- Email: [email protected]
The pharmacokinetics of phenothiazine neuroleptics during chronic co-administration of carbamazepine
B. Preclinical
effects of BIBP3226 on locomotor activity and anxiety-related behavior, the open-field test was carried out in place-conditioned rata. Male Wistar rats were treated with i.c.v. injections either with vehicle only or with BIBP3226 and vehicle in counterbalanced order. A place preference test carried out 2 days after last injection revealed that vehicle treated control rats showed no reliable preference or aversion for either of the place cues. This confirms that an unbiased procedure was used. BIBP3226 treated animals spent in the drug paired and drug unpaired environment: 319 f 28 set and 534 + 29 set, respectively. Thus, four pairings with potentially anxiogenic dose of BIBP3226 (5 yg/6.5 ~1, i.c.v.) produced a conditioned aversion for the drug-associated place. Locomotor activity in the open field test was not affected by acute BIBP3226 treatment. This is the First report showing that the weakening of central NPYergic tone is aversive. Our data provide additional evidence to the hypothesis that the NPY YI receptors are involved in the regulation of affective states. NPY Y1 antagonists are under development as potential antihypertensive and anorexigenic drugs. As the disruption of the functional activity of central NPY Yl receptors is anxiogenic (Kask et al., 1996, 1998) and according to this study can induce aversive state, the NPY YI antagonists which cross blood-brain barrier are likely to have troublesome side effects.
111 Wablestedt. C.. Heilie. M. (1995) Neurotxotide Y and related oeotides. In: Psychoph&acology?he ~ourth’Ge.nerafio~ of Progress. (Eds: &oom, EE., Kupfer, D.J.) Raven Press, New York, 543-55 1. [2] ffisk. A., &go, L. and Harro, J. (1996) Anxiogenic-like effect of the neuropeptide Y YI receptor antagonist BIBP3226: antagonism with diazepam. Eur. J. Pharmacol. 317. R3-R4. [3] Kask, A., &go; L. and Harro, J. (1998) Anxiogenic-like effect of the NPY Y, receptor antagonist BIBP3226 administered into the dorsal periaqueductal gray matter in rats. Regul. Pept. 75-76, 255-262. L
-
m
Neonatal blockade of NMDA experimental psychosis
receptors
a novel
model
of
K. Fijal, W. Zaj+czkowski, A. Czyrak, M. MaCkowiak, A. Chocyk, K. W&ony. Institute of Pharmacology, Polish Academy of Sciences, 12 Smgtna Street,
31-343
Krakbw,
Poland
According to recent findings deficits in glutamatergic neurotransmission in early period of life may result in the appearance of psychosis in adulthood (Weinberger, 1995). Deficits in sensorimotor gating as well as in spatial working memory and selective attention are among typical cognitive disturbances in schizophrenic patients. Above cognitive deficits can be induced in experimental animal models of psychoses (Lipska et al., 1995). Our previous studies showed, that neonatal blockade of NMDA receptors leads to increased spontaneous exploratory activity of adult rats, and to hypersensitivity to dopaminomimetics (amphetamine and quinpirole), what might be indicative of their pro-psychotic behavior. In the present study we examined whether such neonatal treatment impairs process of sensorimotor gating measured in prepulse induced inhibition of acoustic startle response and spatial working memory and selective attention evaluated in the delayed alternation task, phenomenon which corresponds to some aspects of schizophrenia. Rat pups were treated with CGP 40116, the competitive antagonist of NMDA receptor, from the first till 21st day of their life, the critical period for the brain development. All the experiments were performed on adult animals (60 days old). We observed significant decrease in prepulse inhibition of the acoustic startle response in rats neonatally treated with CGP 40116. This deficit was reversed to the control level by neuroleptics: haloperidol (0.1 mg/kg), risperidon (1 mg/kg) and clozapine (2.5 and 10 mg/kg). We did not observe significant impairments in spatial delayed alternation
paradigm
neonatal blockade of NMDA receptors results in increased sensitivity to glutamate antagonists. Our results indicate that neonatal treatment with the competitive NMDA receptor antagonist CGP 40116 produce long-lasting behavioural changes which model some aspects of cognitive dysfunction of schizophrenia. References
[l] Lipska B. K., Swerdlow N. R., Geyer M. A., Jaskiw G. E., Braff D. L., Weinberger D. R. (1995): Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes of prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology, 122: 3543 [2] Weinberger D. R. (1995): Schizophrenia as a neumdevelopmental disorder: A review of a concept. In Hirsch SR, Weinberger DR (eds), Schizophrenia. London, Blackwood, pp. 293-323
(B-41
The effects of chronic atypical antipsychotics behavior and repetitive and aging rats
of rats neonatally
treated
with
CGP
40116.
