The impact of brivaracetam on cognitive processes and anxiety in various experimental models.

BACKGROUND: Memory deficits and anxiety symptoms are undesirable effects that occur in epilepsy patients. They may be associated with the pathophysiology of the disease but also with anticonvulsant therapy. Brivaracetam (BRV) is one of the newest antiseizure drugs. It acts as a ligand for synaptic vesicle glycoprotein 2A (SV2A), which may play a significant role in cognitive processes. Although BRV has a favorable safety profile, its central side effects remain unclear. Hence, this study aimed to evaluate the effect of BRV on various types of memory and anxiety in rats. METHODS: BRV was given to adult male Wistar rats (n = 80) via gastric tube as a single dose (6 mg/kg or 20 mg/kg) or chronically (6 mg/kg). The effect of the drug on spatial memory was evaluated in the Morris water maze (MWM), fear-learning by passive avoidance (PA), and recognition memory with novel object recognition (NOR). The elevated plus maze (EPM) was used to assess anxiety-like behaviors. RESULTS: The impact of BRV on memory is dose-dependent and mainly high doses may alter retrieval memory and fear-learning. Sub-chronic administration also impaired retrieval and spatial memory in animals. Moreover, chronic BRV may increase anxiety levels in rats but did not affect recognition memory. CONCLUSIONS: BRV may cause transient memory deficits as well as anxiety disturbances. However, the results are varied and depend on the type of memory, used dose, and duration of administration.

The Effect of Zonisamide and Ethanol on Various Types of Memory in Rats.

Background: Antiepileptic drugs might be useful in the treatment of alcohol use disorder. One of these drugs is zonisamide, which has been found to decrease alcohol intake and cravings. An important structure in the pathophysiology of addiction is the hippocampus. Memory deficits, which frequently occur in alcoholics, are associated with ethanol-induced changes in hippocampal plasticity and neurogenesis. The aim of this study was to assess the potential protective effect of zonisamide on memory in rats receiving alcohol and after the discontinuation of its administration. Methods: Wistar rats (n = 43) were tested in four behavioral models, namely: Morris water maze (MWM), passive avoidance (PA), contextual fear conditioning (CFC), and cued fear conditioning (CuFC). Results: Zonisamide co-administered with ethanol impaired spatial memory in MWM, but the drug did not affect memory in PA. However, the beneficial effect of zonisamide was observed after the discontinuation of ethanol administration, which was associated with the improvement of associative memory in CFC and the alleviation of alcohol-induced locomotor disturbances in CuFC. Conclusion: Zonisamide has a differential influence on memory, which depends inter alia on type of the memory, length of ethanol administration, or its absence.

The differential effect of levetiracetam on memory and anxiety in rats.

OBJECTIVE: One of the newest antiseizure medication is levetiracetam (LEV). It might be effective in various indications, not only related to convulsions. Central nervous system disorders are common during anticonvulsant therapy. The aim of this study was to assess the effect of LEV on various types of memory and anxiety in rats. METHODS: Adult male Wistar rats (n = 58) were given LV p.o. as a single (100 mg/kg or 500 mg/kg) or repeated doses (300 mg/kg). The effect of the drug on memory was assessed in the Morris water maze (MWM) (spatial memory), the passive avoidance (PA) (emotional memory) and the novel object recognition (NOR) (recognition memory). The anxiety was evaluated in the elevated plus maze (EPM). RESULTS: LEV administered as repeated doses disturbed the long-term recognition memory in NOR and locomotor activity in EPM. A single dose affected emotional memory in PA. LEV did not alter spatial memory in MWM. CONCLUSIONS: LEV may cause memory and locomotor disturbances, but some of these adverse effects seem to be temporary and limited to the effect of acute dose.

The antiepileptic drug lacosamide and memory - A preclinial study.

