1997)
  • R. Granger

    Facilitation of glutamate receptors reverses an age-associated memory impairment in rats

    Synapse

    (1996)
  • S.A. Johnson

    Synergistic interactions between ampakines and antipsychotic drugs

    J. Pharmacol. Exp. Ther.

    (1999)
  • R.R. Gainetdinov

    Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • Cited by (134)

    View all citing articles on Scopus
    View full text