However
administration of a single dose of CGP 40116 (2.5 or 5.0 mg/kg) 1 hour before the test significantly increased the number of errors performed by rats which received above treatment. This observation suggests that
administration of typical and on working memory, motor jaw movements (RJM) in young
H. Rosengarten, D. Quartermain, A.J. Friedhoff. NYU School Medicine,
References
s21
Studies
Department
of Psychiatry,
New York, NY 10016,
of
USA
Neuroleptic induced changes in dopaminergic function have been associated with alterations in motor function and cognition in man and animals. This study was designed to assessthe effects of dopaminergic drugs on these aspects of behavior in rats. Olanzapine, risperidone, seroquel and haloperidol were administered prenatally over days 11-18 of gestation. RJM, aquisition of 8 arm elevated radial maze and motor behavior were evaluated in 3 month old offspring. It was determined that the prenatal administration of haloperidol 1 mgikg/day, risperdal 0.5 mgikg/day and seroquel 10 mg/kg/day impaired working memory in 3 month old rats whereas olanzapine had no effect. These treatments did not affect the motor behavior and did not induce RJM in 3 month old rats exposed in utero to these antipsychotics. Administration of haloperidol, 1 m&g/day in 3 months old rats, for 2.5 months, impaired working memory and increased the rate of spontaneous RJM following withdrawal from chronic haloperidol treatment, whereas olanzapine and clozapine at the dose of 1 m&g/day and 10 m&g/day respectively, had no effect. In 18 month old rats haloperidol and clozapine treatment, chronic, for 2.5 months impaired working memory, whereas olanzapine at the dose of 1 mgikglday had no effect. Haloperidol treatment resulted also in an impairment of motor behavior and in an increase of the rate of spontaneous RJM in aging rats, whereas olanzapine and clozapine had no effect. Olanzapine demonstrated superiority over other antipsychotic drugs used in this study with respect to working memory in young and aging rats. Olanzapine and clozapine demonstrate similar low TD liability in rat model of tardive dyskinesia. 18-51
The pharmacokinetics of phenothiazine neuroleptics during chronic co-administratlon of carbamaxepine
M. Syrek, A. Haduch, J. W6jcikowski, W.A. Daniel. Polish Academy Sciences,
Institute
of Pharmacology,
Smetna 12, 31-343
Krakdw,
of Poland
Combinations of neuroleptics and carbamazepine are administered to psychiatric patients in the therapy of manic and manic-depressive illnesses as well as to optimize the treatment of schizophrenia. Our previous studies showed that chronic administration of promazine and carbamazepine resulted in a slight increase in the neuroleptic concentration in short time after administration, followed by its significant decrease. The purpose of the present work was to investigate a possible influence of carbamazepine on the pharmacokinetics of thioridazine and perazine in the rat. The neuroleptics were injected intraperitoneally (10 mgikg each), twice a day for two weeks, separately or jointly with carbamazepine (15 mg/kg during the 1st and 20 mg/kg during the 2nd week of treatment). The concentrations of thioridazine, perazine and
B. Preclinical
s22
their metabolites were determined in the blood plasma and brain of rats at 30 min, 6 and 12 h after the last dose of the drugs (HPLC). Carbamazepine diminished the concentrations of thioridazine and its metabolites (especially Z-sulfoxide and 2-sulfone) in the plasma after 30 min and 6 h. After 12 h a tendency to decrease in thioridazine concentration and an elevation of N-desmethylthioridazine and 5-sulfoxide levels were observed. At all the time intervals decreases in the concentration ratios of thioridazine/desmethylthioridazine and thioridazinei5 sulfoxide were observed, which suggests an induction of thioridazine demethylation and 5sulfoxidation as well as an induction of another, not investigated by us metabolic pathway of the