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ABSTRACT: The aim of our experiments was to assess the effect of acutely administered corticosterone on the expression of glucocorticoid receptors (GRs) in the brain of rats with high (HR) and low (LR) levels of anxiety. The rats were divided into groups according to their conditioned fear-induced freezing responses and then were subjected to a second conditioned fear session one week after the initial fear conditioning. Immunocytochemical analysis revealed that the second exposure to contextual aversive stimuli resulted in higher levels of GRs expression in cingulate cortex area 1 (Cg1), the secondary motor cortex (M2) of the prefrontal cortex and the dentate gyrus of the hippocampus (DG) in LR rats compared with HR rats. The pretreatment of HR rats with corticosterone (20mg/kg, sc) increased the expression levels of GRs in Cg1, the M2 area and the DG to the levels observed in the LR vehicle group. The increase in the GRs levels was accompanied by a significant decrease in the conditioned fear response in the HR group. The control animals that were not exposed to aversive stimuli had similar levels of receptor-related immunoreactivity in all brain regions, and corticosterone did not change these expression levels. Our results suggest that HR animals may have deficits in the expression of stress-induced GRs in the prefrontal cortex and the DG. In addition, pretreatment with corticosterone increases the expression of GRs and normalizes the fear response in HR rats.
Neuroscience Letters 11/2012; · 2.11 Impact Factor
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ABSTRACT: The aim of the experiment was to assess the effects of an acutely administered corticosterone on the expression of GABA-A receptor alpha-2 subunits in the brain structures of high (HR) and low (LR) anxiety rats (divided according to their conditioned fear-induced freezing response) subjected to a second conditioned fear session (1 week after fear conditioning). We found that corticosterone (20 mg/kg, sc) given to rats prior to the second conditioned fear session significantly enhanced a decrease in fear expression in the HR group. The behavioural effect of fear was accompanied by the increased expression of alpha-2 subunits in the basolateral amygdala (BLA) and the dentate gyrus of the hippocampus (DG) of the HR group. Corticosterone potentiated the effect of fear on alpha-2 subunit expression in the BLA, DG, the cingulate cortex area 1 and the secondary motor cortex (areas Cg1 and M2). The current study provides insight into the mechanisms that may be responsible for the beneficial effects of glucocorticoids in the therapy of some anxiety disorders.
Behavioural brain research 07/2012; 235(1):30-5. · 3.22 Impact Factor
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ABSTRACT: Our study demonstrated that the development of seizures during the electrically induced kindling of seizures is associated with significant changes in the concentration of kynurenic acid (KYNA) and its precursor, tryptophan (TRP). The primary finding of our study was an increase in KYNA levels and the KYNA/TRP ratio (a theoretical index of activity of the kynurenine pathway) in the amygdala and hippocampus of kindled animals. We also found decreases in the concentration of tryptophan in the hippocampus and prefrontal cortex. Changes in the concentration of KYNA and TRP in the amygdala were accompanied by a significant decrease in γ-Aminobutryic Acid (GABA) levels and an increase in the glutamate/GABA ratio. Moreover, we found a significant negative correlation between the local concentrations of KYNA and glutamate in the amygdala of kindled rats. However, there were no changes in the local concentrations of the following amino acids: glutamate, aspartate, glutamine, glycine, taurine and alanine. In conclusion, these new results suggest a modulatory influence of KYNA on the process of epileptogenesis, characterized by a negative relationship between the KYNA and glutamate systems in the amygdala.
