Evaluation of antidepressant and memory-improving efficacy of aripiprazole and fluoxetine in alcohol-preferring rats.

INTRODUCTION AND AIMS: Dependence on ethanol increases the risk of depression in patients and leads to a damage and deficiencies of brain function, which manifest in cognitive functions impairment. Aripiprazole (ARI) is an atypical antipsychotic drug, which has also been shown to have a beneficial effect on cognitive function. Results of many studies show that, for ARI's antidepressant effect to manifest itself, it is necessary to use a combined therapy with a drug from the group of selective serotonin reuptake inhibitors (SSRIs). The aim of this paper was to assess the antidepressant and impact of ARI on spatial memory in alcohol-preferring rats (EtNPRs). DESIGN AND METHODS: In our study, we used Porsolt's forced swimming test (antidepressant effect) and Morris water maze test. The tests have been conducted upon administration of ARI (6 mg/kg i.p.), fluoxetine (FLX; 5 mg/kg p.o.) and combined administration of both drugs in alcohol-dependent rats. RESULTS: The results of behavioural tests carried out have shown a lack of antidepressant and procognitive effects of either ARI or FLX in EtPRs after acute and chronic treatment. Combined administration of both drugs would lead to spatial memory deterioration in the study animals. DISCUSSION AND CONCLUSIONS: Our results suggest that ARI applied in the experiment had no antidepressant effect and failed to improve spatial memory in study rats. Potential antidepressant and procognitive properties of this drug resulting from its mechanism of action encourage attempts (design) of further research aimed at developing a dose, which will show such effects in alcohol-preferring animals.

Evaluation of the antidepressant, anxiolytic and memory-improving efficacy of aripiprazole and fluoxetine in ethanol-treated rats.

Some study results indicate a positive effect of aripiprazole (ARI) on impaired cognitive functions caused by brain damage resulting from chronic EtOH abuse. However, other research shows that to manifest itself, an ARI antidepressant effect requires a combined therapy with another selective serotonin reuptake inhibitor antidepressant, namely, fluoxetine (FLX). The aim of this article was to assess antidepressant and anxiolytic effects of ARI as well as its effect on spatial memory in ethanol-treated (alcoholized) rats. On the basis of alcohol consumption pattern, groups of (1) ethanol-preferring rats, with mean ethanol intake above 50%, and (2) ethanol-nonpreferring rats (EtNPRs), with mean ethanol intake below 50% of total daily fluid intake, were formed. The group of EtNPRs was used for this study, subdivided further into three groups administered ARI, FLX and a combination of both, respectively. Behavioral tests such as Porsolt's forced swimming test, the Morris water maze test and the two-compartment exploratory test were employed. Behavioral test results demonstrated (1) no antidepressant effect of ARI in EtNPRs in subchronic treatment and (2) no procognitive effect of ARI and FLX in EtNPRs in combined single administration. Combined administration of both drugs led to an anxiogenic effect and spatial memory deterioration in study animals. ARI had no antidepressant effect and failed to improve spatial memory in rats. However, potential antidepressant, anxiolytic and procognitive properties of the drug resulting from its mechanism of action encourage further research aimed at developing a dose of both ARI and FLX that will prove such effects in alcoholized EtNPRs.

Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats.

Recent research has suggested that cognitive disorders are a persistent trait of mental illnesses such as schizophrenia. Cognitive deficits in the course of schizophrenia may be due to the disease and/or drug therapy, especially with old-generation drugs. Several clinical experiments have indicated the beneficial effects of new-generation antipsychotics on cognitive processes in patients treated for mental disorders. Aripiprazole is a new, atypical antipsychotic with a unique mechanism of action, which may have positive effects on cognitive functions. The aim of this study was to investigate the effects of aripiprazole on spatial memory in the Morris water maze and antidepressant activity in the Porsolt test. In addition, we examined whether aripiprazole had any side effects in the chimney test. The behavioral tests showed that aripiprazole improved spatial memory in rats and had antidepressant and anxiolytic effects after a single treatment; however, aripiprazole impaired motor coordination after repeated administration. We concluded that aripiprazole could be an effective antipsychotic for the treatment of patients with schizophrenia or bipolar disorder who have associated anxiety and cognitive deficits.