neuroleptic (decrease in the concentration sum of thioridazine + metabolites). Similar changes in thioridazine pharmacokinetics were observed in the brain. Perazine pharmacokinetics was not distinctly affected by carbamazepine, though significant increase in the sulfoxide concentration was observed. In vitro metabolic studies revealed that carbamazepine added to liver microsomes of control rats inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its Ndemethylation or sulfoxidation by carbamazepine was observed. Studies with liver microsomes of rats treated chronically with carbamazepine and/or neuroleptic showed that carbamazepine decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was coadministered with perazine, the effect was less pronounced and did not reach statistical significance. In conclusion, carbamazepine added to the treatment with promazine or thioridazine (an aliphatic- and a piperidine-type phenothiazine neuroleptic, respectively), decreased the neuroleptic concentrations. The pharmacokinetics of perazine, a piperazine-type phenothiazine neuroleptic, was not influenced distinctly by carbamazepine. The observed induction of promazine and thioridazine metabolism in vivo seems to proceed by metabolic pathways other than N-demethylation or sulfoxidation. IB-61
Psychotomimetic effects CGP 40118, a competitive
of MK-801 are antagonized NMDA receptor antagonist
by
W. Zajaczkowski, A. Chocyk, K. Fijak, M. Mackowiak, A. Czyrak, K. Wedzony. Institute of Pharmacology, Polish Academy of Sciences, 12 Smqtna Street,
31-343
Kmkbw,
Poland
Non-competitive NMDA receptor antagonists like phencyclidine (PCP) and its functional congeners (e.g. MK-801) are known from strong psychotomimetic effects both in human and in experimental animals. Interestingly, among drugs which effectively block psychotomimetic effects of non-competitive NMDA receptor antagonists like PCP and MK-801 are antagonists of the glycine, strychnine insensitive modulatory site (GlyB) of the NMDA receptor. Thus, it was of interest to investigate whether those effects are typical for the GlyB site blockade or whether blockade of the major binding site of the NMDA receptor may produce similar effects. The aim of the present study was to compare whether competitive (CGP 40116) and non-competitive (MK-801) NMDA receptor antagonists may produce similar psychotomimetic effects and to evaluate whether competitive NMDA receptor antagonist is able to attenuate psychotomimetic effects induced by MK-801. To answer those questions we tested psychotomimetic effects of both compounds in two different behavioural paradigms: locomotor activity test and prepulse inhibition of the acoustic startle response. Additionally, we also tested their effects on working memory and selective attention evaluated in the delayed alternation task in T-maze. Finally, interaction between both types of the NMDA receptor antagonists was studied. We found that MK-801 (0.4 mg/kg), when given alone produced strong locomotor hyperactivity, while CGP 40116 (1.25, 2.5 and 5 mgkg) was without effect. Moreover, it was found that locomotor stimulatory effect of MK-801 (0.4 mg/kg) was antagonized by prior administration of CGP
Studies
40116 (5 mgkg). Lower doses of CGP 40116 (1.25 and 2.5 mg/kg) were ineffective. In the prep&e inhibition test, MK-801 (0.4 mgkg) disrupted process of sensorimotor gating, while CGP 40116 (2.5 m&g) had no effect. It was also found that CGP 40116 antagonized the MK80 1-evoked disruption of the process of sensorimotor gating. In contrast to the above described effects, CGP 40116 (2.5 and 5 mg/kg), similarly to MK-801 (0.05-0.4 mg/kg), increased the number of errors in the delayed alternation test revealing its detrimental effect on spatial working memory and selective attention. The presented results indicate that non-competitive and competitive NMDA receptor antagonists may produce qualitatively different behavioural effects, as evidenced by the experiments with locomotor activity and prepulse inhibition of the acoustic startle response. Moreover, the competitive NMDA receptor antagonists may attenuate psychotomimetic effects related to the non-competitive blockade of that receptor. However, the potential therapeutic properties of CGP 40116 and other competitive NMDA receptor antagonists should be put forward carefully since in the range of doses effective against MK-801, CGP 40116 may impair some cognitive functions in experimental animals. le-71
