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Nimodipine attenuates psychotigenic effects of ketamine in humans
P.6 Other topics by ANOVA. Furthermore, there was no significant difference between PTNs and non-PTNs. Conclusion: DA affects the response of motor cortical neurons to the stimulation of VL in suppressive manner.
References [1] Huda, K. et al., Dopaminergicmodulation oftranscallosal activity of cat motor conical neurons. Neurosci. Res., In press.
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Nimodipine attenuates psychotigenic effects of ketamine in humans
E. Knapitsky, A. Burakov, T. Romanova, S. Vegso, J. Krystal. Research Laboratory, Leningrad Regional Dispensary of Narcology, St. Petersburg, Russia Department of Psychiatry, Yale University School of Medicine, USA It was shown that ketamine in subanesthetic doses induces psychotigenic effects in healthy volunteers (Krystal et al., 1994). The purpose of this study was to assess the ability of dihydropyfidine calcium channel blocker, nimodipine, to attenuate the psychotigenic effects of NMDA calcium channel antagonist, ketamine. 22 healthy volunteers were randomly assigned to four experimental conditions (one experiment a week, total four experiments for the each of 22 subjects): a) Ketamine (one hour i.v. infusion, 0.5 mg/kg) with nimodipine pretreatment (90 mg every six hours for a total four doses with last dose before ketamine infusion); b) Ketamine infusion with placebo pretreatment; c) Placebo i.v. infusion with nimodipine pretreatment; and d) Placebo infusion with placebo pretreatment. The study design was double blind. The psychotigenic effects of ketamine were evaluated with the Brief Psychiatric Rating Scale (BPRS). BPRS had been administered before ketamine infusion, several times during the infusion and after the termination of ketamine infusion. The results of this study demonstrated that nimodipine attenuates psychotigenic effects of ketamine according to the BPRS. In panicular, nimodipine significantly reduced scores of the following BPRS factors during the ketamine infusion: positive symptoms associated with schizophrenia, negative symptoms associated with schizophrenia, thinking disorders, anxious-depression, and withdrawal-retardation. The obtained results can be considered as an evidence of the implication of dihydropyridine sensitive calcium channels in psychotigenic effects of NMDA calcium channel antagonist ketamine.
References [1] Krystal J.H., Karper L.P., Seibyl J.E, Freeman G.K., Delaney R., Bremmer J.D., Heininger J.R., Bowers M.B., Charney D.S. (1994). Subanestheticeffects of the NMDA antagonist, ketamine, in humans. Arch. Gen. Psychiatry 51: 199-214.
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Effects of N-nitro-L-arginine, a nitric oxide synthase inhibitor, on Ag-NOR activity in striatum of mice
C. Pedraza, J.E Navarro, L.J. Santin, J.L. Arias. Area de Psicobiologia,
Facultad de Psicologia, Universidades de M~ilagay Oviedo, Spain Nitric oxide (NO) is an unconventionial intercellular messenger in the brain synthesised from the aminio acid L-arginine by a family of enzimes called NO synthases (NOS). Recent studies suggest that NO can stimulate release of the excitatory neurotransmitter glutamate and neuromodulate the activity of biogenic amines, especially dopamine, in this sense, it has been demonstrated that NO plays a role in the control of dopamine release in rat striatum. Presumably, NOS inhibitors might decrease locomotor activity by interfering with striatal dopamine (1, 2). The aim of this study was to assess the effect of N-nitro-L-arginine (LNOARG), a potent NOS inhibitor, on neuronal protein synthesis activity in striatum after subchronic administration for 4 consecutive days. For this purpose, 16 albino female mice of the OE1 strain were used (2733 g). Animals arrived in the laboratory at 42 days of age and were
$347
housed in transparent plastic cages (24 × 13.5 x 13 cm) in groups of five under standardised laboratory conditions. After a seven-day period of adaptation, mice were treated daily with L-NOARG (90 mg/kg, i.p) for 4 days. Vehicle group received distilled water plus the same proportion of the solvent used (HCL) to dilute L-NOARG. Two hours after the last injection, animals were anesthetised with ethylic ether prior to the vascular perfusion with 10% formaldehyde in phosphate buffer (0.1 M, pH 7.4). Neuronal protein synthesis activity was analyzed by quantifyng nuclear areas and number of silver-stained nucleolar organiser regions (Ag-NORs) per nucleus. These Ag-NORs may represent the transcriptional activity of the cell. The sections of striatum examined were silver stained according to the method described by Ploton et al. (3). it consists of immersing the slides in a solution of one volume of 2% gelatin in 1% aqueous formic acid and two volumes of 50% silver nitrate for 18 rain at room temperature and in darkness. 100 neurons were selected from each of the animals. The results showed that mean number of Ag-NOR per nucleus significantly increased in the striatum of mice, as compared with the control group (p < 0.05). These findings indicate the existence of an increase in transcriptional activity after L-NOARG treatment, suggesting that the neostriatal dopaminergic innervation quickly develops tolerance to the interruption of dopamine transmission by L-NOARG. This tolerance might be explained by an upregulation of striatal dopaminergic receptors.
