there is no proof that piracetam actually "decreases choline levels"
correct me if im wrong.
Well, since Piracetam stimulates thinking, I always figured that ACh was being used up faster and that the headache/upper back muscle tension sides of Piracetam was alliviated by a choline precursor since choline was being brought back to normal levels.
But is there proof?
This study below suggests that the racetams are known to increase ACh production and use and that there study found Piracetam to lower AChE levels (thereby increasing ACh levels):
"PIM is a member of the pyrrolidones group. Most of the pyrrolidones are known to influence cholinergic functions. ACh production and turnover are stimulated by most pyrrolidones but with varying actions at muscarinic and nicotinic receptors.[8],[11],[24] In our study PIM reduced the AChE activity of the brain."
http://www.ijp-onlin...4;aulast=Shahid[Full Text at that link]
RESEARCH PAPER Year : 2004 |
Volume : 36 |
Issue : 1 |
Page : 20-24
Reversal of phenytoin-induced impairment of spontaneous alternation by piracetam in mice: Involvement of cholinergic system
M Shahid, KK Pillai, Divya Vohora
Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi - 110062,, India
Correspondence Address:Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi - 110062,, India
divyavohora@hotmail.com
» Abstract
Objective: To study the effect of the combined treatment of phenytoin and piracetam on seizure control, cognitive and motor functions in mice. Material and Methods: Increasing current electroshock seizure (ICES) test was used to evaluate the effect of the combination of phenytoin and piracetam on convulsions. Cognitive functions in mice were assessed by spontaneous alternation in behavior on a plus maze while motor functions were screened using rolling roller apparatus and by counting the number of arms entries on a plus maze. Brain acetylcholinesterase (AChE) activity was measured using the Ellman et al method. Results: The study showed that
piracetam when co-administered with phenytoin, significantly reversed phenytoin-induced reduction in spontaneous alternation without altering the efficacy of phenytoin against ICES in both acute and chronic studies. Further, it also
reversed phenytoin-induced increase in AChE activity. Conclusion: Piracetam alleviated the phenytoin–induced cognitive impairment without compromising its antiepileptic efficacy.
» Discussion
The precise mechanism by which PIM exerts its nootropic effect is not known. Multiple mechanisms have been suggested such as an enhancement of oxidative glycolysis,[24] an effect on the Ca2+ channels[25] and an effect on the cholinergic system.[24] The latter is known to have an important role in the learning and memory processes. In our study, PHT, per se (12 mg/kg, p.o.) significantly elevated the
'brain AChE activity'.
PIM (250 mg/kg, p.o.) on the other hand
significantly lowered this activity indicating the counteracting action of the two drugs on the cholinergic system. The impairing effects of PHT on learning and memory have been attributed to alternations in the cholinergic system.
[2],
[16],
[17] It has been reported that PHT lowers brain ACh levels.
[2],
[16],
[17] Our results on AChE are thus consistent with these reports. It is worth noting that PHT at 8 mg/kg, p.o., did not show an impairment and did not affect AChE levels.
PIM is a member of the pyrrolidones group. Most of the pyrrolidones are known to influence cholinergic functions. ACh production and turnover are stimulated by most pyrrolidones but with varying actions at muscarinic and nicotinic receptors.[8],[11],[24] In our study PIM reduced the AChE activity of the brain. But, more importantly, in this context, it is interesting to note that when coadministered with an effective dose of PHT, PIM significantly alleviated the PHT-induced sharp rise in total brain AChE level, indicating the counteracting action of PIM and PHT on the cholinergic system.
To conclude, PIM when coadministered with therapeutic doses of PHT, significantly alleviated the adverse effects of PHT on cognitive function without compromising its antiepileptic efficacy, the effect possibly mediated by an action on the cholinergic system. However, clinical studies are required to explore the full potential of PIM in correcting PHT-induced cognitive deficits and finding a place in the current AED therapy.
This study shows that the racetams increase the utilization of ACh.
1: Clin Neuropharmacol. 1986;9 Suppl 3:S39-47.
Links Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition. Spignoli G,
Pedata F,
Giovannelli L,
Banfi S,
Moroni F,
Pepeu G.
Oxiracetam at 100 and 300 mg/kg i.p. dose levels
increased acetylcholine (ACh) utilization in the rat cerebral cortex and hippocampus. ACh utilization was assessed by measuring, with a gas chromatographic method, the decrease in ACh level after inhibiting its synthesis by 15 micrograms intracerebroventricularly (i.c.v.) injection of hemicholinium (HC-3). ACh steady state levels were not affected.