OBJECTIVE: Lacosamide (LC) belongs to a new generation of antiepileptic drugs (AEDs) and demonstrates unique mechanism of action. The drug also shows neuroprotective activity on the hippocampus. In this study, the impact of LC on learning processes was assessed. METHODS: Adult male Wistar rats (n = 40) were used. Lacosamide was administered p.o. as a single (25 mg/kg or 75 mg/kg) or repeated doses (75 mg/kg). The effect of the drug was assessed in the Morris water maze (spatial memory) and the passive avoidance (PA) (emotional memory). RESULTS: Lacosamide administered at a single dose or repeatedly did not impair spatial memory in Morris water maze. Higher swimming speed was observed in rats after administration of acute doses of LC. In PA, the disturbance of emotional memory was observed only after the single high dose of LC. CONCLUSION: Lacosamide does not impair memory and learning processes. The emotional memory impairment observed after the acute high dose appears to be temporary and did not occur after repeated administration.

Beneficial effect of retigabine on memory in rats receiving ethanol.

BACKGROUND: Retigabine belongs to the novel generation of antiepileptic drugs but its complex mechanism of action causes that the drug might be effective in other diseases, for instance, alcohol dependence. It is known that ethanol abuse impaired the function of brain structures associated with memory and learning such as the hippocampus. In our previous study, retigabine reduced hippocampal changes induced by ethanol in the EEG rhythms in rabbits. This study is focused on the impact of retigabine on memory processes in male rats receiving alcohol. METHODS: Memory was evaluated in various experimental models: Morris water maze, Contextual, and Cued Fear Conditioning tests. Retigabine was administered for 3 weeks directly to the stomach via oral gavage at a dose of 10 mg/kg. Rats received also 20% ethanol (5 g/kg/day in two doses) via oral gavage for 3 weeks and had free access to 5% ethanol in the afternoon and at night. Morris water maze was performed after 1 and 3 weeks of ethanol administration and after 1 week from the discontinuation of ethanol administration. Contextual and Cued Fear Conditioning tests were carried out after 24 h and 72 h of alcohol discontinuation. RESULTS: The drug significantly decreased ethanol-induced memory disturbances during alcohol administration as well as slightly improved learning processes after the discontinuation of ethanol administration. CONCLUSIONS: This beneficial effect of retigabine-ethanol interaction on memory may be a relevant element of the drug's impact on the development of addiction.

The effect of zonisamide on memory processes - A preclinical study.

OBJECTIVE: Zonisamide is an antiepileptic drug with a perspective of a broader use. Although it is regarded as a relatively safe drug, zonisamide might cause disorders of the central nervous system. The study assessed the influence of zonisamide on spatial and emotional memory in adult Wistar rats. METHODS: Morris water maze test was used to examine the effect of zonisamide administered p.o. as single dose (50 mg/kg or 100 mg/kg) or repeatedly (50 mg/kg) on spatial memory. The impact of zonisamide administered as above on emotional memory was assessed in the Passive avoidance test. RESULTS: Zonisamide mainly in a high acute dose impaired the spatial memory, whereas when administered repeatedly, its effect was observed only in the initial phase of the study. Emotional memory disturbances were noted only during repeated administration of zonisamide. CONCLUSION: Zonisamide may impair memory and learning processes in rats but the results are varied and depend on the type of memory.

Can the Impact of Topiramate on Memory Processes be Related to Its 'Antialcoholic Activity'?-A Preclinical Study.