References [1] Navarro JF et al. (1997). Med. Sci. Res., 25, 625-626. [2] Cavas Met al. (1998). Eur. Neuropsychopharmacol.,8 (suppl. 2), 315. [3] Ploton D et al. (1986), Histochem. J., 18, 5-14.
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Absence of tolerance to cataleptic activity of gamma-hydroxybutyric acid after subchronic administration to male mice
C. Pedraza, J.E Navarro, E. Maldonado, M. Cavas. Area de Psicobi-
ologia, Facultad de Psicologia, Universidad de Mdlaga, Spain Gamma-hydroxybutyric acid (GHB), a recreationally used drug popularly known as "liquid ecstasy", is a metabolite of GABA which also acts as neuromodulator or neurotransmitter in the mammalian brain (1). Several pharmacological studies have demonstrated that GHB decreases isolation-induced aggression in mice and it exhibits an anxiolytic action evaluated by means of the elevated plus maze in rats. From a clinical point of view, GHB has been successfully employed in the treatment of narcolepsy, alcohol dependence and opiate withdrawal. Likewise, recently it has been suggested that this compound could represent an useful therapeutic agent for cocaine addiction in humans. The GHB concentration highest in human brain is found in the striatum, a region clearly involved in the control of catalepsy behaviour. In rodents, acute treatment with GHB induces a dose-dependent increment of catalepsy. This state of immobility has been described using different types of behavioural tests (2, 3). However, although the cataleptic action of GHB after its acute administration has been demonstrated, there are no studies in relation to the possible development of tolerance to this pharmacological effect of the drug after repeated administration. Therefore, the aim of this study was to examine the effect of subchronic treatment with GHB on catalepsy behaviour in male mice (N = 86). Drug was administered acutely or subchronically (for 5 days) in four doses: 75 125, 175 and 225 mg/kg. Catalepsy was evaluated by means of the bar test. An aluminium bar of 5 mm in diameter was placed 4 cm above the floor. Animals's forepaws were gently put on the bar and the time it took the animal to place at least one paw on the floow was measured. If 1 min elapsed without movement, the test was interrupted. Two successive evaluations were carried out 30 and 60 after the last injection of GHB or saline. Between determinations, the mice were kept in their home cages. Individual animal were tested in a random order. Kruskall-Wallis analysis showed that there was significant variance in catalepsy scores over different treatment groups (p < 0.01). Paired comparisons (MannWhitney U-tests) revealed that catalepsy scores increased significantly following acute treament with GHB (175 and 225 mg/kg) at 30 min, as
References [1] Huda, K. et al., Dopaminergicmodulation oftranscallosal activity of cat motor conical neurons. Neurosci. Res., In press.
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Nimodipine attenuates psychotigenic effects of ketamine in humans
E. Knapitsky, A. Burakov, T. Romanova, S. Vegso, J. Krystal. Research Laboratory, Leningrad Regional Dispensary of Narcology, St. Petersburg, Russia Department of Psychiatry, Yale University School of Medicine, USA It was shown that ketamine in subanesthetic doses induces psychotigenic effects in healthy volunteers (Krystal et al., 1994). The purpose of this study was to assess the ability of dihydropyfidine calcium channel blocker, nimodipine, to attenuate the psychotigenic effects of NMDA calcium channel antagonist, ketamine. 22 healthy volunteers were randomly assigned to four experimental conditions (one experiment a week, total four experiments for the each of 22 subjects): a) Ketamine (one hour i.v. infusion, 0.5 mg/kg) with nimodipine pretreatment (90 mg every six hours for a total four doses with last dose before ketamine infusion); b) Ketamine infusion with placebo pretreatment; c) Placebo i.v. infusion with nimodipine pretreatment; and d) Placebo infusion with placebo pretreatment. The study design was double blind. The psychotigenic effects of ketamine were evaluated with the Brief Psychiatric Rating Scale (BPRS). BPRS had been administered before ketamine infusion, several times during the infusion and after the termination of ketamine infusion. The results of this study demonstrated that nimodipine attenuates psychotigenic effects of ketamine according to the BPRS. In panicular, nimodipine significantly reduced scores of the following BPRS factors during the ketamine infusion: positive symptoms associated with schizophrenia, negative symptoms associated with schizophrenia, thinking disorders, anxious-depression, and withdrawal-retardation. The obtained results can be considered as an evidence of the implication of dihydropyridine sensitive calcium channels in psychotigenic effects of NMDA calcium channel antagonist ketamine.
References [1] Krystal J.H., Karper L.P., Seibyl J.E, Freeman G.K., Delaney R., Bremmer J.D., Heininger J.R., Bowers M.B., Charney D.S. (1994). Subanestheticeffects of the NMDA antagonist, ketamine, in humans. Arch. Gen. Psychiatry 51: 199-214.