Piracetam (300 mg/kg i.p.)
also increased ACh utilization in the hippocampus. Repeated daily administration of oxiracetam 100 mg/kg i.p. caused a
31% increase in high-affinity choline uptake (HACU) in the hippocampus. A single administration of 300 mg/kg i.p. of oxiracetam and piracetam also increased HACU rate in the hippocampus. However, the effect of piracetam was over within 3 h, while 3 h after its administration oxiracetam still caused a 40% increase in HACU rate. Oxiracetam (100 mg/kg i.p.) significantly antagonized the impairment in the acquisition of an active-avoidance conditioned response (pole climbing) associated with the inhibition of ACh synthesis by HC-3.
These results indicate that oxiracetam enhances the activity of the septohippocampal cholinergic pathways, and to a lesser extent, of the cortical cholinergic network.1: Eur J Pharmacol. 1986 Jul 31;126(3):253-7.<script language="JavaScript1.2">
Links Oxiracetam prevents electroshock-induced decrease in brain acetylcholine and amnesia. Spignoli G,
Pepeu G. In the rat, 1 min following electroshock (ECS) a 46 and 39%
decrease in acetylcholine levels was found in the hippocampus and cerebral cortex, respectively. The decrease in the hippocampus was still statistically significant 30 min after ECS. The ECS applied 1 min after training also disrupted the performance of a passive avoidance conditioned response ('step down') tested 30 min later.
Oxiracetam (100 and 300 mg/kg i.p.) administered 90 min before training
prevented, in a dose-dependent manner, the decrease of acetylcholine in the cerebral cortex and hippocampus. Oxiracetam prevented the ECS disruption of the acquisition of a passive avoidance response. At the dose of 300 mg/kg the acetylcholine level 1 min after ECS was significantly higher than in the sham-treated rats. Piracetam at the same doses was inactive. These results
support the hypothesis that oxiracetam may prevent the disruption of the conditioned response by
acting on cortical and hippocampal cholinergic mechanisms.1: Pharmacopsychiatry. 1989 Oct;22 Suppl 2:116-9.<script language="JavaScript1.2">
Links The relationship between the behavioral effects of cognition-enhancing drugs and brain acetylcholine. Nootropic drugs and brain acetylcholine. Pepeu G,
Spignoli G,
Giovannini MG,
Magnani M. Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
The effect of different doses of the cognition-enhancing agent oxiracetam on the disruption of acquisition of a passive avoidance conditioned response (step-through) by scopolamine 0.6 mg/kg s.c., and on the impairment of performance by scopolamine 0.2 mg/kg s.c. in an eight-arm maze was investigated in adult male Wistar rats. At the end of the experiments, ACh levels were measured in the cerebral cortex and hippocampus by an HPLC method, in order to ascertain whether a relationship exists between the effects of the two drugs on behavior and cholinergic function. In the step-through test, oxiracetam at doses of 50 and 100 mg/kg s. c., given 30 min. before scopolamine, antagonized both scopolamine-induced behavioral disruption and decrease in ACh levels but was inactive at the dose of 300 mg/kg s. c. In the eight-arm maze test, oxiracetam prevented scopolamine-induced disruption of the performance and decrease in brain ACh at the dose of 30 mg/kg s. c. but was inactive at the dose of 100 mg/kg s. c. In conclusion, when scopolamininduced disruption of behavior is prevented or reduced, the scopolamininduced decrease in ACh level, particularly in the hippocampus, is also reduced. The present results therefore offer
further confirmation of a relationship between the cognition-enhancing effects of oxiracetam and its effects on hippocampal and cortical cholinergic mechanisms.
1: Pharmacol Biochem Behav. 1987 Jul;27(3):491-5.<script language="JavaScript1.2">
Links Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine. Spignoli G,
Pepeu G. Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
The effect of cognition-enhancing agents
oxiracetam and aniracetam on scopolamine-induced amnesia and brain acetylcholine decrease was investigated in the rat. Acetylcholine levels were measured by means of a gas-chromatographic method. Scopolamine (0.63 mg/kg IP 60 min before training) prevented the acquisition of a passive avoidance conditioned response ("step through": retest 30 min after training) and brought about a 64, 56 and 42% decrease in acetylcholine level in the cortex, hippocampus and striatum respectively. Oxiracetam (50 and 100 mg/kg IP) administered 30 min before scopolamine reduced the scopolamine-induced amnesic effect and decrease in acetylcholine level in the cortex and hippocampus, but not in the striatum. Lower and higher doses of oxiracetam were ineffective. Aniracetam (100 mg/kg PO) also prevented scopolamine-induced amnesia but attenuated acetylcholine decrease in the hippocampus only. Aniracetam (300 mg PO) reduced acetylcholine decrease in the hippocampus but did not prevent scopolamine-amnesia. In conclusion,
oxiracetam and aniracetam exert a stimulatory effect on specific central cholinergic pathways. However, a direct relationship between cognition-enhancing properties and cholinergic activation needs further confirmation.
