Psychopharmacology

, Volume 179, Issue 1, pp 154–163 | Cite as

Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data

Review

Abstract

Background

Positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators enhance glutamate transmission via the AMPA receptor by altering the rate of desensitization; alone they have no intrinsic activity. They are the only class of compounds known that may pharmacologically separate AMPA subtypes.

Objective

This manuscript will review preclinical work on positive AMPA modulators, with clinical examples where relevant.

Results

The activity of these compounds appears to be determined by the AMPA receptor subunit composition. Studies have shown that splice variant and/or subunit combinations change the desensitization rate of this receptor. Also, these subunits are heterogeneously expressed across the central nervous system. Therefore, the functional outcome of different positive AMPA modulators could indeed be different. The origins of this pharmacological class come from hippocampal long-term potentiation studies, so quite naturally they were first studied in models of short- and long-term memory (e.g., delayed match to sample, maze performance). In general, these agents were procognitive. However, more recent work with different chemical classes has suggested additional therapeutic effects in models of schizophrenia (e.g., amphetamine locomotor activity), depression (e.g., forced swim test), neuroprotection (e.g., NMDA agonist lesions) and Parkinson’s disease (e.g., 6-hydroxydopamine lesion).

Conclusions

In conclusion, positive modulation of AMPA may offer numerous therapeutic avenues for central nervous system drug discovery.

Keywords

AMPA Positive AMPA modulator Schizophrenia Alzheimer’s disease Cognition 

Introduction

Ionotropic glutamate receptors are the major excitatory amino acid neurotransmitter receptors in the vertebrate central nervous system (CNS) and are separated into three functionally distinct subclasses: AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate, and NMDA (N-methyl-d-aspartate) receptors. AMPA receptors mediate the majority of the fast excitatory amino acid synaptic transmission in the CNS. Kainate receptors contribute to the postsynaptic responses at some excitatory synapses and can also modulate presynaptic neurotransmitter release. NMDA receptors play an essential role in the modulation of excitatory synaptic transmission due to their permeability to calcium ions and ability to activate downstream calcium-dependent signal-transduction processes. While the number of NMDA receptors appears relatively stable in the postsynaptic cell membrane, AMPA receptor levels are regulated in a dynamic fashion; their insertion and removal from the postsynaptic cell membrane relating to changes in synaptic plasticity (Malenka 2003; Malinow 2003; Carroll et al. 2001). Despite the importance of ionotropic glutamate receptors in brain physiology, a surprising paucity of drugs affecting the ionotropic glutamate receptors are found in the clinic. Those that are there generally do not have a selective pharmacology for glutamate receptor subtypes (e.g., riluzole, topiramate, memantine, ketamine), especially when one considers subunit make-up of these receptors. As a general rule, antagonists have been used as analgesic or neuroprotective agents and agonists/positive modulators as cognition enhancers.