•
Effects of N-nitro-L-arginine, a nitric oxide synthase inhibitor, on Ag-NOR activity in striatum of mice
C. Pedraza, J.E Navarro, L.J. Santin, J.L. Arias. Area de Psicobiologia,
Facultad de Psicologia, Universidades de M~ilagay Oviedo, Spain Nitric oxide (NO) is an unconventionial intercellular messenger in the brain synthesised from the aminio acid L-arginine by a family of enzimes called NO synthases (NOS). Recent studies suggest that NO can stimulate release of the excitatory neurotransmitter glutamate and neuromodulate the activity of biogenic amines, especially dopamine, in this sense, it has been demonstrated that NO plays a role in the control of dopamine release in rat striatum. Presumably, NOS inhibitors might decrease locomotor activity by interfering with striatal dopamine (1, 2). The aim of this study was to assess the effect of N-nitro-L-arginine (LNOARG), a potent NOS inhibitor, on neuronal protein synthesis activity in striatum after subchronic administration for 4 consecutive days. For this purpose, 16 albino female mice of the OE1 strain were used (2733 g). Animals arrived in the laboratory at 42 days of age and were
$347
housed in transparent plastic cages (24 × 13.5 x 13 cm) in groups of five under standardised laboratory conditions. After a seven-day period of adaptation, mice were treated daily with L-NOARG (90 mg/kg, i.p) for 4 days. Vehicle group received distilled water plus the same proportion of the solvent used (HCL) to dilute L-NOARG. Two hours after the last injection, animals were anesthetised with ethylic ether prior to the vascular perfusion with 10% formaldehyde in phosphate buffer (0.1 M, pH 7.4). Neuronal protein synthesis activity was analyzed by quantifyng nuclear areas and number of silver-stained nucleolar organiser regions (Ag-NORs) per nucleus. These Ag-NORs may represent the transcriptional activity of the cell. The sections of striatum examined were silver stained according to the method described by Ploton et al. (3). it consists of immersing the slides in a solution of one volume of 2% gelatin in 1% aqueous formic acid and two volumes of 50% silver nitrate for 18 rain at room temperature and in darkness. 100 neurons were selected from each of the animals. The results showed that mean number of Ag-NOR per nucleus significantly increased in the striatum of mice, as compared with the control group (p < 0.05). These findings indicate the existence of an increase in transcriptional activity after L-NOARG treatment, suggesting that the neostriatal dopaminergic innervation quickly develops tolerance to the interruption of dopamine transmission by L-NOARG. This tolerance might be explained by an upregulation of striatal dopaminergic receptors.
References [1] Navarro JF et al. (1997). Med. Sci. Res., 25, 625-626. [2] Cavas Met al. (1998). Eur. Neuropsychopharmacol.,8 (suppl. 2), 315. [3] Ploton D et al. (1986), Histochem. J., 18, 5-14.
•
Absence of tolerance to cataleptic activity of gamma-hydroxybutyric acid after subchronic administration to male mice
C. Pedraza, J.E Navarro, E. Maldonado, M. Cavas. Area de Psicobi-
ologia, Facultad de Psicologia, Universidad de Mdlaga, Spain Gamma-hydroxybutyric acid (GHB), a recreationally used drug popularly known as "liquid ecstasy", is a metabolite of GABA which also acts as neuromodulator or neurotransmitter in the mammalian brain (1). Several pharmacological studies have demonstrated that GHB decreases isolation-induced aggression in mice and it exhibits an anxiolytic action evaluated by means of the elevated plus maze in rats. From a clinical point of view, GHB has been successfully employed in the treatment of narcolepsy, alcohol dependence and opiate withdrawal. Likewise, recently it has been suggested that this compound could represent an useful therapeutic agent for cocaine addiction in humans. The GHB concentration highest in human brain is found in the striatum, a region clearly involved in the control of catalepsy behaviour. In rodents, acute treatment with GHB induces a dose-dependent increment of catalepsy. This state of immobility has been described using different types of behavioural tests (2, 3). However, although the cataleptic action of GHB after its acute administration has been demonstrated, there are no studies in relation to the possible development of tolerance to this pharmacological effect of the drug after repeated administration. Therefore, the aim of this study was to examine the effect of subchronic treatment with GHB on catalepsy behaviour in male mice (N = 86). Drug was administered acutely or subchronically (for 5 days) in four doses: 75 125, 175 and 225 mg/kg. Catalepsy was evaluated by means of the bar test. An aluminium bar of 5 mm in diameter was placed 4 cm above the floor. Animals's forepaws were gently put on the bar and the time it took the animal to place at least one paw on the floow was measured. If 1 min elapsed without movement, the test was interrupted. Two successive evaluations were carried out 30 and 60 after the last injection of GHB or saline. Between determinations, the mice were kept in their home cages. Individual animal were tested in a random order. Kruskall-Wallis analysis showed that there was significant variance in catalepsy scores over different treatment groups (p < 0.01). Paired comparisons (MannWhitney U-tests) revealed that catalepsy scores increased significantly following acute treament with GHB (175 and 225 mg/kg) at 30 min, as