by: David Tolson
In part I, we covered the basics on the piracetam analogue aniracetam. This compound is in the realm of 3-10 times as potent as piracetam, and has nootropic, antidepressant, and anxiolytic properties. This article will cover the research on aniracetam’s mechanism of action and discuss some of the systems in the brain that play important roles in learning and memory.
Aniracetam’s effects are primarily centrally mediated . Many of the effects, such as the anxiolytic effect, are due to the metabolites, and not aniracetam itself [2-3]. However, aniracetam itself has been implicated in some of the in vivo effects . According to one reference, aniracetam does not significantly affect cerebral blood flow as piracetam does .
Aniracetam causes a number of changes in the EEG. It was found to normalize the changes in the EEG due to hyperventilation in young humans . In a study in the elderly, aniracetam decreased delta activity, increased alpha and slow beta activity, and accelerated the dominant frequency. These changes generally corresponded to an increase in vigilance, as measured by shortened reaction time and other measures, and improved mood . The EEG changes caused by aniracetam are similar to those caused by piracetam and oxiracetam, although piracetam has been reported to decrease beta activity [8-9].
Adrenalectomy, inhibition of corticosteroid biosynthesis, and blockade of aldosterone receptors blocks the memory-improving effect of aniracetam . This is also the case with piracetam. For further discussion of the importance of this, see Piracetam Part II.
Introduction to AMPA Transmission
Aniracetam’s primary mechanism of action is positive modulation of AMPA receptors, a subtype of glutamate receptor. Before delving into this further, it is necessary to provide a brief overview of glutamate, and more specifically AMPA transmission.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and dysfunction in glutamatergic signaling has been implicated in several neurological disorders . Glutamate receptors are divided into two major types: metabotropic glutamate receptors and ionotropic glutamate receptors. There are at least eight subtypes of metabotropic glutamate receptors . Ionotropic glutamate receptors are subdivided into alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA, kainate), and N-methyl-D-aspartic acid (NMDA) receptors. These receptor types have differences in molecular, biophysical, and pharmacological properties . Activity at one of these subtypes will often cause changes in the activity of the other subtypes .
The majority of the fast excitatory transmission in the central nervous system is mediated by AMPA receptors. These receptors play a significant role in long-term potentiation, and as such they represent a therapeutic target for improving memory [1, 10]. A number of drugs have been created that prevent desensitization and/or deactivation of AMPA receptors through allosteric modulation, and many of these drugs have been found to improve cognitive function in experimental animals and healthy humans, including improvements in both long-term and working memory [10, 12]. AMPA receptors desensitize relatively rapidly when stimulated, and it is theorized that these drugs improve memory encoding by reducing the amount of stimulation required to induce synaptic plasticity [14-15]. Positive allosteric AMPA modulators have been divided into three main groups according to structure – the thiazide-related compounds (such as cyclothiazide), PEPA, and the benzoylpiperidine-related compounds (aniracetam, ampakines such as 1-BCP and CX-516) .
AMPA receptors are formed by various combinations of subunits encoded by four different genes designated GluR1-GluR4 (sometimes GluRA-GluRD), and subunit composition varies across brain regions. There are also “flip” and “flop” variants of these subunits due to alternative splicing of RNA, and the ratio of these variants also differs across brain regions [10, 12, 17-18]. All of these variations cause significant differences among AMPA receptors, and subunit composition and splice variant expression can cause changes in important properties such as the kinetics of deactivation, rate of onset and recovery from desensitization, calcium permeability, agonist and antagonist affinity, and other properties [12, 19]. Among the positive AMPA modulators, there are significant differences among their selectivity for the various isoforms of AMPA receptors, as well as other aspects of their mechanism of action .
Aniracetam and AMPA Transmission
Aniracetam reduces the rate of both deactivation and desensitization of AMPA receptors, leading to a potentiation of AMPA receptor activation [17, 21-23]. Of the subunits discussed above, aniracetam appears to modulate deactivation and desensitization primarily in GluR1 and GluR3 and has preferential flop activity [10, 16, 19]. It may also decrease deactivation in GluR1-flip subunits . The metabolite 2-pyrrolidinone also acts as an AMPA potentiator, while p-anisic acid has a weak effect, and N-anisoyl-GABA does not appear to have a direct effect on AMPA receptors [17, 22]. Preliminary research with 2-pyrrolidinone indicates that the effects on AMPA transmission may be mediated by an increase in protein kinase C activity and/or a calcium/calmodulin-dependent protein kinase II pathway .
The mechanism by which aniracetam potentiates AMPA transmission has been explored thoroughly. Some studies suggest that aniracetam works primarily by slowing the rate of channel closure. It has also been proposed that aniracetam promotes channel reopening after desensitization without necessarily slowing channel closure. Both of these propositions are however only partially supported by some experimental evidence. Therefore, it has been proposed that aniracetam acts via multiple binding sites, giving it a dual action. This effect is congruous with the experimental evidence .
It has been argued that the concentrations needed for AMPA modulation are higher than those that will be reached in vivo after aniracetam administration , but the importance of AMPA modulation in aniracetam’s mechanism of action has since become well established, and supported by numerous observations (e.g., AMPA antagonists block the memory improving effect of aniracetam ).