AIMS: Topiramate causes the inhibition of alcohol consumption in addicts but the mechanism of this action has not been fully understood yet. Nowadays, it seems that memory may have a role in the development of dependence. In this study, the impact of topiramate and ethanol on the bioelectric activity of the brain in rabbits and on spatial memory in rats was evaluated. SHORT SUMMARY: The aim of the study was to assess the effect of co-administration of topiramate and ethanol on bioelectric activity of the rabbits' brain and on spatial memory in rats. Topiramate decreased ethanol-induced changes in all studied brain structures and improved memory and learning processes. METHODS: A pharmaco-electroencephalography study was used to examine the effect of topiramate (25 mg/kg/day) co-administered for 6 weeks with ethanol on the bioelectric activity of the rabbits' brain. The influence of the drug was also assessed in first and second weeks of the abstinence period. Spatial memory was evaluated in rats using Morris water maze task. Topiramate (60 mg/kg/day) was administered with the ethanol for 3 weeks and for 2 weeks in the abstinence. RESULTS: After 6 weeks of topiramate and ethanol administration, the drug decreased ethanol-induced changes in the midbrain reticular formation, hippocampus and frontal cortex. In the abstinence, the drug also inhibited the features of neuronal hyperactivity, especially in the hippocampus. Moreover, topiramate co-administered with ethanol for 3 weeks decreased ethanol-induced memory disturbance in rats. This beneficial effect was also observed in the second week of abstinence. CONCLUSION: These findings reveal that 'antialcoholic' activity of topiramate may be associated with its advantageous effect on memory and learning processes.

The possibility of adverse effect of Kv7-channel opener retigabine on memory processes in rats.

OBJECTIVE: Retigabine is a novel antiepileptic drug with a unique and complex mechanism of action which allows its use in many diseases associated with impaired neuronal activity. This study sought to examine the impact of retigabine on two types of memory in rats. METHODS: Adult male Wistar rats were used to assess the effect of retigabine, administered p.o. as single (10mg/kg or 20mg/kg) or repeated doses, on spatial memory with the Morris water maze test (MWM) and emotional memory, associated with fear, with the passive avoidance test (PA). RESULTS: Retigabine administered at a high single dose transiently impairs learning processes in rats. In the MWM, these changes were delayed in time and of a lesser degree when retigabine was given at low single dose. Additionally, the drug administered repeatedly for 2weeks slowed learning processes in the MWM, but this effect occurred only after 1week of administration in the PA. CONCLUSION: These findings indicate that retigabine may affect memory and learning processes, especially in the first phase of administration.

The Impact of Zonisamide on the Development and Course of Alcohol Dependence in Rabbits. A pharmaco-EEG study.

AIMS: Zonisamide is a new anti-epileptic drug whose mechanism of action is associated with neurotransmission systems also involved in the pathogenesis of addiction. Recently, the role of memory processes and the hippocampus (Hp) is underlined in dependence. In our previous study, we determined that zonisamide decreases changes in hippocampal bioelectric activity induced by a single dose of ethanol. METHODS: This study uses a pharmaco-EEG method to examine the impact of zonisamide on the development and course of alcohol dependence in rabbits. Quantitative changes in EEG were observed in the midbrain reticular formation, Hp and frontal cortex. Zonisamide was administered p.o. once a day at dose of 30 mg/kg/day during the entire experiment. Solutions with increasing concentrations of ethanol were administered for 6 weeks, followed by a 2-week period of abstinence. RESULTS: The long-term administration of ethanol caused characteristic changes in rabbit EEG recordings, which were associated with a shift toward lower frequencies resulting in a depressive effect on the bioelectric activity of selected brain structures. Co-administration of zonisamide and ethanol caused a reduction of ethanol-induced alterations. Changes in EEG recordings were different during period of abstinence and were associated with potent shift toward the high frequencies. Zonisamide significantly decreased encephalographic features of neuronal hyperactivity when administered during the abstinence. CONCLUSION: Zonisamide decreases ethanol- and abstinence-induced changes in the EEG recordings. These effects may be a significant part of drug's mechanism of action in alcohol addiction therapy. SHORT SUMMARY: A pharmaco-EEG method was used to determine the influence of a new anti-epileptic drug zonisamide on the development and course of alcohol dependence in rabbits. The drug co-administered with ethanol decreased alcohol-induced changes in selected brain structures. Zonisamide also decreases abstinence-induced changes in the EEG recordings.

Does retigabine affect the development of alcohol dependence?--A pharmaco-EEG study.