Structure and CNS distribution of AMPA receptors

AMPA receptors are cation-selective tetrameric hetero-oligomers formed by combinations of the subunits GluR1, GluR2, GluR3, and GluR4 (Hollmann et al. 1989; Boulter et al. 1990; Keinanen et al. 1990; Wisden and Seeburg 1993; Sommer and Seeburg 1992; Fletcher and Lodge 1996; Quirk and Nisenbaum 2002; Suzuki et al. 2003; Brorson et al. 2004). These subunits are of about 900 amino acids and contain a large extracellular N-terminal domain. Each subunit can be expressed as a flip or flop splice variant (Sommer et al. 1990; Lomeli et al. 1994; Quirk and Nisenbaum 2002; Malenka 2003; Brorson et al. 2004). These two splice variants, generated by alternate RNA splicing, differ in sequence by fewer than ten amino acids. Expression is regulated regionally (Boulter et al. 1990; Keinanen et al. 1990; Sommer et al. 1990; Fletcher and Lodge 1996; Wisden and Seeburg 1993; Frye and Fincher 2000; Park et al. 2003; Rosa et al. 2002; Beneyto and Meador-Woodruff 2004) and developmentally (Monyer et al. 1991; Stine et al. 2001). A recent paper compared each subunit (GluR1–4) across the whole brain of a Macaque using in situ hybridization (Beneyto and Meador-Woodruff 2004). This paper highlighted not only remarkable differences in regional expression across many brain structures but also the cellular differentiation of GluR1–4. Other studies have examined the cellular/regional distribution of GluR1–4 in rodents and come to similar conclusions (Boulter et al. 1990; Keinanen et al. 1990; Sommer et al. 1990; Fletcher and Lodge 1996; Petralia and Wenthold 1992; Wisden and Seeburg 1993; Frye and Fincher 2000; Park et al. 2003; Rosa et al. 2002). In the hippocampus, dentate granule, CA1, and CA3 cells express GluR1, GluR2, and GluR3; only CA1 cells express GluR4 also (Wisden and Seeburg 1993; Monyer et al. 1991; Frye and Fincher 2000; Park et al. 2003; Rosa et al. 2002). Cerebellar granule cells express only GluR2 and GluR4; Bergmann glia express GluR1 and GluR4; and spinal cord motoneurons express GluR1, GluR2, GluR3, and GluR4 subunits (Fletcher and Lodge 1996; Wisden and Seeburg 1993; Tomiyama et al. 1999). Broadly speaking, the abundance of GluR1 and GluR2 subunits is high in projection glutamatergic neurons, while interneurons [often γ-aminobutyric acid (GABA)ergic] express fewer GluR2 and more GluR4 (Geiger et al. 1995). Table 1 is an attempt to capture the diversity of AMPA receptor subunits across the mammalian brain. Subregion differences in AMPA receptor subunits increase the diversity further.
Table 1

Regional variation of AMPA receptor subunits and splice variants in mammalian braina

Structure

GluR1

GluR2

GluR3

GluR4

Flip/flop ratio

Reference

Frontal lobe

+++

++

++

+

Flip=flop

1, 2, 7

Parietal lobe

++

+++

+++

+

Flip=flop

3, 7

Cingulate gyrus

+++

+++

+++

++

Flip=flop

1, 7

Hippocampus

+++

+++

+++

+

GluR1 flip>flop; GluR2 flop=flip; GluR3 flop>flip

3, 4, 7

Subiculum

++

+++

+++

Flop>flip

1, 7

Striatum

+++

++

+++

Flop>flip

1, 3, 5

Nucleus accumbens

++

+

+++

Core flip>flop; Shell flop>flip

1, 2, 7

Septum

+++

++

++

++

Flop>flip

7, 8

Thalamusb

++/+++

+/++

+/++

+/+++

Flop>flip

1, 7

SNcc

++

+++

++

++

Flip>flop

1, 7

SNrc

+++

+

+++

5, 7

Cerebellar cortex

+++

+++

+++

+++

Flop>flip

6, 7

aAs no study captures all the above information in one species, both rodent and primate studies are represented here

bLarge variation between individual thalamic nuclei

cSubstantia nigra pars compacta-SNc; Substantia nigra pars reticulata-SNr

1Brene et al. 1998; 2Stine et al. 2001; 3Park et al. 2003; 4Rosa et al. 2002; 5Tallaksen-Greene and Albin 1996; 6Tomiyama et al. 1999; 7Beneyto and Meador-Woodruff 2004; 8Frye and Fincher 2000

Additional diversity comes from the flip and flop splice variants of GluR1–4. Projection neurons preferentially express flip variants (although, hippocampal CA1 pyramidal cells express predominantly flop variants), while interneurons predominantly express flop variants (Wisden and Seeburg 1993; Geiger et al. 1995; Beneyto and Meador-Woodruff 2004). Flip variants predominate before birth and continue to be expressed in adult rats, whereas flop variants are in low abundance before the eighth postnatal day and are upregulated to about the same level as the flip forms in adult animals (Monyer et al. 1991; Stine et al. 2001). The flip variants desensitize more slowly and to a lesser extent than the flop variants (Sommer et al. 1990; Lambolez et al. 1996; Mosbucher et al. 1994; Koike et al. 2000).

