In part I of this series we discussed the history and uses of the nootropic agent piracetam. Piracetam significantly improves memory in animal models and humans when memory is compromised, and moderately improves memory in healthy humans and animals. Despite decades of research, piracetam’s mechanism of action is still largely elusive. Part II will discuss the effects piracetam has on the brain and their proposed mechanisms.
Piracetam’s effects are centrally mediated. This is supported by the fact that it reverses the action of central, but not peripheral anticholinergics, among other things . Piracetam also improves both cerebral blood flow and glucose utilization and alters EEG activity [1-2]. This last effect has been researched in some detail.
Spontaneous EEG readings indicate that piracetam causes a decrease in delta, theta, and beta activity and an increase in alpha activity . Alpha wave activity is usually associated with a state of being awake and alert, yet relaxed, and is commonly elevated in those undergoing activities such as yoga and meditation [4-5]. Piracetam also changes the late components of event-related potentials (ERPs), which are responsible for information processing .
One way in which multichannel EEG recordings are classified is by the measure of global dimensional complexity. A newer and related scale is global omega-complexity. These scales are correlated with mental activity, vigilance levels, and drug effects, and are said to measure “the degree of cooperation of the processes generating the electric field of the brain” . A decrease in complexity usually represents an increase in the brain’s functional state, and single doses of piracetam decrease both measures with a U-shaped dose response curve, with the largest decrease seen at 2.4 g . Although this information is useful for establishing dose-response curves, the usefulness of correlating changes in global complexity with behavior and cognition is debatable.
Piracetam also facilitates the interhemispheric transfer of information, as evidenced by early studies in both humans and animals [6-7]. The importance of this to piracetam’s activity, and whether this is a specific effect or a result of piracetam’s effect at large, is unknown.
Because of the wide variety of effects, it has been argued that piracetam’s mechanism of action is nonspecific. This is supported by the fact that a single common mechanism of the racetams has yet to be established. However, the fact that the dose-response curve for piracetam is bell-shaped would indicate a specific mode of action . We will now discuss the action of piracetam at the molecular level, to see if it sheds any light on this debate.
Since piracetam is a cyclic derivative of GABA and structurally similar, and the GABAergic system plays a role in learning and memory, it seems to be the most likely system to be effected by piracetam. However, piracetam shows no GABA receptor binding until extremely high concentrations are reached, and likewise does not affect uptake of GABA or levels of GABA in the brain or plasma [1, 6]. Piracetam does significantly decrease the I-wave peak size, an effect seen with GABAergic drugs such as benzodiazapenes, but this could be due to activation of neurotransmitter systems other than the GABA system which suppress generation of I-waves .
Although the GABAergic system does not appear to play a significant role in piracetam’s activity, there is some evidence of an effect relating to GABA-B receptors. In one study, piracetam had a similar pharmacological profile to the GABA-B antagonist CGP 35348, as it reduced analgesia caused by both direct and indirect GABA-B receptor activation and amnesia from direct GABA-B activation . It was hypothesized that piracetam had an effect on G-proteins or G-protein-mediated effects which caused it to have action similar to GABA-B antagonists. However, piracetam reduces analgesia caused by non-GABA related drugs as well, so the evidence for a GABAergic mechanism is still weak.
Piracetam can alter monamine levels and turnover in many ways. In general, piracetam most reliably leads to an increase in dopamine levels in animals. One study using 20 and 100 mg/kg found no significant effect on dopamine levels , but other studies with 100-600 mg/kg find increased levels and turnover of dopamine in various areas of the brain [1, 13-14]. This means that any effect piracetam has on dopamine levels in normal doses is likely to be insignificant.
The information on serotonergic and adrenergic transmission is even less conclusive. 20 mg/kg decreased brain 5-HT levels, while 100 mg/kg has been reported to increase total brain 5-HT but decrease 5-HT in the striatum [12-13]. 600 mg/kg increased serotonin levels and turnover in the cortex, but decreased both in the striatum, brain stem and hypothalamus . Doses of 20 mg/kg and 600 mg/kg were reported to increase norepinephrine levels, while 100 mg/kg caused a decrease [1, 12, 14].
This all goes to show that piracetam produces widely differential effects on the levels and turnover of monoamines in the brain, which are probably very condition-specific. Other studies indicate that piracetam decreases serotonin, dopamine, and norepinephrine brain concentrations in rats, or increases levels of all three [1, 9]. Piracetam yields differential effects on MAO as well, with studies finding either net inhibition or net stimulation [1, 10]. All of this taken together seems to indicate that any effect on monoamines probably occurs far downstream of the original effect, and this would be in line with the observation that no direct effect on dopaminergic, serotenergic, or adrenergic transmission has been found .
The glutamatergic system is the only receptor system which piracetam seems to have a direct effect on [1, 8, 15]. Piracetam binds to some glutamate receptors, although this may not be at all relevant in normal doses . Despite this, one review contends that the glutamatergic system may play a central role in piracetam’s nootropic activity .
