Dyk

AMPA-receptor insertion and removal from the neuronal membrane (receptor trafficking). They are composed of four protein subunits (tetramers) clustered around an ion channel and which are denoted by GluR1-4. These sub-units can also exist as "flip" and "flop" variants. There is therefore AMPA-receptor subtype diversity throughout the brain. The calcium permeability of the receptors depends on the subunit composition - those containing GluR2 subunits are impermeable. The ► hippocampus and the ► amygdala are areas of the brain containing receptors that lack the GluR2 subunit and as a consequence, they have high calcium permeability.

There are two ways in which glutamate neurotransmission at AMPA-receptors is terminated. In the first case, deactivation, glutamate dissociates from the binding site and the ion channel closes. In the second, desensitization, glutamate remains bound, but a conformational change in the receptor causes a closing of the ion channel with the ligand trapped (see Fig. 2). The subunit constitution of the receptor can alter the rate at which it desensitizes. In principle then, any compound that prevents the deactiva-tion or the desensitization of the receptor should prolong the receptor response to glutamate. Such drugs are termed AMPAkines or AMPA-receptor potentiators and most act by preventing desensitization.

Four main classes of AMPA-receptor potentiators have been developed to date (see Table 1).

The exact pharmacology of each compound varies due to receptor diversity, but all can enhance glutamatergic neurotransmission at AMPA-receptors and this has a number of consequences. First, because AMPA-receptors play a key role in LTP, potentiation of their activity can remove the magnesium block on NMDA-receptors resulting in the enhancement of synaptic plasticity. Second, their activation can also increase the expression of the neurotrophin ► brain derived neurotrophic factor (BDNF); the result of this is to increase neurogenesis. It is therefore not surprising that AMPA-receptor poten-tiators should be of interest in regard to cognition enhancement.

The preclinical profile of the AMPA-receptor poten-tiators, with respect to therapeutic potential, including as cognition enhancers was reviewed by Black (2005). Several studies have shown that they can have beneficial effects on new learning. These procognitive actions have been reported in rodent maze tasks tapping spatial memory and in conditioning tests, such as passive avoidance or conditioned fear. In primate studies, they can also reverse pharmacologically-induced deficits in new learning. Also, there is evidence for positive benefits on ► working memory in both rodents (using models such as ► delayed

Cognitive Enhancers: Role of the Glutamate System. Fig. 2. Schematic diagram of different states of the AMPA receptor. (a) and (b) show resting and activation by glutamate respectively. Deactivation (c) and desensitisation (d) represent two different mechanisms by which glutamatergic neurotransmission at AMPA-receptors is terminated.

Cognitive Enhancers: Role of the Glutamate System. Table 1. The main classes of AMPA-receptor potentiators. (From O'Neill and Dix 2007.)

Chemical class

Examples

Pyrrolidones

Aniracetam, piracetam

Piperidines

1-BCP, CX-516

Benzothiazides

Diazoxide, cyclothiazide, IDRA-21

Biarrlpropylsulphonamides

LY-392098, LY-404187

matching to sample tests) and primates (► delayed non-matching to sample) and for improved performance in object recognition tests. Enhanced impulse control has been reported in rat studies. This latter finding, however, rests solely on the effect of aniracetam, and it is not yet clear whether this is a class effect of the AMPA-receptor potentiators.

Preclinically then, the cognitive effects of the AMPA-receptor potentiators are in many ways similar to those of drugs aimed at positively modulating the NMDA-receptor, perhaps because of their ability to enhance LTP, although this picture is likely to be biased by the use of animal models designed to detect specific pharmacological effects believed to be therapeutically useful in particular disorders.

Very few studies on the effects of AMPA-receptor potentiators have been carried out in humans. An early study found some evidence for improved free recall of nonsense syllables in elderly volunteers and a small clinical trial in younger adults was also able to detect enhanced performance in four different memory tasks (Lynch 2004). There is also some evidence for alerting effects in sleep deprived volunteers. In schizophrenic patients, equivocal results have been obtained, with CX516 as an add-on treatment to current antipsychotic medication. Results have also been disappointing with LY451395 in a trial in patients with Alzheimer's disease, where the measure of cognitive assessment was the cognitive subscale of the Alzheimer's disease assessment scale. Lastly, no improvement was seen in a variety of cognitive measures in a trial of CX516 in patients with ► Fragile X Syndrome. Fragile X Syndrome is an inherited disorder characterized by intellectual and emotional disabilities and where there may be abnormalities of AMPA-receptor trafficking. The reason for the negative results in patients is unclear, although some of the AMPA-receptor potentiators are not particularly potent drugs and the difficulty of achieving adequate concentrations has been debated.

Overall, the preclinical studies indicate that AMPA-receptor potentiators can promote learning and memory. However, there is room for investigation of their effects across more cognitive domains. There is a paucity of clinical studies, although those carried out in healthy volunteers are suggestive of some of the preclinical findings being translatable to humans.

Cognition Enhancers as Investigational Tools

For the most part, drugs such as the GRIs and the AMPA-receptor potentiators have been developed in attempts to provide new medicines for specific psychiatric disorders, most notably for schizophrenia. While this hopefully proves fruitful, many of the positive modulators of ionotrophic-receptor activity can also be used effectively as tools to investigate the role of ► glutamate in a broader range of cognitive functions and aspects of other mental health disorders. One obvious area for their use as tools is in addiction studies. This is partly because a role for glutamate-mediated neuroadaptations in addiction has been known for some time (see Kauer and Malenka 2007) partly as many drugs of abuse induce glutamate release in reward-related areas of the brain and also because the cognitive aspects of addictions, such as inhibitory control over drug-seeking behavior, are increasingly being recognized.

With the possible exception of the compounds that may require large doses, many of the drugs mentioned above could be used as tools in addiction research, in both animal and human studies. In using them as tools, one important factor needs to be taken into account. A common property of the GlycineB-site agonists, GRIs and the AMPA-receptor potentiators is that they do not directly activate receptors themselves. Instead, as they modulate the action of glutamate, it may be presumed that some level of endogenous activity would be required for their effects to emerge. In the case of the GlycineB-site agonists and the GRIs, the endogenous levels of glycine and d-serine are also likely to be a factor. It might be possible to predict however, certain situations where a level of endogenous activity is to be expected. First, where new learning occurs during the extinction of drug-taking behavior, thus in an analogy with the studies on fear extinction, these drugs would be expected to facilitate the process. Second, in line with much evidence from studies using NMDA-antagonists which indicates a role for glutamate in inhibitory control, it could be predicted that the GlycineB-site agonists and GRIs would aid active inhibition of impulsive behavior.

d-cycloserine, the partial agonist at the GlycineB-site, is well tolerated in humans and therefore being used increasingly as an investigative tool. As d-cycloserine is a partial agonist, it has the ability not only to potentiate glutamate-receptor function, but for a given dose, it can also block the action of glycine through its antagonist property. Like any partial agonist then, the "direction" of its behavioural effect depends on levels of endogenous activity. As a pure cognitive enhancer the effects of d-cycloserine therefore, may only be useful under particular conditions, but for the purposes of investigating the role of glutamate in cognition and behavior it may be a uniquely useful tool. A recent study by Jackson and colleagues illustrates how it can be used.

As there is a considerable amount of preclinical evidence implicating a role for glutamate in the effects of nicotine, d-cycloserine was used to investigate the role of glutamate in the cognitive and subjective effects of smoking in humans. Figure 3 illustrates the theoretical approach that was used for the study. Volunteers were asked

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