Therefore, a large amount of heterogeneity of AMPA receptors is seen across the CNS. There is regional heterogeneity of GluR1–4 that is further differentiated by cellular heterogeneity and differentiated further by splice variants (Table 1). This heterogeneity of AMPA would not be so important therapeutically if it did not convey a difference in function. In this regard, the abundance of GluR2 conveys a positive correlation with desensitization time of AMPA receptors, while GluR4 conveys the opposite effect (Geiger et al. 1995; Sommer et al. 1990; Brorson et al. 2004). Therefore, the rise and fall time of AMPA transmission (open versus closed or desensitized channel) across the CNS depends on the subunit composition. Calcium permeability is also correlated with subunit composition. Studies have shown that recombinant AMPA receptors lacking GluR2 subunits have a high Ca2+ permeability, while recombinant receptors expressing GluR2 show a low Ca2+ permeability (Hume et al. 1991; Burnashev et al. 1992; Brorson et al. 2004). This has obvious implications for calcium influx-related phenomena, such as long-lasting changes in synaptic strength (Malenka 1991; Teyler et al. 1994; Malenka 2003; Malinow 2003) and neurotoxicity (Choi 1988; Doble 1999). The regional, cellular, and splice variant modalities of the AMPA subunit could be viewed as immensely complex. However, it has been suggested earlier in this review that the paucity of glutamate ionotropic drugs in the clinic could be due to the preclinical pharmacology having too broad a spectrum of effect at these receptors. Global positive modulator/agonist or negative modulator/antagonist effects on AMPA transmission could well elicit an intolerable level of toxicity. Exploring the complexity of AMPA receptor subtypes in a functional manner may offer the therapeutic efficacy drug discovery scientists drive for, while limiting the overt global effects and thus lessening toxicity.

To date, one class of compounds has been shown to distinguish AMPA receptors pharmacologically, based on subunit composition and isoform conformation—these are the positive AMPA modulators. These agents do not bind to the glutamate binding site, rather they interact with the receptor at an allosteric site and augment function by decreasing desensitization and/or deactivation. Kinetic studies have shown that some positive AMPA modulators slow deactivation (e.g., aniracetam) of the agonist/receptor complex, whereas others (e.g., cyclothiazide) attenuate the desensitization of this complex (Yamada 1998). Hippocampal slice experiments have shown enhancement of maximal response or prolongation of the half-life of the response (Arai et al. 1994, 2004) with such drugs. These data are suggestive of multiple allosteric sites each with different structural requirements rather than a sole site of action accessed by multiple chemical classes. As suggested by the title, recent evidence indicates that certain chemical classes have a selective action on AMPA receptor subunit types. AMPA receptors can be homogeneous or heterogeneous, with regard to their subunit composition: and subunit composition varies markedly across the brain (Table 1). Therefore, the functional in vivo outcome of such drugs would thus be complicated, e.g., would a GluR2 flip-preferring compound have greater effects in the substantia nigra pars compacta than the substantia nigra pars reticulta and greater effects in cortical structures than striatum and nucleus accumbens? The answers to such questions are not yet known. Are some subunit compositions of AMPA more prevalent than others? It appears that certain subunit compositions of the GABAA receptor are more prevalent than others (Whiting 2003) and drugs acting selectively on subunits may offer different therapeutic indices (Mohler et al. 2002). It is suggested that we may see a similar scenario established with AMPA receptors. In terms of pharmacology, the positive AMPA modulators appear to be somewhat selective for AMPA subtypes, though progress needs to be made. Efforts have also begun to discover subunit-selective agents that interact with the glutamate recognition site (Zeng et al. 2002, 2003).