New antiepileptic drugs have been investigated for their potential role in the treatment of alcohol dependence. One of these drugs is retigabine and this study examines the effect of retigabine co-administered with ethanol on the development of alcohol dependence and the course of acute withdrawal syndrome. A pharmaco-EEG method was used to examine this impact in selected brain structures of rabbits (midbrain reticular formation, hippocampus and frontal cortex). Retigabine was administered p.o. at a dose of 5mg/kg/day with ethanol ad libitum for 6 weeks and then alone for 2 weeks during an abstinence period. Changes in bioelectric activity, which demonstrated the inhibitory effect of alcohol on the brain structures, were already visible after 2 weeks of ethanol administration. In the abstinence period, changes were of a different nature and significant neuronal hyperactivity was observed, particularly in the midbrain reticular formation and the hippocampus. This findings reveal that retigabine decreased ethanol-induced changes during both alcohol administration and abstinence periods. In particular, the modulatory effect of retigabine on the hippocampus may be a significant element of its mechanism of action in alcohol dependence therapy.

[Long-term use of estrogens: benefit or risk]. / Estrogeny stosowane dlugotrwale: korzysci czy ryzyko.

Estrogens are widely used in hormone replacement therapy, gynecology, urogynecology and rarely in dermatology. Non-therapeutic use of estrogens is very widespread. Estrogens are used as contraceptives, which cause a lot of serious side effects. A common clinical problem is skin hyperpigmentation (melasma), occurring mainly in women who take contraceptives with high doses of estrogens. But low doses of estrogens may also cause skin side effects. The mechanism of melasma development is very complicated and not fully understood. It is very likely that UV radiation and genetic background can affect melasma development. Effective therapy should lead to prevention or alleviation of relapses. Treatment should also reduce the area of lesions and improve the appearance of skin. There is no effective and universal pattern of treatment, in which only one substance or method is used. A combination of different methods is used to optimize the therapy. An important role is attributed to prevention, especially protection from UV radiation.

A pharmaco-EEG study of the interaction between ethanol and retigabine in rabbits.

BACKGROUND: Retigabine is a new antiepileptic drug with multiple mechanisms of action. It may well interact with ethanol, as both have an influence on GABA-ergic and glutamate neurotransmission. OBJECTIVES: To assess the effect of retigabine, administered as single or repeated doses, on ethanol-induced changes in the bioelectric activity of selected brain structures in rabbits. METHODS: 30 rabbits were used to assess the effect of retigabine on ethanol-induced changes in EEGs using the pharmaco-EEG method. Retigabine was administered p.o. as a single dose (5 mg/kg or 10 mg/kg) or repeatedly at a dose of 5 mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 60 min after the administration of retigabine. RESULTS: Retigabine, administered as a single high or low dose, increased the depressive effect of an acute dose of ethanol on the bioelectric activity of the frontal cortex in rabbits. These changes were also visible in the recordings from the hippocampus and midbrain reticular formation after administration of a high dose of the drug. Retigabine administered in repeated doses decreased ethanol-induced changes in the rabbit EEG recordings from the hippocampus. CONCLUSION: Retigabine in multiple doses decreases the sensitivity of the hippocampus to an acute dose of ethanol in rabbits. Given the role of hippocampal-related memory processes to addiction, retigabine may have therapeutic potential.

A pharmaco-EEG-based assessment of the interaction between ethanol and zonisamide.

AIMS: Recent research suggests a potential role for a new generation of anticonvulsant drugs, including zonisamide, in the treatment of alcohol dependence. Some elements of the central mechanism of action that zonisamide has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. METHODS: This study uses a pharmaco-EEG method to examine the interaction of ethanol with zonisamide. The influence of zonisamide on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Zonisamide was administered p.o. as a single dose (20 or 60 mg/kg) or repeatedly at a dose of 30 mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 180 min after the administration of zonisamide. RESULTS: Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13-30 and 30-45 Hz). Changes in the EEG recordings after zonisamide alone were more significant compared with these after repeated doses. In the hippocampus after single dose of drug the proportion of the low frequency (0.5-4 Hz) increased, whereas the proportion of high frequencies decreased. Combined administration of ethanol and zonisamide (60 mg/kg) resulted in a markedly synergistic effect in the examined structures. A beneficial effect of repeatedly administered zonisamide on ethanol-induced EEG changes was observed, especially in the hippocampus. CONCLUSION: Zonisamide in repeated doses decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.