Interactions of nicotine and drugs used in the treatment of mental illnesses with respect to cognitive functions.

Cognitive disorders in the course of mental illnesses are one of the most important and most difficult therapeutic problems related to those illnesses and they regard attention, memory, learning and sensory modulation. The limited number of nicotinic receptors (subtypes alpha7 and alpha4beta2) seems to cause the incidence and exacerbation of cognitive deficits in such patients. In patients with schizophrenia, the impairment of cognitive processes is also a side-effect of neuroleptics. The characteristics and intensity of the negative effect of antipsychotics on cognitive functions depends on the pharmacological action of those drugs and on the effect on dopamine and serotoninergic receptors in particular. Cognitive function deficits observed in various mental illnesses can be modified with the use of nicotine. A cholinergic neurotransmission system is a common transmission system in the central nervous system. The effect of nicotine on other neurotransmission systems--the dopaminergic and glutaminergic systems--seems to be significant for their efficacious cognitive effects in combination with antipsychotic drugs. Nicotine may also alleviate symptoms of depression, as it amplifies serotoninergic and noradrenergic neuronal activity. When studies on treating cognitive disorders with nicotine are carried out, nicotine's interactions with other drugs used in therapy of those disorders must be taken into account as well as the effect of this substance on neurotransmission systems.

Effect of valproic acid and environmental enrichment on behavioral functions in rats.

Deficits of cognitive functions are perceived as an important pathogenic factor of many neurological and psychiatric diseases. Such symptoms can be a result of a disease process or appear due to applied medication. Epilepsy is a disease in which cognitive deficits can occur before first seizures, during seizures and remissions. Valproic acid (VAL, CAS 77372-61-3) is a medicine applied in order to control epileptic seizures and mood stabilizing in bipolar disorders and mania. Its activity is related to the effect on neurotransmission of many systems. The present study was conducted to investigate whether enriched environment (EE) conditions affect learning and memory, and influence the antidepressant effect in rats. VAL improves spatial memory upon repeated administration both in the rats housed in standard conditions (SC) (after 21 days of treatment) and those housed in enriched environment (as early as after 14 days of treatment). VAL has an antidepressant effect on the forced swimming test both in the rats housed in standard conditions and those housed in EE. In rats housed in EE, the antidepressant effect occurred much earlier (as early as after 7 days ofVAL administration). It is worth noting that VAL has a low profile of adverse effects (Activity Meter, chimney test). The correlations observed may be translated into clinical effects, leading to new, more effective VAL therapies in depression or memory disorders in patients with underlying epilepsy.

Effect of lamotrigine and environmental enrichment on spatial memory and other behavioral functions in rats.

Epileptic patients are at risk of experiencing cognitive deficits as a result of pharmacotherapy as well as etiology of epilepsy. Antiepileptic drugs increase inhibitory neurotransmission and reduce the responsiveness of neurons, and thereby may have a negative impact on memory. The enriched environment intensifies exploration of the new area behavior, which may have a positive impact on spatial memory in rats. Depression is among the most common affective disorders in epileptic patients, and using antidepressant drugs together with antiepileptics brings about the risk of interactions and intensifying side effects, The aim of the study was to assess the effects of lamotrigine (CAS 84057-84-1, LTG) (10 mg/kg i.p.), a new anticonvulsant with antidepresssant and neuroprotective properties, for memory and other behavioral functions in rats in standard and enriched environments (EE). LTG improved spatial memory upon repeated administration of the drug both in the rats housed in standard conditions and those housed in EE. Exposure to an enriched environmentsignificantly improved spatial learning. LTG showed antidepressant effect on the forced swimming test both in the rats housed in standard conditions and those housed in EE. In rats housed in EE the antidepressant effect occurred earlier. LTG had a low profile of adverse effects (activity meter, chimney test).

Cognitive effects of GABAergic antiepileptic drugs.