In the late 1980s, certain lectins were shown to reverse AMPA desensitization. That was shortly followed by reports showing that certain nootropic (Greek: “toward the mind”) agents such as aniracetam and piracetam also possessed a similar action. Lynch et al. then developed a series of pyrrolidinone compounds based on aniracetam that showed potentiating effects on AMPA transmission (due to decreased desensitization and deactivation) and coined the term Ampakine. These Ampakines were tested in a series of rodent and primate cognition models and subsequently entered into clinical trials. The lead compound, CX516, although perhaps being scientifically ahead of its time, had drug characteristics (low potency, short half-life, extensive metabolism, etc.) that led to exceedingly high doses (approximately 1 g) being administered over short time intervals (Lynch et al. 1996, 1997; Ingvar et al. 1997). More recently, reports have emerged showing Ampakines that not only have greatly improved potency and pharmacokinetic profiles (Arai et al. 2004) but certain properties differentiating them from CX516 based on AMPA subunit or splice variant complement (Nagarajan et al. 2001). This is an important distinction, as not all positive AMPA modulators will have the same effect in preclinical or clinical settings—it will depend on which complement of AMPA subunits are affected by that individual drug. Indeed, other structural classes have shown a similar output—increased AMPA function—via different subunits (Lynch 2004; Yamada 1998; Quirk and Nisenbaum 2002).

Pharmacological investigation into positive AMPA receptor modulators and therapeutics—historical data

Modulation of the AMPA receptor has long been reported to affect cognition. Lynch and Baudry hypothesized that long-term potentiation (LTP) was due to an increased number of glutamate receptors (Lynch and Baudry 1984). The recent demonstration of AMPA receptor trafficking to the synapse, during changes in plasticity, supports this hypothesis (Malenka 2003; Malinow 2003; Carroll et al. 2001). The origins of the pharmacological class come from hippocampal LTP studies. Therefore, a natural progression was to test these agents in models of memory—both short-term working memory as well as long-term retrieval memory. A simple definition is that short-term working memory involves tasks in which a cue is “held” in the brain for a matter of seconds or minutes and then an appropriate response is made, while long-term reference memory is the ability to recall a cue that was presented hours if not days (often 24 h) beforehand. Long-term memory can also be subdivided into declarative (e.g., learning of facts) and procedural (e.g., learning of motor skills) memory. These subdivisions are also associated with different brain regions (declarative memory—hippocampus; procedural memory—cerebellum); therefore, potentially, drugs acting selectively on different AMPA receptors could preferentially affect one form of the other.

Diazoxide and cyclothiazide are examples of thiazides that have been extensively explored as positive modulators of AMPA. The lack of blood–brain barrier penetration prevented in vivo explorations. However, diazoxide derivatives (IDRA21), benzoylpiperidines (aniracetam), benzoylpyrrolidines (Ampakines), and arylpropylsulfonamides (LY404187) penetrate the blood–brain barrier (Table 2).
Table 2

Summary of preclinical data and clinical status of positive AMPA modulators. DNMTS delayed non-match to sample, BDNF brain-derived neurotrophic factor, LTP long-term potentiation,6-OHDA 6-hydroxydopamine, MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Drug

