Image Map

by: David Tolson

Brain Food: Aniracetam – Part II

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.

General Effects

Aniracetam’s effects are primarily centrally mediated [1]. 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 [4]. According to one reference, aniracetam does not significantly affect cerebral blood flow as piracetam does [5].

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 [6]. 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 [7]. 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 [6]. 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 [10]. 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 [11]. 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 [12]. Activity at one of these subtypes will often cause changes in the activity of the other subtypes [13].

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) [16].

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 [20].

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 [16]. 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 [22].

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 [21].


It has been argued that the concentrations needed for AMPA modulation are higher than those that will be reached in vivo after aniracetam administration [24], 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 [25]).

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 [24]. However, newer research comparing aniracetam, piracetam, and nefiracetam found that only aniracetam potentiated AMPA currents [26]. The metabolites of aniracetam also have nootropic effects independent of AMPA modulation [27]. 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 [28]. Nevertheless, this effect may augment aniracetam’s or its metabolites effect on some glutamate receptor subtypes [29]. 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 [13].

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 [32], while another found NMDA receptor modulation at an even lower concentration than that required to affect AMPA receptors [33]. 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 [13]. 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 [13]. 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 [34], 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 [35]. 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 [27]. An increase in acetylcholine may possibly function as a mechanism by which aniracetam increases glutamate release, further stimulating NMDA and AMPA receptors [29]. 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 [29] [37]. Aniracetam also prevents the age-related decrease in monoamine levels in rats [38]. The monoaminergic effects have been primarily attributed to the metabolites N-anisoyl-GABA and p-anisic acid [2].

Both cholinergic and glutamatergic stimulation are involved in aniracetam-induced monoamine release [2]. 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 [27]. In short, there are many experimentally supported mechanisms by which aniracetam increases monoamine levels, including cholinergic-monoaminergic, glutamatergic-monoaminergic, and cholinergic-glutamatergic-monoaminergic interactions [2]. 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.

For questions or comments regarding this article, email [email protected].



1. J Pharmacol Exp Ther. 2000 Jun;293(3):921-8. Effects of aniracetam on bladder overactivity in rats with cerebral infarction. Nakada Y, Yokoyama O, Komatsu K, Kodama K, Yotsuyanagi S, Niikura S, Nagasaka Y, Namiki M.

2. Brain Res. 2001 Oct 19;916(1-2):211-21. Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP. Shirane M, Nakamura K.

3. Eur J Pharmacol. 2001 May 18;420(1):33-43. Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism. Nakamura K, Kurasawa M.

4. Pharmacol Biochem Behav. 2001 Jan;68(1):65-9. Aniracetam restores motivation reduced by satiation in a choice reaction task in aged rats. Nakamura K, Kurasawa M.

5. Lancet. 2001 Dec 1;358(9296):1885-92. Pyrrolidone derivatives. Shorvon S.

6. Gouliaev AH, Senning A. Piracetam and other structurally related nootropics. Brain Res Brain Res Rev. 1994 May;19(2):180-222.

7. Methods Find Exp Clin Pharmacol. 1980 Oct;2(5):269-85. Quantitative EEG and psychometric analyses in assessing CNS-activity of Ro 13-5057–a cerebral insufficiency improver. Saletu B, Grunberger J, Linzmayer L.

8. Kondakor I, Michel CM, Wackermann J, Koenig T, Tanaka H, Peuvot J, Lehmann D. Single-dose piracetam effects on global complexity measures of human spontaneous multichannel EEG. Int J Psychophysiol. 1999 Oct;34(1):81-7.

9. Nootropics – Reviewing the Smart-Drugs. South J.

10. J Neurosci. 2003 Nov 26;23(34):10953-62. Multiple molecular determinants for allosteric modulation of alternatively spliced AMPA receptors. Quirk JC, Nisenbaum ES.

11. Neuropharmacology. 2000 Mar 3;39(5):866-72. Group II metabotropic glutamate receptors are a common target of N-anisoyl-GABA and 1S,3R-ACPD in enhancing ACh release in the prefrontal cortex of freely moving SHRSP. Shirane M, Nakamura K.

12. Neuropharmacology. 2001 Jun;40(8):992-1002. LY392098, a novel AMPA receptor potentiator: electrophysiological studies in prefrontal cortical neurons. Baumbarger P, Muhlhauser M, Yang CR, Nisenbaum ES.

13. Synapse. 2000 Dec 1;38(3):294-304. Ionotropic glutamate receptor modulation preferentially affects NMDA receptor expression in rat hippocampus. Healy DJ, Meador-Woodruff JH.

14. Neuroscience. 2001;102(1):101-11. Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor-mediated stimulation of glutamate and GABA release in the rat striatum in vivo: a dual-label microdialysis study. Patel DR, Young AM, Croucher MJ.

15. Synapse. 2001 May;40(2):154-8. Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors. Suppiramaniam V, Bahr BA, Sinnarajah S, Owens K, Rogers G, Yilma S, Vodyanoy V.

16. Br J Pharmacol. 2002 Aug;136(7):1033-41. A desensitization-selective potentiator of AMPA-type glutamate receptors. Sekiguchi M, Nishikawa K, Aoki S, Wada K.