Many patients undergoing long-term treatment of epilepsy complain of memory disorders, which entail worse quality of life. The risk factors generating memory disorders include: morphological brain damage, the duration and course of epileptic seizures (conscience disorders), the time of diagnosis (the risk is greater if epileptic seizures start early in life), drug resistance, the presence of interseizure changes in the EEG in the form of sharp-wave discharges or sharp spike-wave/ slow spike-wave complexes and improper pharmacotherapy (exceeding the admissible concentration of drugs in blood serum, polytherapy). GABAergic neurotransmission of older antiepileptic drugs (barbiturates, benzodiazepines) makes them particularly prone to produce modest, but statistically significant disruption of cognitive processes. This explains the search for new antiepileptic drugs that will improve, or at least not impair, cognitive functions. The improvement of cognitive functions by new generation antiepileptic drugs results, among others, from their non-GABAergic mechanisms: they influence the ion channels and glutaminergic transmission.

Memory improving and antidepressant effects of topiramate in rats.

Topiramate (TOP, CAS 97240-79-4) particularly potentiates gamma-aminobutyric acid (GABA) neuroinhibition, and GABA and glutamate receptors, which have also been implicated in memory formation. Patients' giving up treatment due to adverse effects (disorders of attention, memory, and verbal fluency) is the main problem with a therapy based on this drug. The antidepressant effect of TOP administered to rats in the dose of 15 mg/kg is observed only after 14 and 21 days of treatment. The delay in the antidepressant effect of TOP may be due to the modulation of GABA A receptors as well as due to the influence of the drug on receptors for type AMPA/KAIN excitatory amino acids. The research has also shown that long-term treatment with TOP in a dose of 15 mg/kg improved spatial memory, as tested in rats with Morris test. Probably, this results from the influence of the drug on GABA A receptors and the function of glutaminergic receptors (especially in processes like coding, retrieving, and potentiation of information), adaptive processes in the brain, notwithstanding, being an important factor. As TOP is a normothymic drug, its use in the treatment of epilepsy may also positively influence cognitive processes in the so-called interseizure intervals with memory disorders; the same effects can be expected in the treatments of bipolar disorder.

Influences of chronic venlafaxine, olanzapine and nicotine on the hippocampal and cortical concentrations of brain-derived neurotrophic factor (BDNF).

Brain-derived neurotrophic factor (BDNF) is a key neurotrophic factor in the brain. It plays an important role in the etiopathogenesis and pharmacotherapy of mental disorders, such as depression or schizophrenia. In recent years, studies have shown that cognitive processes, which are impaired in the course of mental disorders, significantly change BDNF levels in the brain. Administered to rats at a dose of 20 mg/kg (b.d. for 5 weeks), venlafaxine (VEN) increases BDNF levels in the hippocampus and cortex, compared to controls. Administered at a dose of 0.5 mg/kg (b.d. for 5 weeks), olanzapine (OLA) significantly increases BDNF levels in both the cortex and the hippocampus. Similarly, nicotine (NIC) administered at a dose of 0.2 mg/kg (b.d. for 5 weeks) increases BDNF concentrations in both the hippocampus and the cortex. Combined administration of NIC with VEN or OLA does not increase BDNF levels in the hippocampus or the cortex. Based on our study, it can be claimed that BDNF mediates behavioral responses only to drugs used individually and participates in the antidepressant and procognitive effects of the study compounds. BDNF also initiates plastic changes and modulation of synaptic activity in rat brains.

Cost analysis of therapy for patients with multiple sclerosis (MS) in Poland.

Multiple sclerosis (MS) is a neurological disease of the central nervous system in which dissipated demyelination lesions develop. The currently available pharmacotherapy and rehabilitation for this disease aims to preserve the patients' physical abilities and prevent disease progression and nervous system damage. The study evaluated the direct and indirect costs associated with two different treatment regimens for multiple sclerosis diagnosed patients by comparing two groups of 60 subjects (Group A--patients receiving continuous interferon therapy (Betaferon) and steroids during relapses, and Group B--patients receiving steroid-only (Solu-Medrol, Metypred) treatment). The study was conducted over two years (2004-2005). The pharmacotherapy costs for MS patients were: PLN 4,555,360.68 (1,171,043.88euro) total for Group A and PLN 75,922.68 (19,517.40euro) per patient, and PLN 72,582.00 (18,658.61euro) total for Group B and PLN 1,209.70 (310.98euro) per patient. Total direct and indirect costs for Group A and Group B amounted to PLN 5,595,968.58 (1,438,552.33euro) and PLN 1,655,658.30 (425,619.10euro), respectively.