Preclinical positive results

Potential indication

Current clinical status

Reference

Aniracetam

LTP in vitro and in vivo

Cognition

Launched

21, 23, 26

Spatial maze performance—rodent

Cognition

13, 21

DNMTS—primate

Cognition

19

Passive avoidance maze—rodent

Cognition

32

Four-response chain—primate

Cognition

27

Two-lever choice reaction maze—rodent

Cognition

14

Increased glutamate transmission in prefrontal cortex—rodent

Schizophrenia

29

Forced swim test

Depression

16

Elevated plus-maze

Anxiety

16

Conditioned fear stress

Anxiety

16

Social interaction tests

Anxiety

16

PEPA

Postischemic memory impairment maze—rodent

Cognition/stroke

Preclinical

24

IDRA21

LTP in vitro

Cognition

Preclinical

1

Spatial maze performance—rodent

Cognition

32

Passive avoidance

Cognition

32

Four-response chain—primate

Cognition

28

DMTS—primate

Cognition

4

Ampakines

LTP in vitro and in vivo

Cognition

Phase II—ORG24448

26, 27

• CX516

Conditioned fear

Cognition

Phase II—CX516

22

• CX546

Olfactory learning

Cognition

Phase I—S18986–

27

• ORG24448

2 odor discrimination

Cognition

27

• S18986

Spatial maze performance—rodent

Cognition

7, 27

DNMTS

Cognition

10

Hippocampal neuronal activity during working memory

Cognition

9

Conditioned eyeblink

Cognition

25

Mono- and coadministration with antipsychotics

Schizophrenia

11, 31

Submissive behavior

Depression

33

Increased BDNF expression

Depression

34, 35

Lilly AMPA modulators

Increased prefrontal cortex AMPA function in vitro and in vivo

Cognition

Phase II—LY451395

3

• LY404187

Increased hippocampal AMPA function in vitro and in vivo

Cognition

8, 30

• LY392098

Forced swim test

Depression

2

• LY395153

Neuroprotection

Stroke

7

• LY451646

Increased BDNF expression

Depression

12

• LY451395

6-OHDA rotation

Parkinson’s disease

18, 36

• LY503430

MPTP toxicity

Parkinson’s disease

18

Spatial maze performance—rodent

Cognition

20

1Arai et al. 1996; 2Bai et al. 2001; 3Baumbarger et al. 2001; 4. Buccafusco et al. 2004; 5Cumin et al. 1982; 6Davis et al. 1997; 7Dicou et al. 2003; 8Gates et al. 2001; 9Hampson et al. 1998a; 10Hampson et al. 1998b; 11Johnson et al. 1999; 12Mackowiak et al. 2002; 13Martin et al. 1992; 14Nakamura 2002; 15Nakamura et al. 2000; 16Nakamura and Kurasawa 2001; 17Nakamura and Tanaka 2001; 18O’Neill et al. 2004; 19Pontecorvo and Evans 1985; 20Quirk and Nisenbaum 2002; 21Rao et al. 2001; 22Rogan et al. 1997; 23Satoh et al. 1986; 24Sekiguchi et al. 2001; 25Shors et al. 1995; 26Stäubli et al. 1992; 27Stäubli et al. 1994; 28Thompson et al. 1995; 29Togashi et al. 2002; 30Vandergriff et al. 2001; 31Vanover 1997; 32Zivkovic et al. 1995; 33Knapp et al. 2002; 34Lauterborn et al. 2000; 35Lauterborn et al. 2003; 36Murray et al. 2003

Aniracetam augments AMPA transmission in the hippocampus (Ito et al. 1990). In rodent studies it improved long-term spatial memory in the radial maze (Martin et al. 1992). In primate studies, aniracetam did not improve normal acquisition and performance during a four-response chain task but it did reverse those deficits induced by the benzodiazepine alprazolam (Thompson et al. 1995) and improved performance in delayed match to sample (Pontecorvo and Evans 1985). It was also effective in short- and long-term retention in rodent passive avoidance tests as well as reversal of cognitive performance induced by scopolamine and cyclohexamide (Cumin et al. 1982). In other paradigms designed to look at short-term (working) memory and long-term (reference) memory, aniracetam also proved effective (Zajaczkowski and Danysz 1997; Bartolini et al. 1992; Ohno et al. 1990; Ogasawara et al. 1999; Hori et al. 1991). Therefore, despite a relatively low potency, a variety of positive effects on cognition can be seen with aniracetam. There is little evidence of side effects with this class of compounds. An obvious problem to global positive modulation of AMPA could be convulsions/seizures. Aniracetam is not proconvulsant itself but can reverse the effect of anticonvulsants (De Sarro et al. 2000; Chapman et al. 1993). Aniracetam is marketed in Italy, Greece, and Switzerland for mild to moderate senile dementia of the Alzheimer type (Lee and Benfield 1994). A series of recent reports (reviewed in Nakamura 2002) highlight the potential of aniracetam in attention deficit hyperactivity disorder (Nakamura et al. 2000, Nakamura and Kurasawa 2000), depression (Nakamura et al. 2000), and schizophrenia (Nakamura et al. 1998a, b; 2000).