1: Alcohol. 1999 Aug;19(1):65-74.
<script language="JavaScript1.2">
Links GM1 and piracetam do not revert the alcohol-induced depletion of cholinergic fibers in the hippocampal formation of the rat. Brandão F,
Ribeiro-da-Silva A,
Cadete-Leite A. Department of Anatomy, Porto Medical School, Alameda do Prof. Hernâni Monteiro, Portugal.
Chronic alcohol consumption causes a depletion of the cholinergic fiber network in the rat hippocampal formation, which is not ameliorated by alcohol withdrawal. Following withdrawal from alcohol, there is a further loss of intrinsic hippocampal cholinergic neurons. In this study, we investigated whether treatment with putative neuroprotective agents during the entire withdrawal period would have beneficial effects upon the hippocampal cholinergic innervation. Adult male rats were alcohol-fed for 6 months and subsequently withdrawn from alcohol for 6 months. Some animals were treated with either ganglioside GM1 (35 mg/kg body weight s.c.), vehicle (saline s.c.), or piracetam (800 mg/kg body weight p.o.) for the entire withdrawal period. Choline acetyltransferase (ChAT) immunoreactive (IR) fibers and neurons were analyzed quantitatively in all four animal groups. There were no significant differences in the density of the ChAT-IR hippocampal fiber network when the pure withdrawal and withdrawal + vehicle groups were compared to the withdrawal + GM1 or withdrawal + piracetam groups. In contrast, the number of ChAT-IR interneurons in the hippocampal formation was higher in the withdrawal + GM1 or withdrawal + piracetam groups than in the pure withdrawal and withdrawal + vehicle groups.
These results indicate that, in the doses used, neither neuroprotective agent had an effect upon the extrinsic cholinergic innervation, but they had a beneficial effect upon the hippocampal intrinsic cholinergic system.1: Nippon Yakurigaku Zasshi. 1992 Jan;99(1):27-35.<script language="JavaScript1.2">
Links [Biochemical studies of oxiracetam (CT-848) on cholinergic neurons] [Article in Japanese]
Mochizuki D,
Sugiyama S,
Shinoda Y. Exploratory Research Laboratories, Toyo Jozo Co., Ltd., Shizuoka, Japan.
Effects of oxiracetam on cholinergic neurons were investigated by biochemical methods. 1) Oxiracetam did not inhibit 3H-QNB binding in the cerebral cortex and hippocampus. 2) In the 3H-QNB binding study, oxiracetam did not change the inhibition-concentration curve for the muscarinic agonist carbachol and had no effect on GppNHp-induced inhibition of oxotremorine binding. 3) Oxiracetam (10-100 microM) enhanced K(+)-induced ACh release from slices of rat hippocampus. 4) In the in vitro perfusion studies, oxiracetam (10-100 microM), but not aniracetam and piracetam, enhanced choline-acetyltransferase (ChAT) activity in the hippocampal slices. 5) Repeated administration of oxiracetam (100 or 500 mg/kg, p.o., once daily) to old rats significantly enhanced ChAT activities in the cerebral cortex, hippocampus and striatum, while it did not influence the Bmax and Kd for 3H-QNB binding in the hippocampus. 6) Oxiracetam did not affect the acetylcholinesterase activity in mouse brain homogenate.
These results suggest that oxiracetam enhances precholinergic functions.1: Neuropsychobiology. 1988;19(3):139-45.<script language="JavaScript1.2">
Links Effects of piracetam on single central neurons. Maillis A,
Karayanidis F,
Koutsoukos E,
Angelopoulos E,
Stefanis C. Department of Psychiatry, Athens University, Eginition Hospital, Greece.
Piracetam, when applied microiontophoretically and/or by hydropneumatic pump on the somatosensory cortex and hippocampus of the rat, affected neuronal activity by depressing or facilitating the spontaneous firing rate, depending on the area studied. Its effect were either additive or counteracting the actions of
glutamate, gamma-aminobutyric acid and acetylcholine, when administered together on the same neuron, thus supporting the assumption that its action is directed towards specific membrane elements, presumably the synaptic sites.