Opposite effects of imipramine glucocorticoid receptor-mediated An in vitro study
and cocaine on the gene expression -
B. Budziszewska, M. Leskiewicz, L. Jaworska-Feil, W. Lasot’t. Department of Endocrinology, Institute of Pharmacology Sciences, PL 31-343 Kratiw, Poland
Polish
Academy
of
Both depression and drug addiction are associated with impairment of the glucocorticoid receptor-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis. On the other hand, chronic administration of antidepressant drugs increases, whereas treatment with psychostimulants decreases the level of glucocorticoid receptors in rat hippocampus [ 11. Less is known about drug-related alterations in the functional transcriptional activity of glucocorticoid receptors [2]. In the present study we evaluated the effects of imipramine, and cocaine on the glucocorticoid receptor-mediated gene expression in mouse fibroblast cells (L929) which were stable transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter plasmid (LMCAT cells). LMCAT cells were treated with vehicle, imipramine (0.1-100 yM) or cocaine (0.1-100 PM) for 4 days, followed by treatment with the vehicle, imipramine or cocaine plus dexamethasone (0.1; 10 PM), corticosterone (10 PM) or the vehicle (20% y-cyclodextrine) for 24 hr. The CAT enzyme activity was determined as described previously [2]. The obtained results show that imipramine (100 pM) significantly inhibits the CAT-gene expression in LMCAT cells, while cocaine (100 FM) tends to increase this parameter. The present in study further confirms differences between the molecular effect of imipramine and cocaine on corticosteroid receptors. References [1] Budziszewska, B., La&, W., 1994. Pharmacological modulation of glucocorticoid and mineralocorticoid receptors in the rat central nervous system. Pal. J. Pharmacol. 46, 97-102. [2] Pariante, CM., Pearce, B.D., Pisell, T.L., Owens, M.J., Miller, A.H., 1997. Steroid-independent tramlocation of the glucocorticoid receptor by the antidepressant desipramine. Mol. Pharmacol. 52, 571-581.
effects of BIBP3226 on locomotor activity and anxiety-related behavior, the open-field test was carried out in place-conditioned rata. Male Wistar rats were treated with i.c.v. injections either with vehicle only or with BIBP3226 and vehicle in counterbalanced order. A place preference test carried out 2 days after last injection revealed that vehicle treated control rats showed no reliable preference or aversion for either of the place cues. This confirms that an unbiased procedure was used. BIBP3226 treated animals spent in the drug paired and drug unpaired environment: 319 f 28 set and 534 + 29 set, respectively. Thus, four pairings with potentially anxiogenic dose of BIBP3226 (5 yg/6.5 ~1, i.c.v.) produced a conditioned aversion for the drug-associated place. Locomotor activity in the open field test was not affected by acute BIBP3226 treatment. This is the First report showing that the weakening of central NPYergic tone is aversive. Our data provide additional evidence to the hypothesis that the NPY YI receptors are involved in the regulation of affective states. NPY Y1 antagonists are under development as potential antihypertensive and anorexigenic drugs. As the disruption of the functional activity of central NPY Yl receptors is anxiogenic (Kask et al., 1996, 1998) and according to this study can induce aversive state, the NPY YI antagonists which cross blood-brain barrier are likely to have troublesome side effects.