IDRA21 reversibly increases AMPA transmission in the hippocampus (Bertolino et al. 1993) and augments LTP (Arai et al. 1996). In rodent water maze experiments, IDRA21 improved performance by decreasing the number of errors required to exit a novel maze (Zivkovic et al. 1995). It also reversed maze learning and retention deficits induced by the AMPA antagonist NBQX, the benzodiazepine alprazolam, and the muscarinic antagonist scopolamine. Therefore, IDRA21 enhanced pharmacologically impaired cognitive function in the short term. It also reversed alprazolam-induced amnesia over a 24-h period in the rodent passive avoidance test (Zivkovic et al. 1995). In primates, IDRA21 did not improve normal acquisition and performance during a four-response chain task but it did reverse those deficits induced by alprazolam (Thompson et al. 1995). In a primate delayed match to sample paradigm, IDRA21 improved short-term working memory; this effect was more robust in young than old rhesus monkeys (Buccafusco et al. 2004). The overall performance during the testing period was carried over into nondrug days. The reasons for this discrepancy between pharmacodynamic and pharmacokinetic effects are unclear. Therefore, IDRA21 appears to have a reasonably wide spectrum of positive effects on cognition, both in terms of long-term reference memory and short-term working memory.

By far the most explored set of AMPA modulators are the Ampakines. All of these benzoylpyrrolidine compounds (1-BCP, CX516, CX546) augment AMPA transmission and promote LTP formation (Granger et al. 1993; Stäubli et al. 1994; Arai et al. 1994) in the hippocampal slice. Differences have been seen on AMPA receptor kinetics among different AMPA modulators (Arai et al. 1996). More recently it has been noted that even within the Ampakines, response differences can be seen. For example CX516 enhances response amplitudes more than response duration in the hippocampus, whereas CX546 enhances response duration greatly, with only modest increases in response amplitude (Arai et al. 2004), thus further raising the potential for differentially acting positive AMPA modulators having different functional outcomes and different therapeutic profiles (Table 2).

As the Ampakines promoted LTP, experiments were performed in models of memory. Ampakines were shown to be effective in a variety of long-term reference memory (24 h or greater) tasks such as the Morris water maze, conditioned fear, olfactory learning and two-odor discrimination (Stäubli et al. 1994; Rogan et al. 1997; Larson et al. 1996), but also short-term working memory in the eight-arm radial maze (Stäubli et al. 1994). CX516 was subsequently shown to improve working memory in the delayed non-match-to-sample (DNMTS) task (Hampson et al. 1998a). Interestingly, a “carry over effect” was seen on nondrug days, indicating that, as with IDRA21, a pharmacodynamic/pharmacokinetic disparity may exist (Buccafusco et al. 2004). In an accompanying paper, chronically implanted electrodes monitored CA1 and CA3 hippocampal activity during the DNMTS procedure. It was found that while the hippocampus responds to the stimulus (lever presented), it also has increased activity during the delay phase (holding the information) and responds again on a correct non-match response (Hampson et al. 1998b). One could hypothesize that this engaged activity during the delay phase of seconds represents activity between the hippocampus and prefrontal cortex (PFC) and is representative of energy required to hold information in working memory. CX516 not only enhanced the response to stimulus and delivery of the correct non-match response but also greatly increased the hippocampal activity during the delay period, possibly indicating enhanced working memory as well as retrieval. In a conditioned eye-blink procedure (Shors et al. 1995), it was shown that CX516 not only enhances acquisition of a conditioned reflex but also promotes learning of a sub-threshold conditioning, thereby lending weight to the ability of positive AMPA modulation to “turn up the gain” and improve plasticity.

This preclinical work was followed up with exploratory clinical studies with CX516. Modest improvements in short-term retention memory of nonsense syllables (1–3 h) were seen in young as well as older humans (Lynch et al. 1996; Lynch et al. 1997) at doses of almost 1 g orally. A closer look at memory types influenced revealed that while verbal recall was not affected, visual and odor recall as well as maze performance was enhanced over a 5-day period using 300 mg CX516 (Ingvar et al. 1997). Therefore, within a decade, positive AMPA modulators have progressed from brain slice LTP studies through rodent models of memory to human trials in cognition. The predominant emphasis was, however, long-term retrieval memory with a view to treatment of disorders of cognition such as Alzheimer’s disease and mild cognitive impairment, no doubt because of the original observations in hippocampal LTP studies. However, along the way, suggestions of efficacy in short-term (working) memory and problem solving were also seen (Hampson et al. 1998a, b; Stäubli et al. 1994; Ingvar et al. 1997), functions traditionally associated with the frontal cortices. Indeed, in a comparative study looking at the effects of AMPA on brain slices, CX516 failed to show a significant enhancement in the hippocampus whereas it did in PFC slices (Black et al. 2000). CX516 has been shown to augment in vitro and in vivo AMPA responses in the PFC (Baumbarger et al. 2001). In more recent years, emphasis has appeared to divert from long-term (hippocampal) retrieval memory to short-term working (frontal cortical) memory. Short-term (working) memory is known to be defective in diseases such as schizophrenia.