Given that this mechanism of action is relatively well understood and well established, it could be proposed that it represents a universal mechanism of action of the racetam nootropics. Piracetam and oxiracetam have both been reported to facilitate AMPA transmission in vitro . However, newer research comparing aniracetam, piracetam, and nefiracetam found that only aniracetam potentiated AMPA currents . The metabolites of aniracetam also have nootropic effects independent of AMPA modulation . It is therefore unlikely that facilitation of AMPA transmission is a necessary aspect of the racetam nootropics.
We will now explore some aniracetam’s other pharmacological properties. Some of these occur as a direct result of aniracetam’s effects on AMPA transmission, while others occur independently, often via aniracetam’s metabolites.
Aniracetam and its metabolites have a number of effects on other types of glutamate receptors. Aniracetam increases glutamate and aspartate in some areas of the brain, but the difference is slight . Nevertheless, this effect may augment aniracetam’s or its metabolites effect on some glutamate receptor subtypes . N-anisoyl-GABA may positively modulate group II metabotropic glutamate receptors, while aniracetam and the other metabolites do not appear to have an effect on metabotropic glutamate receptors [11, 30]. Aniracetam may decrease kainate receptor sensitivity, most likely indirectly through AMPA activation .
The research isn’t consistent regarding the effects aniracetam has on NMDA transmission. The NMDA antagonist MK801 prevents some of the behavioral effects of aniracetam, and aniracetam antagonizes kynurenic acid NMDA antagonism [4, 31]. One in vitro study indicated that aniracetam had no direct effect on NMDA receptors , while another found NMDA receptor modulation at an even lower concentration than that required to affect AMPA receptors . There will be at least some effect on NMDA transmission through AMPA modulation, as AMPA receptors play a permissive role for NMDA receptor activity. On the other hand, aniracetam prevents NMDA-induced neurotoxicity . It is clear that further research is needed to fully elucidate aniracetam’s role in this area.
As mentioned above, aniracetam decreases kainate receptor sensitivity. It has been hypothesized that this serves as a negative feedback mechanism to prevent an excessive amount of excitatory transmission, as kainate receptors decrease GABAergic activity . However, on balance, the effects of aniracetam on GABA levels tend to be small and inconsistent [28-29]. A weak direct interaction with GABA receptors is possible, but it is doubtful that it has much relevance [5-6]. Aniracetam has been found to reduce GABA-B receptor-mediated analgesia, and from there it was hypothesized that it has an effect on GABA-B receptors , but this theory doesn’t hold much water (see the GABA section of Piracetam Part II).
Glutamate receptor activation can promote the release of several other neurotransmitters . N-anisoyl-GABA increases acetylcholine (ACh) release in the prefrontal cortex of stroke-prone spontaneously hypertensive rats (SHRSP) through its positive modulation of group II metabotropic glutamate receptors, while aniracetam itself does not have this effect. However, 2-pyrrolidinone and aniracetam have been implicated in muscarinic receptor stimulation [27, 36]. Systemic aniracetam administration enhances acetylcholine release in the hippocampus, nucleus reticularis thalami and prefrontal cortex of rats, reverses scopolamine-induced decreases in ACh, and increases choline acetyltransferase activity . An increase in acetylcholine may possibly function as a mechanism by which aniracetam increases glutamate release, further stimulating NMDA and AMPA receptors . Muscarinic cholinergic activation may play a role in the improvement of circadian temporal regulation of behavior seen with aniracetam treatment, while the anxiolytic and antidepressant effects appear to be mediated by nicotinic receptor activation, as they can be blocked by the nicotinic ACh receptor antagonist mecamylamine [27, 37].
Administration of aniracetam to SHRSP, which normally have dopaminergic hypofunction, increases dopamine (DA) and serotonin (5-HT) release in the prefrontal cortex, basolateral amygdala, and dorsal hippocampus, areas which play important roles in regulation of emotion and mood, motivation, sleep-wakefulness, and cognition  . Aniracetam also prevents the age-related decrease in monoamine levels in rats . The monoaminergic effects have been primarily attributed to the metabolites N-anisoyl-GABA and p-anisic acid .
Both cholinergic and glutamatergic stimulation are involved in aniracetam-induced monoamine release . Both stimulation of nicotinic cholinergic receptors and consequently NMDA receptors and a direct effect on NMDA receptors in the ventral tegmental area and dorsal raphe nucleus may respectively lead to an increase in dopamine and both dopamine and serotonin . In short, there are many experimentally supported mechanisms by which aniracetam increases monoamine levels, including cholinergic-monoaminergic, glutamatergic-monoaminergic, and cholinergic-glutamatergic-monoaminergic interactions . Behaviorally, the increases in DA and 5-HT are implicated in the anxiolytic and antidepressant effects of aniracetam, and partially implicated in other effects, such as improved temporal regulation of behavior [2, 27].
We have discussed the therapeutic uses and experimental research on aniracetam. This compound appears to be a stronger nootropic agent than piracetam, although the possibility that piracetam has beneficial properties not shared by aniracetam cannot be excluded. Despite the complexities, such as multiple metabolites with different pharmacokinetic profiles, aniracetam’s mechanism of action is better understood than that of piracetam. AMPA modulation remains one of the most promising targets for cognition enhancing agents.
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