One of the main supporting pieces of evidence for this hypothesis is that the memory-enhancing effects of piracetam can be easily blocked by NMDA channel blockers. Both ketamine and MK-801 antagonize the nootropic effect. In contrast, when MK-801 is administered along with the AChE inhibitor physostigmine it still markedly improves memory. In a Russian study, it was found that piracetam potentiated the response to glutamate and aspartate through the glycine site of the NMDA receptor, and this effect may be obscured by the presence of glycine. This would indicate a direct effect at the glycine site, and another 2-pyrrolidinone derivative, HA-966, exhibits antagonistic properties at the glycine site . Again, this effect has not been demonstrated to be relevant in normal doses. Piracetam also prevents the age-related decrease in NMDA receptor density , but this could easily be due to nonspecific action.
Piracetam may also have important effects on AMPA receptors. As is the case with NMDA receptors, it increases the density of AMPA receptor sites [1, 16]. More importantly, piracetam increases the efficiency, but not potency, of AMPA-induced calcium influx and antagonizes the effect of the L-type calcium channel blocker nifedipine. This represents a promising and largely unexplored mode of action, since positive modulation of AMPA receptors is also an effect shared by other cognition enhancers such as the ampakines and aniracetam.
The majority of the secondary literature reports that piracetam operates primarily via a cholinergic mechanism, which is not surprising, since the role of the central cholinergic system in learning and memory is fairly well-established, while the role other systems play is not as well-known . There is evidence both for and against the proposition that cholinergic transmission plays an important role in piracetam’s memory enhancing action.
The most reliable effect piracetam has on the cholinergic system is a restoration of muscarinic receptor density in aged rats and mice [1, 3, 15-16]. Studies on whether muscarinic receptor density is increased by piracetam in normal animals are contradictory, with one showing an effect and another showing none [1, 16]. However, as is the case with NMDA and AMPA receptors, an increase in receptor density does not imply a specific effect on that system, but could occur downstream of a different effect such as altered membrane fluidity. Another piece of evidence presented to support a cholinergic mechanism of piracetam is the fact that piracetam reverses scopolamine-induced amnesia, and scopolamine is an anticholinergic [1, 17-18]. Again, this does not necessarily show a specific action on the cholinergic system, especially since piracetam reverses the effects of many amnestic agents which do not exert their effects via the cholinergic system. Additionally, reversal of scopolamine-induced amnesia generally only implies that a drug may be useful for treating dementia, and would not explain piracetam’s effects in healthy individuals .
Most researchers also report that piracetam increases brain acetylcholine release in animals, particularly in the hippocampus, while others (including some in which cognitive enhancement is demonstrated) find no effect on acetylcholine [1, 3, 11, 16, 20]. Piracetam may also increase high-affinity choline uptake, although the majority of the research has failed to confirm this . Taken as a whole, the data indicates that piracetam generally increases cholinergic transmission, but this effect is not necessary for it to improve memory. This is further evidenced by the fact that piracetam has many qualities independent of drugs that improve memory primarily through cholinergic mechanisms – it can increase memory consolidation when administrated up to eight hours after a trial, as opposed to two, and unlike some cholinomimetics, the action of piracetam is reported to be steroid-dependent [1, 21].
Taken as a whole, it would seem that if there is a specific mechanism of action for piracetam, it does not involve an action exclusive to any neurotransmitter system. It could be that piracetam relies on a multitude of simultaneous events to improve memory, but this does not seem congruous with the wide variety of situations in which it proves effective. So it follows that the effects may not be mediated by a neurotransmitter system, but a different system in the brain.
A consistent observation in the literature has been that piracetam’s cognitive effects are steroid-dependent [1, 21]. In rats, it was reported that adrenalectomy, aminoglutethimide, and epoxymexrenone all interfere with piracetam’s nootropic effect, even though they did not decrease learning ability in and of themselves. When aldosterone or corticosterone was administered to adrenalectomised rats, the nootropic effect was restored. On the other side of the spectrum, high doses of aldosterone or corticosterone abolished piracetam’s memory improving effects.
The relationship between piracetam, corticosteroids, and memory was further researched in a passive avoidance model in day-old chicks. In this model, strong training results in avoidance for days or even weeks, while weak training results in avoidance for only a few hours. It was found that strong training, but not weak training, resulted in an elevation of corticosteroid levels, as well as corresponding changes in the synthesis of cell adhesion molecules and synaptic connectivity in some forebrain regions. Corticosteroid receptor antagonists also interfered with long-term retention with strong training, while intracerebral corticosterone facilitated learning from weak training . This is in opposition to the earlier results which implied that reduced corticosteroid levels did not significantly affect memory and learning. This is also in line with earlier studies that indicated that the stress response and corticosterone release are key factors in long-term memory consolidation .