111 Wablestedt. C.. Heilie. M. (1995) Neurotxotide Y and related oeotides. In: Psychoph&acology?he ~ourth’Ge.nerafio~ of Progress. (Eds: &oom, EE., Kupfer, D.J.) Raven Press, New York, 543-55 1. [2] ffisk. A., &go, L. and Harro, J. (1996) Anxiogenic-like effect of the neuropeptide Y YI receptor antagonist BIBP3226: antagonism with diazepam. Eur. J. Pharmacol. 317. R3-R4. [3] Kask, A., &go; L. and Harro, J. (1998) Anxiogenic-like effect of the NPY Y, receptor antagonist BIBP3226 administered into the dorsal periaqueductal gray matter in rats. Regul. Pept. 75-76, 255-262. L
-
m
Neonatal blockade of NMDA experimental psychosis
receptors
a novel
model
of
K. Fijal, W. Zaj+czkowski, A. Czyrak, M. MaCkowiak, A. Chocyk, K. W&ony. Institute of Pharmacology, Polish Academy of Sciences, 12 Smgtna Street,
31-343
Krakbw,
Poland
According to recent findings deficits in glutamatergic neurotransmission in early period of life may result in the appearance of psychosis in adulthood (Weinberger, 1995). Deficits in sensorimotor gating as well as in spatial working memory and selective attention are among typical cognitive disturbances in schizophrenic patients. Above cognitive deficits can be induced in experimental animal models of psychoses (Lipska et al., 1995). Our previous studies showed, that neonatal blockade of NMDA receptors leads to increased spontaneous exploratory activity of adult rats, and to hypersensitivity to dopaminomimetics (amphetamine and quinpirole), what might be indicative of their pro-psychotic behavior. In the present study we examined whether such neonatal treatment impairs process of sensorimotor gating measured in prepulse induced inhibition of acoustic startle response and spatial working memory and selective attention evaluated in the delayed alternation task, phenomenon which corresponds to some aspects of schizophrenia. Rat pups were treated with CGP 40116, the competitive antagonist of NMDA receptor, from the first till 21st day of their life, the critical period for the brain development. All the experiments were performed on adult animals (60 days old). We observed significant decrease in prepulse inhibition of the acoustic startle response in rats neonatally treated with CGP 40116. This deficit was reversed to the control level by neuroleptics: haloperidol (0.1 mg/kg), risperidon (1 mg/kg) and clozapine (2.5 and 10 mg/kg). We did not observe significant impairments in spatial delayed alternation
paradigm
neonatal blockade of NMDA receptors results in increased sensitivity to glutamate antagonists. Our results indicate that neonatal treatment with the competitive NMDA receptor antagonist CGP 40116 produce long-lasting behavioural changes which model some aspects of cognitive dysfunction of schizophrenia. References
[l] Lipska B. K., Swerdlow N. R., Geyer M. A., Jaskiw G. E., Braff D. L., Weinberger D. R. (1995): Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes of prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology, 122: 3543 [2] Weinberger D. R. (1995): Schizophrenia as a neumdevelopmental disorder: A review of a concept. In Hirsch SR, Weinberger DR (eds), Schizophrenia. London, Blackwood, pp. 293-323
(B-41
The effects of chronic atypical antipsychotics behavior and repetitive and aging rats
of rats neonatally
treated
with
CGP
40116.
However
administration of a single dose of CGP 40116 (2.5 or 5.0 mg/kg) 1 hour before the test significantly increased the number of errors performed by rats which received above treatment. This observation suggests that
administration of typical and on working memory, motor jaw movements (RJM) in young
H. Rosengarten, D. Quartermain, A.J. Friedhoff. NYU School Medicine,
References
s21
Studies
Department
of Psychiatry,
New York, NY 10016,
of
USA
Neuroleptic induced changes in dopaminergic function have been associated with alterations in motor function and cognition in man and animals. This study was designed to assessthe effects of dopaminergic drugs on these aspects of behavior in rats. Olanzapine, risperidone, seroquel and haloperidol were administered prenatally over days 11-18 of gestation. RJM, aquisition of 8 arm elevated radial maze and motor behavior were evaluated in 3 month old offspring. It was determined that the prenatal administration of haloperidol 1 mgikg/day, risperdal 0.5 mgikg/day and seroquel 10 mg/kg/day impaired working memory in 3 month old rats whereas olanzapine had no effect. These treatments did not affect the motor behavior and did not induce RJM in 3 month old rats exposed in utero to these antipsychotics. Administration of haloperidol, 1 