Jana Pistovčáková

Felbamate reduces hormone release and locomotor hypoactivity induced by repeated stress of social defeat in mice

Glutamatergic neurotransmission plays a role in stress hormone release and the development of mood diseases. The aim of these studies was to verify the hypothesis that repeated treatment with felbamate, an antiepileptic drug modulating glutamatergic neurotransmission, affects hormone release in response to chronic stress. A mouse model of repeated social defeat (nonaggressive male mouse repeatedly defeated by aggressive counterparts) was used. The results showed that acute treatment with felbamate reduced hypolocomotion in an open field induced by repeated social conflict. The same stress procedure resulted in increased release of corticosterone and dopamine. Felbamate decreased noradrenaline concentrations and inhibited stress-induced rise in corticosterone and dopamine. It is suggested that modulation of stress hormone release may be induced by the action of felbamate on glutamate neurotransmission, and neuroendocrine changes could contribute to behavioural effects of the drug. Antidepressant action of this mood-stabilizing drug suggested by clinicians needs further verification.

The effects of methamphetamine self-administration on behavioural sensitization in the olfactory bulbectomy rat model of depression

Depression is frequently comorbid with a drug addiction and may seriously complicate its treatment. Currently, there is no routinely used animal model to investigate this comorbidity. In this study the effect of repeated administration of methamphetamine on i.v. drug self-administration in an olfactory bulbectomy model of depression in rats was investigated in order to propose and validate a rat model of comorbid depression and addiction. Male Wistar rats were either olfactory-bulbectomized (OBX) or sham-operated. They subsequently underwent a methamphetamine sensitization regime, which consisted of daily i.p. injections of methamphetamine for a 14-d period; controls received Sal injections at the same frequency. The i.v. self-administration of methamphetamine (0.08 mg/kg in one infusion) paradigm on a fixed ratio schedule of reinforcement was performed using operant chambers. A significant decrease of the drug intake was recorded in sham-operated animals pretreated with methamphetamine when compared to the unpretreated group. This was not apparent in the OBX groups. Both groups of OBX animals exhibited a higher intake of methamphetamine compared to the corresponding sham-operated groups, thus confirming the hypothesis of higher drug intake in depressive conditions in this rodent model. The procedure of behavioural sensitization to methamphetamine decreased the number of self-administered drug doses per session in the sham-operated rats. It is hypothesized that this phenomenon resulted from increasing efficacy of the drug after behavioural sensitization caused by repeated methamphetamine intermittent administration.

Pregnanolone glutamate, a novel use-dependent NMDA receptor inhibitor, exerts antidepressant-like properties in animal models

A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. Highlights: - 3α5β-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.- We demonstrated that PG did not induce significant hyperlocomotion.- We showed that PG displayed anxiolytic-like and antidepressant-like properties.

Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats.

SummaryMethamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam’s metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

P.1.d.017 Effect of aripiprazole on behaviour and leukocyte phagocytosis in the olfactory bulbectomy model of depression in rats

Aripiprazole is an atypical antipsychotic, which displays partial agonist activity at the dopamine D2 receptor and is approved also for the treatment of affective disorders. Present study was undertaken to evaluate the applicability of the well-established olfactory bulbectomy (OB) rat model of experimental depression for the assessment of aripiprazole antidepressant effects. Since the affective disorders are often accompanied by the immune system dysfunction [2], the leukocyte phagocytosis representing the cell immune function was measured together with the behavioural changes. Aripiprazole exhibited a significant positive influence on the impaired behavioural and immune changes in the OB rats serving as model of depression. Thus, chronic treatment with this antipsychotic drug can modulate the cell immune function, which may add to its clinical efficacy.

Prenatal exposure to modafinil alters behavioural response to methamphetamine in adult male mice

Modafinil is a psychostimulant drug prescribed for treatment of narcolepsy. However, it is used as a “smart drug” especially by young adults to increase wakefulness, concentration and mental performance. Therefore, it can also be used by women with childbearing potential and its developmental effects can become a concern. The aim of this study was to assess behavioural and immune effects of prenatal modafinil exposure in mice and to evaluate the reaction to methamphetamine exposure on these animals in adult age.