[Retigabine - a new antiepileptic drug with a different mechanism of action]. / Retigabina ­ nowy lek przeciwpadaczkowy o odmiennym mechanizmie dzialania.

Retigabine belongs to a new generation of antiepileptic drugs. Its mechanism of action is different from that previously known. Retigabine opens potassium channels of subfamily Kv 7, especially Kv 7.2 and Kv 7.3. The drug enhances GABA-ergic transmission. It is well absorbed from the digestive system and undergoes metabolism via glucuronidation and acetylation. There is no interaction between retigabine and other antiepileptic drugs except lamotrigine. The drug has been registered as treatment of partial onset seizures with or without secondary generalization in adults. The efficacy of retigabine is being tested in other types of seizures and disorders characterized by neuronal hyperexcitability. Neuroprotective activity of retigabine is also being researched.

Effect of topiramate on hippocampus-dependent spatial memory in rats.

BACKGROUND: Topiramate, a new generation antiepileptic agent with a complex mechanism of action, has a broad pharmacological profile which includes a neuroprotective effect. It has been proven to be efficacious in treating alcohol dependence through a previously confirmed association with memory processes. METHODS: Topiramate was administered in single doses of 120 and 40 mg/kg and multiple doses of 60 mg/kg for 12 days. Its influence on the spatial memory of rats was evaluated using the Morris water maze test. The time needed to localize the platform, the distance travelled and time spent in the platform zone were recorded. RESULTS: Single doses of topiramate induce deterioration of spatial memory, with high doses having more pronounced and longer lasting effects. Multiple administration of a medial dose does not significantly affect the learning process. CONCLUSIONS: The influence of topiramate on the hippocampus-related memory processes may play a key role in its "anti-alcohol" effect.

[The role of the cannabinoid system in the pathogenesis and treatment of alcohol dependence]. / Rola ukladu kannabinoidowego w patogenezie oraz poszukiwaniu nowych mozliwosci farmakoterapii zespolu zaleznosci alkoholowej.

The lack of satisfactory results of alcohol dependence treatment force us to search for new directions of research. Recent studies concentrate on endocannabinoid transmission. The results show an interplay between the endocannabinoid and dopaminergic signaling in activation of the limbic reward system. The mechanisms leading to development of dependence are very complex and poorly recognized. Endogenous cannabinoids seem to have an important role in the functioning of this system, both directly and indirectly affecting the level of different neurotransmitters. The effect of alcohol on the endocannabinoid system is also complex and involves changes at the molecular level. Experimental studies have demonstrated an important role of the CB1 receptors in the neurochemical mechanism of alcohol consumption and its regulation. SR141716 (rimonabant), a CB1 receptor antagonist, significantly lowers voluntary alcohol intake and motivation for its consumption in various experimental studies. Very encouraging results of preclinical studies were not completely confirmed in the clinical studies. However, further clinical studies are still necessary.

[The role of the glutamatergic system in the pathogenesis and treatment of alcohol dependence]. / Rola ukladu glutaminianergicznego w patogenezie oraz terapii zespolu zaleznosci alkoholowej.

The lack of satisfactory results of alcohol dependence treatment has necessitated the search for new directions of studies. One of them is connected with glutamatergic transmission. The influence of alcohol on this transmission is very complex and relates to changes including at the molecular level. However, the diversity of glutamatergic receptors creates a new possibility of modulation of its activity. It leads to decrease of alcohol reward abilities, prolongs abstinence time and reduces the incidence of acute alcohol intoxication in alcohol addicts. The use of acamprosate--a glutamatergic transmission modulator drug--and naltrexone (an opioid receptor antagonist) improves therapy effectiveness of acamprosate alone. Satisfactory results were achieved in the studies of topiramate--an antagonist of AMPA and KA receptors. Its effectiveness was proved in clinical studies. Topiramate reduced alcohol craving and prolonged abstinence time, which decreased the probability of relapse. There are promising preclinical results of groups I and II metabotropic receptor antagonists. However, further studies are necessary to elucidate precisely their role in alcohol dependence.

