Corresponding author: Igor I. Abramets ( abrametz2009@yandex.ru ) Academic editor: Mikhail Korokin
© 2019 Igor I. Abramets, Yuriy V. Kuznetsov, Dmitriy V. Evdokimov, Tamara O. Zaika.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Abramets I, Kuznetsov Y, Evdokimov D, Zaika T (2019) Piracetam potentiates neuronal and behavioral effects of ketamine. Research Results in Pharmacology 5(2): 49-55. https://doi.org/10.3897/rrpharmacology.5.35530
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Introduction: Ketamine has a fast, but short-term antidepressant effect. To support the therapeutic effect, repeated administrations of the drug are needed, which causes cognitive disorders. The drugs with cerebroprotective action can potentially intensify the main and weaken the side effects of drugs.
Materials and methods: The impact of ketamine (5 and 20 μM), piracetam (100 μM), and their combinations on the synaptic transmission was studied on hippocampal slices in the CA1 area of rat hippocampus by means of electrophysiological methods. In behavioral experiments were aimed at studying an impact of the used drugs on the predictors which mark depressant behavior of rats: the duration of immobilization in a forced swimming test and preference for the consumption of sucrose solution (comparably with water). The behavioral experiments were performed on intact rats and rats with behavioral depression induced by chronic swimming stress.
Results and discussion: Ketamine (5 and 20 μM) potentiates synaptic transmission in the radial layer of the CA1 hippocampal area. At a smaller concentration, ketamine potentiates synaptic transmission only due to the postsynaptic action, and at a greater concentration – with help of post- and presynaptic action. Piracetam (100 µM), like ketamine at a concentration of 5 μM stimulated synaptic transmission, but to a lesser degree. Ketamine at a concentration 5 μM under combined effect with piracetam induced the same effect as that at a concentration of 20 μM without piracetam, only due to a postsynaptic action. Ketamine at doses of 5 and 20 mg/kg one hour after a single systemic administration resulted in the reduced immobilization duration, but not predictors of preference for consuming a sweet solution; piracetam at a dose of 100 mg/kg under these conditions had no impact on the parameters of the rats’ behavior. The studied behavior parameters in cases of behavioral depression also changed after a single administration of ketamine at the doses of 5 and 20 mg/kg. Piracetam significantly stimulated an antidepressant action of ketamine under these circumstances.
Conclusion: Piracetam potentiates a ketamine-induced enhancement of the synaptic transmission at the radial layer of the CA1 hippocampal area when investigating at the brain slices. Piracetam stimulates an antidepressant action of a single dose of ketamine in cases of behavioral depression, though it has no antidepressant effect when administered at a single dose.
Major depressive disorder (MDD), prevailing in 7–12% of men and 20–25% of women, is a leading cause of disability and a serious public health problem. The current estimates by the WHO caution that MDD will become the second leading cause of disability after 2020. In addition to the increasing prevalence and the behavioral sequelae with it, MDD is an enormous economic burden on society. The existing treatments of MDD usually last from weeks to months to achieve their antidepressant effects, and many patients do not experience any sufficient improvement even after months of treatment. There is a danger of patients committing suicides during treatment. The fact is that twice as many people die from committing suicide each year than by homicide, and every fourth suicide victim had been treated by antidepressants until death (
Early 2000 showed that a single sub-anesthetic dose (0.5 mg/kg) of ketamine, a non-selective non-competitive antagonist of ionotropic N-methyl-D-aspartate (NMDA) glutamatergic receptors, produced a rapid and long-lasting antidepressant effects in patients suffering from MDD (
In pre-clinical trial, it was discovered that drugs with brain protective activity, e.g. piracetam (nootropil), reinforce an impact of tricyclic antidepressant imipramine on manifestations of behavioral depression in rats caused by a swimming stress (
The paper presents the results of studying the influence of nootropic drug piracetam on changes of glutamatergic synaptic transmission in the CA1 hippocampal area caused by sub-anesthetic doses of ketamine. At the same time, the paper looks at the changes of influence of ketamine on a duration of immobility in the forced swimming test and the preference for consuming sweet solution in cases of behavioral depression induced by chronic swimming stress at the background of piracetam action.