Schizophrenia is characterized by a variety of symptoms that can be clustered into three categories: positive symptoms, negative symptoms and cognitive deficits. The cognitive impairments are typified by inattention and deficits in several mnemonic processes, particularly working memory (Liddle 1992; Weinberger and Berman 1996). Although the pathophysiology of schizophrenia has not been elucidated, several lines of evidence have suggested that dysfunction of glutamatergic neurotransmission within specific circuits in the brain may contribute to the symptoms of this disease. The “glutamate hypothesis” or “hypoglutamatergia hypothesis” has stemmed from the observation that administration of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist (Anis et al. 1983), can produce a psychotomimetic state in healthy individuals that includes positive and negative symptoms and cognitive deficits (Luby et al. 1959). In addition, ketamine, a congener of PCP, has been shown to have similar effects in normal subjects and to exacerbate psychosis in schizophrenia patients (Krystal et al. 1999a, b). PCP and other noncompetitive NMDA antagonists have been used to model aspects of schizophrenia symptomatology in preclinical research (for reviews see Olney et al. 1999 and Javitt and Zukin 1991). Therefore, there is a strong rationale for glutamatergic therapies in schizophrenia. As mentioned previously, some studies suggest beneficial effects of positive AMPA modulators on short-term working as well as long-term reference memory (Hampson et al. 1998a, b; Stäubli et al. 1994; Ingvar et al. 1997). Working memory is often assessed using delayed-response tasks in which a delay is introduced between a cue and a required appropriate response. Electrophysiological studies in primates have indicated that changes in PFC and hippocampal neuronal activity are seen when subjects are engaged during the execution of working memory tasks (Goldman-Rakic 1994; c.f. Hampson et al. 1998b) and clinical studies have linked prefrontal cortical activity with working memory performance. In schizophrenia patients, decreased functioning of the PFC has been demonstrated concomitant with poor performance on working memory tasks (Weinberger and Berman 1996). Analogous imaging experiments in humans have shown that administration of PCP or ketamine will disrupt working memory in conjunction with a selective decrease in PFC activity (Javitt and Zukin 1991; Krystal et al. 1994). Although the source of PFC dysfunction is unknown, evidence suggests that deficits in glutamatergic excitatory transmission may be involved (Romanides et al. 1999; Dudkin et al. 1997; Weinberger and Berman 1996; Eastwood et al. 1997; Goldman-Rakic 1994; Javitt and Zukin 1991).

Not surprisingly, Ampakines were tested in models predictive of antipsychotic activity. When given alone, CX516 was inactive against methamphetamine or MK801-induced locomotor activity (Vanover 1997; Johnson et al. 1999). However, when coadministered with an atypical antipsychotic, CX516 potentiated the antipsychotic effect (Johnson et al. 1999). Other structurally related ampakines were effective alone against methamphetamine-induced behaviors (Vanover 1997; Larson et al. 1996). Therefore, it appears that some ampakines were effective alone in these models, whereas others only potentiated the effect of antipsychotics; once again hinting at therapeutic selectivity stemming from a difference of effect at the AMPA subunit level. These data were replicated in small human studies where CX516 was ineffective as a monotherapy but potentiated the effects of an atypical antipsychotic, particularly in the cognitive and negative realms (Marenco et al. 2002; Goff et al. 2001).

Interestingly, in rodents, flip/flop ratios change from adolescence to adulthood (Monyer et al. 1991; Stine et al. 2001) and are affected (decreased GluR3 flop in the PFC) by a neurodevelopmental model of schizophrenia (Stine et al. 2001). In post-mortem tissue from schizophrenia patients, decreases in hippocampal GluR2 flip and flop were reported (Eastwood et al. 1997); as the decrease was greatest for the flop isoform of GluR2, the flip/flop ratio changed the most. Because flop variants show a faster desensitization rate, a change in flip/flop ratio, rather than total subunit amount, may alter glutamatergic transmission and could underlie some aspects of disease state. AMPA receptor binding is decreased in the hippocampus (Meador-Woodruff and Healy 2000) and increased in the anterior cingulate cortex (Zavitsanou et al. 2002) of schizophrenia patients. Therefore, further clinical trials in the treatment of schizophrenia with more potent positive AMPA modulators could be of great value.