17. Brain Res Mol Brain Res. 2002 Jan 31;98(1-2):130-4. The aniracetam metabolite 2-pyrrolidinone induces a long-term enhancement in AMPA receptor responses via a CaMKII pathway. Nishizaki T, Matsumura T.

18. Eur J Pharmacol. 2000 Apr 7;394(1):85-90. Effect of AMPA receptor modulators on hippocampal and cortical function. Black MD, Wotanis J, Schilp DE, Hanak SE, Sorensen SM, Wettstein JG.

19. J Neurosci. 1997 Aug 1;17(15):5760-71. A novel allosteric potentiator of AMPA receptors: 4–2-(phenylsulfonylamino)ethylthio–2,6-difluoro-phenoxyaceta mide. Sekiguchi M, Fleck MW, Mayer ML, Takeo J, Chiba Y, Yamashita S, Wada K.

20. Neuropharmacology. 2001 Jun;40(8):984-91. Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro. Gates M, Ogden A, Bleakman D.

21. Mol Pharmacol. 2003 Aug;64(2):269-78. The mechanism of action of aniracetam at synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors: indirect and direct effects on desensitization. Lawrence JJ, Brenowitz S, Trussell LO.

22. Brain Res Mol Brain Res. 2003 Sep 10;117(1):91-6. 2-pyrrolidinone induces a long-lasting facilitation of hippocampal synaptic transmission by enhancing alpha7 ACh receptor responses via a PKC pathway. Miyamoto H, Yaguchi T, Ohta K, Nagai K, Nagata T, Yamamoto S, Nishizaki T.

23. Ann N Y Acad Sci. 2003 May;993:229-75; discussion 287-8. Multiple sclerosis and glutamate. Groom AJ, Smith T, Turski L.

24. Pharmacol Biochem Behav. 1997 Jan;56(1):21-9. Effects of D-cycloserine and aniracetam on spatial learning in rats with entorhinal cortex lesions. Zajaczkowski W, Danysz W.

25. Restor Neurol Neurosci. 1998;13(1-2):41-57. 2,3-benzodiazepine AMPA antagonists. Tarnawa I, Vize ES.

26. Brain Res. 2000 Jul 7;870(1-2):157-62. Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action. Nomura T, Nishizaki T.

27. Pharmacol Biochem Behav. 2002 May;72(1-2):45-53. Cholinergic and dopaminergic mechanisms involved in the recovery of circadian anticipation by aniracetam in aged rats. Tanaka Y, Kurasawa M, Nakamura K.

28. Neurosci Lett. 2003 Mar 27;339(3):187-90. Effects of aniracetam on extracellular levels of transmitter amino acids in the hippocampus of the conscious gerbils: an intracranial microdialysis study. Yu S, Cai J.

29. Neurosci Lett. 2002 Mar 8;320(3):109-12. Aniracetam enhances glutamatergic transmission in the prefrontal cortex of stroke-prone spontaneously hypertensive rats. Togashi H, Nakamura K, Matsumoto M, Ueno K, Ohashi S, Saito H, Yoshioka M.

30. Brain Res. 2001 Apr 6;897(1-2):82-92. Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats. Nakamura K, Shirane M, Koshikawa N.

31. Eur J Pharmacol. 1995 Jan 16;272(2-3):203-9. Putative cognition enhancers reverse kynurenic acid antagonism at hippocampal NMDA receptors. Pittaluga A, Pattarini R, Raiteri M.

32. Mol Pharmacol. 2001 Apr;59(4):674-83. Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons. Zhao X, Kuryatov A, Lindstrom JM, Yeh JZ, Narahashi T.

33. J Pharmacol Exp Ther. 1999 Jul;290(1):423-8. Activity of putative cognition enhancers in kynurenate test performed with human neocortex slices. Pittaluga A, Pattarini R, Andrioli GC, Viola C, Munari C, Raiteri M.

34. Pharmacol Biochem Behav. 1996 Apr;53(4):943-50. Piracetam and aniracetam antagonism of centrally active drug-induced antinociception. Galeotti N, Ghelardini C, Bartolini A.

35. Eur J Pharmacol. 2000 Aug 4;401(2):145-53. (S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [3H]noradrenaline release from rat hippocampal and frontal cortex slices. Lockhart B, Iop F, Closier M, Lestage P.

36. Curr Pharm Des. 2002;8(2):125-38. Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs. Gualtieri F, Manetti D, Romanelli MN, Ghelardini C.

37. Psychopharmacology (Berl). 2001 Nov;158(2):205-12. Antidepressant-like effects of aniracetam in aged rats and its mode of action. Nakamura K, Tanaka Y.

38. Gen Pharmacol. 1994 Sep;25(5):981-7. Biogenic monoamine uptake by rat brain synaptosomes during aging. Effects of nootropic drugs. Stancheva SL, Alova LG.

MM 20 OFF ALL PH 022417


Cutting Andro Kit
someone from Howell
Total order for 99.96 USD
someone from Los Angeles
Total order for 37.49 USD
Battle Hardener Kit
someone from Corona
Total order for 75.96 USD
someone from Mattoon
Total order for 37.49 USD
small_4AD_PHCaps (1)
someone from Greenville
Total order for 65.94 USD