1: Zh Vyssh Nerv Deiat Im I P Pavlova. 1995 Jul-Aug;45(4):791-801.<script language="JavaScript1.2">
Links [Changes in the indices of neuronal functional activity under the action of piracetam as a possible basis for realizing the effects of nootropic agents] [Article in Russian]
Vernyĭ IaI,
Derzhiruk LP,
Mogilevskiĭ AIa. Effects of piracetam (PA, 4-20 mM) on some electric characteristics of neuron activity were studied in vitro in identified neurons of Lymnaea stagnalis. Stimulation, single-electrode voltage clamping and recording of activity of the neuron were realized via the same intracellular microelectrode. PA-induced alterations of the characteristics under study were observed in 60-70% of recorded neurons. Modifications of action potential generation threshold, of the slope and shape of steady-state membrane current-voltage characteristics and appearance of PA-induced transmembrane ion currents occurred more frequently than changes in other parameters. Typically, Ca channel blockers (nifedipine and Cd ions) reversed or reduced the influence of PA on the studied characteristics of tested cell activity, i. e., acted as PA antagonists. This suggests that realization of observed PA effects is due to its
action on Ca channel functioning. Selective modification of the latter can determine development of various PA effects at the cellular level.
An assumption is discussed that piracetam, being a highly efficient cellular adaptogen and modifying specifically Ca channels of cells, is capable of moving them to a new level of functioning which is necessary for ensuring complex forms of nervous activity.
From
Piracetam - The Original Nootropic By James South MAhttp://www.eternitym...04...htm"Animal research has also shown that PIR increases high-affinity choline uptake (HACU), a process that occurs in cholinergic nerve endings which facilitates acetylcholine (ACH) formation. (23,29) "HACU rate has been shown to be directly coupled to the impulse flow through the cholinergic nerve endings and it is a good indicator of ... ACH utilization .... nootropic drugs [including PIR] activate brain cholinergic neurons ...." (29) HC-3 induces both amnesia and death through blocking HACU in the brain an din peripheral nerves that control breathing. Since PIR blocks HC-3 asphyxiation death and amnesia, this is further evidence of PIR's pro-HACU actions. (23,29)
Scopalamine (SCO) is a drug that blockades ACH receptors and disrupts energy metabolism in cholinergic nerves. When rats were given SCO, it prevented the learning of a passive avoidance task, and reduced glucose utilization in key cholinergic brain areas. When rats given SCO were pretreated with 100mg/kg PIR, their learning performance became almost identical to rats not given SCO. (36) The PIR treatment also reduced the SCO depression of glucose-energy metabolism in the rats' hippocampus and anterior cingulate cortex, key areas of nerve damage and glucose metabolism reduction in Alzheimer's disease. (36)
German researchers added to the picture of PIR's cholinergic effects in 1988 and 1991. Treatment for 2 weeks with high dose oral PIR in aged mice elevated the density of frontal cortex ACh receptors 30-40%, restoring the levels to those of healthy young mice. A similar decline in cortex ACh receptors occurs in "normal" aging in humans. (37) The same group of researchers then discovered that there is a serious decline in the functional activity of ACh receptors in aged mice; with many receptors becoming "desensitized" and inactive. Oral treatment with high dose PIR also partially restored the activity of ACh cortex nerves, as measured by the release of their "second messenger," inositol-1-phosphate. (38)"
"Yet as noted in the section on glutamate, because PIR is a cholinergic/glutamatergic activator, there is the potential for symptoms related to cholinergic/glutamatergic excess to occur, especially in those unusually sensitive to PIR. Such symptoms - anxiety, insomnia, irritability, headache, agitation, nervousness and tremor - are occasionally reported in some people taking PIR. (11,18) Reducing dosage, or taking magnesium supplements (300-500mg/day), which reduce neural activity, will frequently alleviate such "over-stimulation" effects. Persons consuming large amounts of MSG (monosodium glutamate) and/or aspartame in their diet should be cautious in using PIR, as should those who are highly sensitive to MSG-laden food (the "Chinese restaurant syndrome"). Caffeine also potentiates PIRŒs effects, as do other nootropics such as deprenyl, idebenone, vinpocetine and centrophenoxine, and it may be necessary to use PIR in a lower dosage range if also using any of these drugs regularly. Those wishing to augment PIRŒs cholinergic effects may wish to combine it with cyprodenate or centrophenoxine, which are much more powerful Ach enhancers than choline or lecithin."
Edited by Rags847, 07 August 2008 - 12:22 AM.