Pharmacological investigation into positive AMPA receptor modulators and therapeutics—recent data and what’s next?

Despite the low potency and short half-life, CX516 made a remarkable transition from brain slice observations to clinical studies. One can only hypothesize what it could have done if it had better potency and pharmacokinetic profile. Recent years have seen the emergence of compounds with much greater potency and presumably better pharmacokinetic qualities. Eli Lilly has reported on a number of compounds with low to submicromolar potency in vitro (at recombinant human AMPA receptors). These arylpropylsulfonamide compounds (LY404187, LY392098, LY395153, LY451646) demonstrate functional AMPA receptor subunit selectivity, differing effects on the kinetics of AMPA activity (Miu et al. 2001), and interact with different sites from other positive AMPA modulators (Quirk and Nisenbaum 2003). Potent in vitro (low micromolar/nanomolar) and in vivo (single digit milligrams per kilogram or less-parenteral routes) potentiation of evoked AMPA responses has been reported in the frontal cortex as well as hippocampus of rodents (Quirk and Nisenbaum 2002, 2003). So far, and somewhat surprisingly, few reports have emerged on measures of cognition. Rather, reports on the effects of these positive AMPA modulators in models of depression [including increases in BDNF (brain-derived neurotrophic factor) levels], Parkinson’s disease, and neuroprotection have emerged (Dicou et al. 2003; Gates et al. 2001; Mackowiak et al. 2002; Bai et al. 2001; Baumbarger et al. 2001; Martin et al. 1992; O’Neill et al. 2004; Quirk and Nisenbaum 2002; Vandergriff et al. 2001). Perhaps the structural class and concomitant AMPA subunit pharmacology of these compounds lend them more toward therapies for affect and neuroprotection than cognition. At first glance the potential therapeutic roles of positive AMPA modulators in neuroprotection appears incongruent. In the first paragraph of this manuscript I stated “As a general rule antagonists have been used as analgesic or neuroprotective agents and agonists/positive modulators as cognition enhancers.” However, positive AMPA modulators may break this general rule. As stated previously, a number of positive AMPA modulators have been shown to increase BDNF production (Lauterborn et al. 2000, 2003; Mackowiak et al. 2002; Murray et al. 2003), potentially via Lyn kinase (Hayashi et al. 1999). BDNF has been reported to have neuroprotective as well as antidepressant roles (Siegel and Chauhan 2000; Hashimoto et al. 2004). This raises the question of whether all AMPA receptors, and their subunits, are linked to BDNF; and of course will all positive AMPA modulators increase BDNF? The answers to this and other questions regarding specificity of the drugs to AMPA subunits and subsequent “subunit specificity” to certain biological events, e.g., BDNF production, are not yet clear. It will be interesting to watch the development of these compounds as they progress to the clinic. If Table 1 is used as a guide, a compound that modulates just GluR4 would likely only affect AMPA receptors in the cerebellum and certain thalamic areas, whereas modulating GluR1 would predominantly affect the frontal lobes and hippocampus. The resultant biological effect and therefore the therapeutic potential of such compounds would be very different. Just as agents acting on serotonin receptors have a plethora of biological/therapeutic effects, when one considers four AMPA subunits—each of which can exist as a flip or flop variant—with each subunit being differentially distributed across the brain, the permutations are enormous. This diversity could offer numerous therapeutic potentials.

Notes

Acknowledgements

The author would like to thank Beth Borowsky, Kathleen McMonagle-Strucko, and Sam Kongsamut for scientific and technical discussion during the preparation of this manuscript.

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© Springer-Verlag 2005

Authors and Affiliations

  1. 1.CNS PharmacologySanofi-aventisBridgewaterUSA

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