m&g/day in 3 months old rats, for 2.5 months, impaired working memory and increased the rate of spontaneous RJM following withdrawal from chronic haloperidol treatment, whereas olanzapine and clozapine at the dose of 1 m&g/day and 10 m&g/day respectively, had no effect. In 18 month old rats haloperidol and clozapine treatment, chronic, for 2.5 months impaired working memory, whereas olanzapine at the dose of 1 mgikglday had no effect. Haloperidol treatment resulted also in an impairment of motor behavior and in an increase of the rate of spontaneous RJM in aging rats, whereas olanzapine and clozapine had no effect. Olanzapine demonstrated superiority over other antipsychotic drugs used in this study with respect to working memory in young and aging rats. Olanzapine and clozapine demonstrate similar low TD liability in rat model of tardive dyskinesia. 18-51
The pharmacokinetics of phenothiazine neuroleptics during chronic co-administratlon of carbamaxepine
M. Syrek, A. Haduch, J. W6jcikowski, W.A. Daniel. Polish Academy Sciences,
Institute
of Pharmacology,
Smetna 12, 31-343
Krakdw,
of Poland
Combinations of neuroleptics and carbamazepine are administered to psychiatric patients in the therapy of manic and manic-depressive illnesses as well as to optimize the treatment of schizophrenia. Our previous studies showed that chronic administration of promazine and carbamazepine resulted in a slight increase in the neuroleptic concentration in short time after administration, followed by its significant decrease. The purpose of the present work was to investigate a possible influence of carbamazepine on the pharmacokinetics of thioridazine and perazine in the rat. The neuroleptics were injected intraperitoneally (10 mgikg each), twice a day for two weeks, separately or jointly with carbamazepine (15 mg/kg during the 1st and 20 mg/kg during the 2nd week of treatment). The concentrations of thioridazine, perazine and
B. Preclinical
s22
their metabolites were determined in the blood plasma and brain of rats at 30 min, 6 and 12 h after the last dose of the drugs (HPLC). Carbamazepine diminished the concentrations of thioridazine and its metabolites (especially Z-sulfoxide and 2-sulfone) in the plasma after 30 min and 6 h. After 12 h a tendency to decrease in thioridazine concentration and an elevation of N-desmethylthioridazine and 5-sulfoxide levels were observed. At all the time intervals decreases in the concentration ratios of thioridazine/desmethylthioridazine and thioridazinei5 sulfoxide were observed, which suggests an induction of thioridazine demethylation and 5sulfoxidation as well as an induction of another, not investigated by us metabolic pathway of the neuroleptic (decrease in the concentration sum of thioridazine + metabolites). Similar changes in thioridazine pharmacokinetics were observed in the brain. Perazine pharmacokinetics was not distinctly affected by carbamazepine, though significant increase in the sulfoxide concentration was observed. In vitro metabolic studies revealed that carbamazepine added to liver microsomes of control rats inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its Ndemethylation or sulfoxidation by carbamazepine was observed. Studies with liver microsomes of rats treated chronically with carbamazepine and/or neuroleptic showed that carbamazepine decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was coadministered with perazine, the effect was less pronounced and did not reach statistical significance. In conclusion, carbamazepine added to the treatment with promazine or thioridazine (an aliphatic- and a piperidine-type phenothiazine neuroleptic, respectively), decreased the neuroleptic concentrations. The pharmacokinetics of perazine, a piperazine-type phenothiazine neuroleptic, was not influenced distinctly by carbamazepine. The observed induction of promazine and thioridazine metabolism in vivo seems to proceed by metabolic pathways other than N-demethylation or sulfoxidation. IB-61
Psychotomimetic effects CGP 40118, a competitive
of MK-801 are antagonized NMDA receptor antagonist
by
W. Zajaczkowski, A. Chocyk, K. Fijak, M. Mackowiak, A. Czyrak, K. Wedzony. Institute of Pharmacology, Polish Academy of Sciences, 12 Smqtna Street,
31-343
Kmkbw,
Poland