The research was performed on white inbred rats. The impact of ketamine and piracetam on glutamatergic transmission in the synapses formed by axons of pyramidal neurons of the CA3 area (Schaffer’s collaterals) and by dendrites of pyramidal neurons of the CA1 area was studied on the slices of the hippocampus, using a conventional electrophysiological method. The electrophysiological studies were performed on the slices of the rat dorsal hippocampus. The details of the method were given in (
The level of depressiveness in rats was assessed by recording the parameters of the forced swimming test (FST) (
The test of sucrose preference characterizing a hedonic behavior of rats was carried out by the method from (
(1)
First, an impact of intraperitoneally (i/p) administrated ketamine (5 and 20 mg/kg) and piracetam (100 mg/kg) on rats’ immobilization duration in FST was studied, as well as the percentage of preference for consumption of sucrose solution (PCSS) in the intact rats. Then, a depression syndrome was simulated according to the method from (
The research results were analyzed using the conventional methods of variation statistics and licensed Medstat software. For each series, the mean and standard error of the mean were determined. The significance of the differences in the compared values was assessed using a paired Student t-test.
The study looked at the impact of (R,S)-ketamine at concentration of 5 and 20 μM, which approximately corresponded to the doses of 5 and 20 mg/kg systemically administrated to rats, on glutmatergic excitatory synaptic transmission in the CA1 area of hippocampus. Amplitudes of fEPSPs of pyramidal neurons of the CA1 area significantly increased to 122.1±4.9 % (p<0.05) against control under the influence of Krebs solution with 5 μM of ketamine on the slices for 60 min. With ketamine at a dose of 20 μM influencing the slices, the amplitude of fEPSPs increased (p<0.01) to a greater extent to 166.8±6.6 % (Fig.
Impact of ketamine on parameters of synaptic transmission in pyramidal neurons of CA1 hippocampal area. Note: A – oscillograms of complex fEPSPs of pyramidal neurons, obtained in a separate experiment; 1 – control, 2 –one hour later with 5 μM of ketamine, 3 – one hour later with 20 μM of ketamine; B – three overlapping oscillograms; C – dependence of changes in amplitudes of complex fEPSPs on acting concentrations of ketamine; 1 – control, 2 and 3 – ketamine action at concentrations of 5 and 20 μM, respectively; D – changes of PPR of fEPSPs with ketamine impact on slices; 1–3 – as in C; E – ketamine impact on amplitudes of NMDA components of fEPSPs of pyramidal neurons; 1 – control, 2 and 3 – with ketamine at concentrations of 5 and 20 μM, respectively. Calibrations – 0.2 mV; 5 ms. * and ** – differences are significant at p<0.05 and p<0.01, respectively.
When affecting hippocampal slices, ketamine, though it noncompetitively blocks all types of NMDA glutamate receptors, caused increased amplitudes in fEPSP of pyramidal neurons (Fig.
Ketamine-induced enhancement of glutamatergic synaptic transmission in hippocampus was also observed by other researchers (
Enhancement of glutamate presynaptic release, caused by 20 µM ketamine, is associated with blockade of more ketamine-sensitive NMDA glutamate receptors, containing GluN2C and GluN2D subunits, in Schaffer’s collaterals (
The nootropic drug piracetam influenced the synaptic transmission at synapses formed by Schaffer’s collaterals and dendrites of pyramidal neurons of the CA1 area of hippocampus. When piracetam (100 μM) affects slices, the amplitudes of complex fEPSPs of pyramidal neurons significantly (p<0.05) increased to 122.4±5.1 % in relation to control (Fig.
Piracetam enhances synaptic transmission in pyramidal neurons of the CA1 hippocampal area. Note: A top – overlapping oscillograms of complex fEPSPs of pyramidal neurons before (1), 30 min after piracetam’s (100 μM) action on slices (2); A bottom – overlapping oscillograms of NMDA components of fEPSPs of pyramidal neurons before (1) and after (2) piracetam’s action. The oscillograms were obtained in a separate experiment. B and C –impact of 100 μM of piracetam on amplitudes of complex fEPSPs of pyramidal neurons and PPR, respectively. Calibrations – 0.2 mV; 5 ms. * – differences are significant at p<0.05.
Piracetam enhanced an impact of ketamine on synaptic transmission in the CA1 area of hippocampus. In fact, preliminary action of 100 μM piracetam for 30 min on the slices caused an increase in amplitudes of complex fEPSPs of pyramidal neurons to 121.3±4.7 % in relation to control. The influence of 5 μM ketamine on slices in the presence of piracetam 60 min later induced a further increase in amplitudes of complex fEPSPs to 167.6±5.8 % in relation to control (Fig.