When piracetam was introduced into this model, some interesting effects were seen. First, after weak training, piracetam caused a small increase in plasma corticosterone. This may functionally indicate that piracetam renders the physiological response to weak training closer to that of strong training, in other words, facilitation of long-term storage of what would otherwise be short-term memories. The second finding was in agreement with earlier findings, and indicated that corticosteroid antagonists (for both type I and type II receptors) prevented piracetam from facilitating long-term storage.
These effects must be interpreted with caution. First of all, although they show that piracetam’s effects are dependent on corticosteroids, they also show that memory and learning in general is dependent on corticosteroids. Also, elevated corticosteroid levels are by no means desirable, and block the effects of many memory improving drugs. A small elevation in corticosteroid levels is a necessary aspect of long-term memory consolidation, but that does not mean that it is the only aspect, or that the relationship is linear. Finally, there is conflicting data – although this study found piracetam increased corticosterone in response to a learning trial, an earlier study in rats which did not involve a learning trial found that piracetam decreased both basal and morphine-induced serum corticosterone levels . This could be due to difference in species or other experimental conditions. These results go to show that piracetam’s nootropic effect can be blocked by corticosteroid antagonists, but the evidence for a specific mechanism of action of piracetam involving corticosteroids is still weak – and again, nothing has been demonstrated at the molecular level, so these effects could just be further downstream.
In 1993, Gouliaev et al.  thoroughly reviewed the available research on piracetam’s mode of action. For most systems of the brain, their conclusions were similar to the ones here, although research from the past ten years has also been integrated. They concluded that the many different biological effects of piracetam (and other racetam compounds) were more than likely secondary to a more specific primary effect, and hypothesized that this effect was mediated by ion carriers or ion channels. A specific effect at the ion channel level would be expected to have an impact in every system of the brain, and in the case of piracetam, this net effect would coincide with an increase in memory and learning capability. There is also a large amount of experimental evidence supporting this proposition, although most of it stems from the assumption that the racetams share a similar mechanism of action.
The most promising target, especially given research in the last ten years, seems to be in the regulation of pre- and postsynaptic calcium levels by a change in calcium and/or potassium ion channel conductance. Both calcium and potassium antagonists have shown nootropic activity, and are respectively associated with a prevention of calcium ion entry into the cell (which prevents the cell from overload) and an increase of calcium influx into presynaptic nerve terminals. A study with isolated snail neurons using concentrations of piracetam similar to those that enhance cognition in vivo found that it suppressed both high-threshold Ca2+ and K+ currents. Both of these effects independently are associated with improved cognition, but when put together, the end result would be either an increase or decrease in intracellular calcium depending on cell type. 
Various other effects on ion channels have been noted with piracetam and other racetam compounds [1, 23], but there are too many to cover here, and the mechanism described above appears to be the most significant. However, we once again encounter the same weakness in this theory as we did with the others, because it would seem that if this was piracetam’s primary action, then it would be a single action, as opposed to many. Additionally, the evidence for a structure-activity relationship  seems contrived. Despite this, this is one of the better theories, as it would explain the majority of piracetam’s properties, and our inability to pin the mechanism of action on a single neurotransmitter system.
Both in vitro in mouse, rat, and human tissue and in vivo in rodents, piracetam increases brain membrane fluidity [1, 24]. Decreased membrane fluidity has been implicated in a wide variety of neurological deficits associated with aging, such as changes in signal transduction, enzyme activities, receptor numbers, and receptor functions . Piracetam particularly increases membrane fluidity in rodents that have decreased membrane fluidity to begin with, such as aged or scopolamine treated rats, and in these cases it brings membrane fluidity to the level of healthy controls [1, 24]. This increase occurs in most, but not all areas of the brain . Although the literature reports no increase in membrane fluidity in normal animals, it is noteworthy that the data always shows a nonsignificant trend toward an increase.
This increase in membrane fluidity is one of the best working theories for piracetam’s mechanism of action. For one, it would explain the lack of toxicity, as it brings membrane fluidity to a certain, optimal level, as opposed to increasing fluidity independent of other factors . This also explains why piracetam is most effective in situations where brain function is normally impaired . Secondly, given that piracetam changes membrane fluidity at a very rapid rate in vitro, the idea that this effect is downstream from a different effect such as altered lipid peroxidation or cholesterol/phospholipid ratios has been dismissed . Next, a specific structure-activity relationship has been theorized. There is evidence from multiple experiments indicating that piracetam partitions into the phospholipid bilayer of brain membranes and interacts with phosphate head groups, thus changing membrane properties [3, 8, 11, 15, 24]. Piracetam also affects blood cell membranes, which is presumably the cause for the positive cardiovascular effects [11, 25-26]. Finally, this model effectively explains most, if not all of piracetam’s known effects [16, 26].
Despite decades of research, there is still no commonly accepted mechanism of action for piracetam. A number of theories have emerged over the years, some stronger than others. The most likely explanation is that piracetam increases membrane fluidity, especially in compromised situations. Hopefully, further research will lead to more conclusive answers.
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