Non-competitive NMDA receptor antagonists like phencyclidine (PCP) and its functional congeners (e.g. MK-801) are known from strong psychotomimetic effects both in human and in experimental animals. Interestingly, among drugs which effectively block psychotomimetic effects of non-competitive NMDA receptor antagonists like PCP and MK-801 are antagonists of the glycine, strychnine insensitive modulatory site (GlyB) of the NMDA receptor. Thus, it was of interest to investigate whether those effects are typical for the GlyB site blockade or whether blockade of the major binding site of the NMDA receptor may produce similar effects. The aim of the present study was to compare whether competitive (CGP 40116) and non-competitive (MK-801) NMDA receptor antagonists may produce similar psychotomimetic effects and to evaluate whether competitive NMDA receptor antagonist is able to attenuate psychotomimetic effects induced by MK-801. To answer those questions we tested psychotomimetic effects of both compounds in two different behavioural paradigms: locomotor activity test and prepulse inhibition of the acoustic startle response. Additionally, we also tested their effects on working memory and selective attention evaluated in the delayed alternation task in T-maze. Finally, interaction between both types of the NMDA receptor antagonists was studied. We found that MK-801 (0.4 mg/kg), when given alone produced strong locomotor hyperactivity, while CGP 40116 (1.25, 2.5 and 5 mgkg) was without effect. Moreover, it was found that locomotor stimulatory effect of MK-801 (0.4 mg/kg) was antagonized by prior administration of CGP
Studies
40116 (5 mgkg). Lower doses of CGP 40116 (1.25 and 2.5 mg/kg) were ineffective. In the prep&e inhibition test, MK-801 (0.4 mgkg) disrupted process of sensorimotor gating, while CGP 40116 (2.5 m&g) had no effect. It was also found that CGP 40116 antagonized the MK80 1-evoked disruption of the process of sensorimotor gating. In contrast to the above described effects, CGP 40116 (2.5 and 5 mg/kg), similarly to MK-801 (0.05-0.4 mg/kg), increased the number of errors in the delayed alternation test revealing its detrimental effect on spatial working memory and selective attention. The presented results indicate that non-competitive and competitive NMDA receptor antagonists may produce qualitatively different behavioural effects, as evidenced by the experiments with locomotor activity and prepulse inhibition of the acoustic startle response. Moreover, the competitive NMDA receptor antagonists may attenuate psychotomimetic effects related to the non-competitive blockade of that receptor. However, the potential therapeutic properties of CGP 40116 and other competitive NMDA receptor antagonists should be put forward carefully since in the range of doses effective against MK-801, CGP 40116 may impair some cognitive functions in experimental animals. le-71
Opposite effects of imipramine glucocorticoid receptor-mediated An in vitro study
and cocaine on the gene expression -
B. Budziszewska, M. Leskiewicz, L. Jaworska-Feil, W. Lasot’t. Department of Endocrinology, Institute of Pharmacology Sciences, PL 31-343 Kratiw, Poland
Polish
Academy
of
Both depression and drug addiction are associated with impairment of the glucocorticoid receptor-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis. On the other hand, chronic administration of antidepressant drugs increases, whereas treatment with psychostimulants decreases the level of glucocorticoid receptors in rat hippocampus [ 11. Less is known about drug-related alterations in the functional transcriptional activity of glucocorticoid receptors [2]. In the present study we evaluated the effects of imipramine, and cocaine on the glucocorticoid receptor-mediated gene expression in mouse fibroblast cells (L929) which were stable transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter plasmid (LMCAT cells). LMCAT cells were treated with vehicle, imipramine (0.1-100 yM) or cocaine (0.1-100 PM) for 4 days, followed by treatment with the vehicle, imipramine or cocaine plus dexamethasone (0.1; 10 PM), corticosterone (10 PM) or the vehicle (20% y-cyclodextrine) for 24 hr. The CAT enzyme activity was determined as described previously [2]. The obtained results show that imipramine (100 pM) significantly inhibits the CAT-gene expression in LMCAT cells, while cocaine (100 FM) tends to increase this parameter. The present in study further confirms differences between the molecular effect of imipramine and cocaine on corticosteroid receptors. References [1] Budziszewska, B., La&, W., 1994. Pharmacological modulation of glucocorticoid and mineralocorticoid receptors in the rat central nervous system. Pal. J. Pharmacol. 46, 97-102. [2] Pariante, CM., Pearce, B.D., Pisell, T.L., Owens, M.J., Miller, A.H., 1997. Steroid-independent tramlocation of the glucocorticoid receptor by the antidepressant desipramine. Mol. Pharmacol. 52, 571-581.