The influence of tobacco smoke and nicotine on antidepressant and memory-improving effects of venlafaxine.

In experimental and clinical studies, central nicotinic systems have been shown to play an important role in cognitive function. Nicotinic acetylcholine receptors also mediate the reinforcing properties of nicotine (NIC) in tobacco products. A variety of studies have shown that acute treatment with NIC or nicotinic agonists can improve working memory function. Moreover, it is known that the monoaminergic system plays an important role in memory function. And there is evidence suggesting that prolonged use of NIC may exert antidepressant action via nicotinic receptors. The purpose of this study was to investigate the interactions between a novel antidepressant, venlafaxine (VEN), a blocker of noradrenaline and 5-hydroxytryptamine reuptake sites, and pure NIC in the context of antidepressant and memory function in tobacco smoke exposed and nonexposed rats. The animals were subjected to Porsolt's test for testing antidepressant activity and their memory function (spatial memory) was evaluated in the Morris Water Maze Test. In tobacco smoke non-exposed and exposed rats both single and chronic administration of VEN (20 mg/kg po) shortened immobility time. NIC (0.2 mg/kg sc) significantly reduced immobility time on the 1st, 7th and 14th test days in both non-exposed and exposed rats. Combined VEN+NIC treatment in tobacco smoke non-exposed rats reduced immobility too. This effect of the combination of drugs was significantly stronger as compared to the effects obtained after individual administration of VEN or NIC. In the group exposed to tobacco smoke, joint administration of VEN+ NIC induced a significant reduction of immobility as compared to the control and NIC groups. In the Morris Water Maze Test single and chronic administration of VEN, lower values of escape latencies and lower numbers of crossed quadrants were noted in both exposed and non-exposed rats, which indicates improved performance. After administering NIC we could observe improvement of spatial memory in both the exposed and non-exposed group. A similar effect of improvement of spatial memory was observed after joint administration of VEN and NIC. The study results support the involvement of nicotinic systems in memory processes in rats. Memory improvement and antidepressant effects following joint administration of VEN and NIC may depend on nicotinic interactions with monoaminergic systems and VEN may represent a new therapeutic approach to smoking cessation.

Influence of haloperidol and clozapine on some behavioral effects in rats.

The experiments presented in the following paper aimed to investigate the influence of atypical antipsychotic clozapine (CLO, CAS 578-21-0) classified also as normothymic drug on spatial memory in rats in Morris water maze test. The study also investigated the probably occurring side effects (measuring cataleptic activity and motor coordination) following single and chronic administration of CLO compared to haloperidol (HAL, CAS 52-86-8), a conventional antipsychotic. All the tests were carried out on male Wistar rats. CLO 10 mg/kg was administered orally 30 min before the tests and HAL 0.15 mg/kg was administered orally 60 min before the tests. In the Morris test memory improvement only after chronic administration of CLO on the 7th and 14th day of treatment was observed, whereas after 14 days of HAL treatment spatial memory impairment was noted. CLO did not induce catalepsy after single as well as chronic administration, but administrated chronically induced a tendency for its occurrence. HAL evoked a strong cataleptic effect both after acute and chronic treatment. CLO had no impact on motor coordination in the chimney test except on day 14 when statistically significant impairments were observed. HAL disturbed motor coordination in rats after single as well as chronic administration. The wide and unique spectrum of receptor activity of CLO in comparison with HAL as well as some neurotransmitters' interactions may explain its usefulness in long-term therapy of bipolar affective disorder and schizoaffective disorder with co-occurred cognitive deficits.