Piracetam potentiates an impact of ketamine on synaptic transmission in pyramidal neurons of the CA1hippocampal area. Note: A left – overlapping oscillograms of complex fEPSPs of pyramidal neurons before (1) and 30 min after applying 100 μM of piracetam onto slices (2) and 60 min after applying ketamine (5 μM) in the presence of piracetam (3). A at center – changes in amplitudes of complex fEPSPs. A right – changes in PPRs in control (1), under the influence of piracetam (2) and of ketamine and piracetam (3). B – the same under the influence of piracetam (100 μM) and ketamine (20 μM) on slices. Calibrations – 0.2 mV; 5 ms. * and ** – differences are significant at p<0.05 and p<0.01, respectively.
Further, the study examined an impact of ketamine and piracetam on behavioral parameters of the intact rats relating to behavioral depression. One hour after i/p administration of 5 mg/kg ketamine, the time of immobilization of the rats in forced swimming test (FST) significantly reduced; after administration of a greater (20 mg/kg) dose, the time of immobilization reduced to a greater extent (Table
An impact of tested drugs on behavioral responses in control rats.
Administered drugs | Time of immobilization (s) | % preference for consumption of sucrose solution |
Control (vehicle) | 59.4±3.4 | 79.4±2.4 |
Ketamine 5 mg/kg after 60 min | 46.4±3.2* | 72.1±2.5 |
Ketamine 20 mg/kg after 60 min | 38.7±3.6* | 83.6±3.1 |
Piracetam 100 mg/kg after 60 min | 62.2±3.6 | 75.8±4.24 |
One day after the termination of the swimming stress impact, behavioral depression was observed, which was marked by an increased immobilization duration in FST and by anhedonia – a decreased PCSS (Table
Impact of tested drugs on behavioral responses of rats in behavioral depression caused by swimming stress.
Administered drugs | Time of immobilization (s) | % preference for consumption of sucrose solution |
Control (vehicle) | 59.4±3.4 | 79.4±2.4 |
1th day after termination of swimming stress (vehicle) | 114.0±5.1* | 54.0±1.8* |
Ketamine 5 mg/kg after 60 min | 79.8±3.9# | 66.1±2.1# |
Ketamine 20 mg/kg after 60 min | 68.4±3.7# | 71.2±2.3# |
Piracetam 100 mg/kg after 30 min | 99.4±5.4 | 59.6±2.4 |
Piracetam 100 mg/kg after 30 min + ketamine 5 mg/kg after 60 min | 54.7±3.1# ^ | 85.5±3.2# ^ |
Piracetam 100 mg/kg after 30 min + ketamine 20 mg/kg after 60 min | 47.4±4.1# ^ | 88.3±4.2# ^ |
The main advantage of ketamine is it fast antidepressant effect, but it lasts a week at most, therefore requiring the repeated administration of the drug. This is accompanied by adverse side effects – cognitive disturbances, disorders of memory, psychotic symptoms, increasing of oxidative stress in brain and developing drug addiction (
Piracetam potentiates enhancement of the ketamine-induced synaptic transmission in the radial layer of the CA1 hippocampal area in studies of the brain slices. When administered systemically, piracetam enhances an antidepressant effect of single-administered ketamine in behavioral depression, though piracetam has no antidepressant effect on its own in single administration.
Igor I. Abramets, Doctor of Medical Sciences, Full Professor of the Department of Pharmacology and Clinical Pharmacology named after I.V. Komissarov. e-mail: abramets4141@mail.ru, ORCID ID 0000-0002-2229-7541. The author developed the idea of the study, analyzed the results, and prepared the conclusion.
Yuriy V. Kuznetsov, PhD in Medical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology named after I.V. Komissarov. e-mail: far6@yandex.ru, ORCID ID 0000-0002-8368-5644. The author performed electrophysiological and behavioral studies and processed the results.
Dmitriy V. Evdokimov, PhD in Medical Sciences, Associate Professor of the Department of Pharmacology and Clinical Pharmacology named after I.V. Komissarov. e-mail: evdokimov.dmit@yandex.ru, ORCID ID 0000-0003-2989-7811. The author performed electrophysiological studies and processed the results.
Tamara O. Zaika, Assistant Lecturer of the Department of Pharmacology and Clinical Pharmacology named after I.V. Komissarov. e-mail: odoramenta@mail.ru, ORCID ID 0000-0003-0950-5999. The author performed behavioral and electrophysiological studies and processed the results.