P.4.06 Aripiprazole impact on methamphetamine i.v. self-administration in the olfactory-bulbectomy model of depression in rats

In the present study the effect of aripiprazole on methamphetamine (MET) I.V. self-administration in olfactory-bulbectomy model of depression in conditions of behavioural sensitization to MET in rats was investigated.

P.2.17 Endocrine and immune changesfollowing chronic treatment with tiagabine and amisulpride in the olfactory bulbectomized rat model of depression

The purpose of the study was to test endocrine and immune effects of antiepileptic drug tiagabine (TGB) and atypical neuroleptic amisulpride (AMS) in the well established animal model of depression bilateral olfactory bulbectomy (OB) in rats. The tested drugs elicited changes that resemble those seen following chronic treatment with clinically used antidepressants. Thus, they support further the clinical reports that TGB and AMS in addition to their antiepileptic/antipsychotic efficacy respectively may possess also antidepressant activity.

P.2.28 Antidepressant-like effects of tiagabine on locomotor/exploratory behaviour and leukocyte phagocytosis in rats

The purpose of the study was to test a potential antidepressant effect of the 3rd generation antiepileptic tiagabine in rats with bilateral olfactory bulbectomy (OB), which is a well-established animal model of human depression resembling behavioural, immune and endocrine changes. In rats we examined tiagabine effect on locomotor/exploratory activities in the open-field test, and on phagocytosis of leukocytes. Compared to the sham-operated animals OB rats showed a characteristic locomotor hyperactivity in the open-field and a significant suppression of leukocyte phagocytosis. Repeated tiagabine treatment (12 mg/kg/day, 10 days, intraperitoneally) elicited a significant decrease of the locomotor hyperactivity in the open field test, and significant disinhibition of leukocyte phagocytosis. Taking into account that clinically approved antidepressants reverse OB related behavioural and immune disorders (Leonard and Tuite, 1981) the results of both present experiments indicate the hypothesized antidepressant activity of tiagabine.

P.1.050 Effects of valproate on leukocyte phagocytosis in mice and in a rat model of depression

Study with sodium valproate (VAL) was performed in mice and in a rat model of depression measuring drug effect on leukocyte phagocytosis, one of the cell immune functions. The differential white cell count was also analysed as there are controversial reports regarding the VAL effect on the number of leukocyte cells. One-hour chemiluminometric curve (measurement every 5th minute) analysis of leukocyte zymosan induced luminol aided phagocytic activity was performed in vitro (blood samples were collected from the retro-orbital plexus under a short ether anaesthesia) after repeated administration of VAL in vivo. In mice VAL doses of 37.5, 75, and 150 mg/kg/day were administered orally for 5 days. In both, sham-operated and OB rats VAL was administered orally at the dose of 75 mg/kg/day for 14 days. The leukocyte phagocytosis in VAL treated groups of naive mice and sham-operated rats was significantly (p<0.05) below the control values. However, these findings were inconsistent in mice with insignificantly increased total leukocyte count after the two highest VAL doses (75 and 150 mg/kg/day for 5 days) in comparison with the data of the control group. In OB rats the leukocyte phagocytosis was strongly decreased compared with the sham-operated group. The same dose, which suppressed the leukocyte phagocytic activity in the control group, exhibited a positive influence on the impaired leukocyte phagocytosis in the OB rats serving as model of depression. Attenuation or normalization of the OB related changes by chronic (but not acute) antidepressant treatment are interpreted as antidepressant-like effects (Kelly et al., 1997).There was no statistically significant difference in the total leukocyte count in rats between sham-operated and OB groups. The present immune data acquired from the OB rat model are in agreement with accepted antidepressant activity of valproate. Results of both these experiments, however, indicate that VAL itself may cause an immunosupressive effect on physiological leukocyte phagocytosis.