Pharmaco-EEG-based assessment of the interaction between ethanol and oxcarbazepine.

Oxcarbazepine is a representative molecule for a new class of anticonvulsant drugs that can treat alcohol dependence in addition to other disorders. Interestingly, the central mechanism of action in oxcarbazepine is very similar to ethanol, suggesting that these two agents may interact and cause enhanced effects in the central nervous system. In this study, we used a pharmaco-EEG method to examine the influence of oxcarbazepine on the effect of ethanol on the EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex). Oxcarbazepine was administered po as a single dose (20 mg/kg or 80 mg/kg) or repeatedly at a dose of 40 mg/kg/day for 14 days. Ethanol was injected iv at a dose of 0.8 g/kg 60 min after the administration of oxcarbazepine. Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recordings, and it caused a marked decrease in higher frequencies (13-30 Hz and 30-45 Hz). Oxcarbazepine altered the EEG pattern in rabbits; this interaction was dependent on the dose of the drug and whether it was administered as a single dose or as multiple doses. Oxcarbazepine administered at a lower dose had a synergistic effect with ethanol in the frontal cortex and midbrain reticular formation, and a similar effect was observed in the hippocampus at a higher dose. Changes in EEG recordings after the administration of oxcarbazepine alone were more pronounced after multiple administrations. The drug decreased the sensitivity of the hippocampus to ethanol, an observation that may be important for the treatment of alcohol addiction.

Pharmaco-EEG-based assessment of interaction between ethanol and levetiracetam.

Recent research suggests a potential role for a new generation of anticonvulsant drugs, including levetiracetam, in the treatment of alcohol dependence. Some elements of the central mechanism of action that levetiracetam has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. In this study, we have used a pharmaco-electroencephalographic (EEG) method to examine the interaction of ethanol with levetiracetam. The influence of levetiracetam on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Levetiracetam was administered p.o. as a single dose (50mg/kg or 200mg/kg) or repeatedly at a dose of 100mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 60 min after the administration of levetiracetam. Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13-30 Hz and 30-45 Hz). Changes in the EEG recordings after levetiracetam alone were more significant when the drug was given in repeated doses. Combined administration of ethanol and levetiracetam (200mg/kg) resulted in a markedly synergistic effect in the frontal cortex and the midbrain reticular formation. The drug decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.

The effect of combined administration of ethanol and gabapentin on rabbit electroencephalographic activity.

The central effect of ethanol is mainly connected with the effect on GABAergic, glutamatergic, serotonergic and opioid transmission. The mechanism of gabapentin effect suggests that it may alleviate the rewarding effect of ethanol, which may be used in the treatment of addiction. We decided to examine the interaction of ethanol with gabapentin by a pharmaco-electroencephalographic (EEG) method. The influence of gabapentin on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was tested. Gabapentin was administered at a single dose (25 and 100 mg/kg orally) or repeatedly twice a day at a total dose of 25 mg/kg for 14 days. Ethanol was injected at a dose of 0.8 g/kg 60 min. after gabapentin treatment. Ethanol caused an increase in the slow frequencies (0.5-4 Hz) in the recording, as well as a marked decrease of the fastest frequencies (13-30 and 30-45 Hz). Gabapentin lead to changes in rabbit EEG recording suggesting an depressant effect on the CNS (increase of slow and decrease of fast frequencies). The effects were less pronounced after repeated doses, which may indicate adaptative changes in the receptors. Gabapentin administered both in a single dose and for 7 days markedly enhanced the effect of ethanol on EEG recordings in rabbits. Repeated doses of gabapentin decrease the sensitivity of the hippocampus to the effect of ethanol.