Acta Neurovegetativa 08/2011; 119(2):141-9. · 2.73 Impact Factor
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ABSTRACT: The influence of intracerebroventricular-administered selective corticotropin-releasing factor receptor 2 (CRF(2)) antagonists (antisauvagine-30, astressin-2B), on rat anxiety-like behavior, expression levels of c-Fos and CRF, and plasma corticosterone levels were examined in the present study. In fear-conditioned animals, both CRF receptor antagonists enhanced a conditioned freezing fear response and increased the conditioned fear-elevated concentration of serum corticosterone. Exogenously administered antisauvagine-30 increased the aversive context-induced expression of c-Fos in the 1 and 2 areas of the cingulate cortex (Cg1, Cg2), the central amygdala (CeA) and parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN), and it enhanced the effect of conditioned fear in the secondary motor cortex (M2) and medial amygdala (MeA). Immunocytochemistry demonstrated an increase in CRF expression in the Cg1, M2 areas of the cortex, and pPVN, and it revealed the effect of conditioned fear in the CeA 35 min after antisauvagine-30 administration and 10 min after the conditioned fear test. Furthermore, astressin-2B, another CRF(2) receptor antagonist, enhanced expression of c-Fos and CRF in the CeA and pPVN, and revealed the effect of conditioned fear in the Cg1. These data support a model in which an excess in CRF(1) receptor activation, combined with reduced CRF(2) receptor signaling, may contribute to stronger expression of anxiety-like responses.
Behavioural brain research 03/2011; 221(1):155-65. · 3.22 Impact Factor
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P Maciejak,
M Lehner,
D Turzyńska,
J Szyndler,
A Bidziński,
E Taracha,
A Sobolewska,
J Walkowiak,
A Skórzewska,
A Wisłowska,
A Hamed, A Płaźnik
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ABSTRACT: In the present paper, we analyzed the effects of hippocampal mGluR1 on the consolidation of a fear-conditioned response and on hippocampal glutamate and GABA concentration in rats subjected to the chemically-induced kindling of seizures. We hypothesized the important role of this glutamate receptor subpopulation in behavioural disturbances accompanying epilepsy. To this end, the behavioural and biochemical effects of selective mGluR1 and 5 receptor ligands were compared in sham and kindled animals (pentylenetetrazol-induced seizures). It was found that despite the fact that the freezing response to the aversively conditioned context was not changed by kindling itself, post-training intrahippocampal (dentate gyrus) injection of AIDA (a mGluR1 antagonist) oppositely influenced rat freezing behaviour in the non-kindled and kindled animals (i.e. the receptor ligand increased and decreased duration of the fear reaction, respectively). Kindling of seizures also enhanced the Glutamate/GABA ratio in the dorsal hippocampus (in vivo microdialysis), indicating an enhancement of excitatory processes in the brain. Altogether, the results showed that kindling of seizures led the potentiation of excitatory processes in the hippocampus, changing the role of the local mGluRs1 population in the conditioned fear learning.
Brain Research 02/2008; 1187:184-93. · 2.73 Impact Factor
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ABSTRACT: The effect of midazolam on expression of c-Fos protein was examined in the rat hippocampus, following the open field test of neophobia. It was found that pretreatment of rats with midazolam, at the dose of 0.5 mg/kg, enhanced rat exploratory behavior, and inhibited neophobia related stimulation of c-Fos in the CA-1 and CA-3 areas of the hippocampus. The presented results provide new immunocytochemical data on the involvement of hippocampus in emotional processes related to neophobia, and indicate a possible site of action of benzodiazepines.
Acta Neurovegetativa 02/2006; 113(1):43-8. · 2.73 Impact Factor
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P Maciejak,
A I Członkowska,
A Bidziński,
J Walkowiak,
J Szyndler,
M Lehner,
A Skórzewska,
D Turzyńska,
M Zienowicz,
A Wisłowska,
E Taracha,
P Krzaścik, A Płaźnik
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ABSTRACT: The aim of the present study was to analyze biochemical effects of a neurosteroid, pregnenolone sulfate (PS), which accompany changes in the threshold of seizures, and to establish the contribution of local, hippocampal monoaminergic and amino acid systems, to the control of convulsive activity. Pretreatment of mice with PS (intracerebroventricularly) selectively enhanced the potency of peripherally (intraperitoneally) administered NMDA at the LD16 (88.0 mg/kg) to induce clonic-tonic convulsions (PS, LD84 = 184.7 nM; 95% CL = 181.4-188.1). The proconvulsive actions of picrotoxin and bicuculline, the GABA-A receptor antagonists, were not modified by pretreatment of mice with PS. Administration of PS alone (up to 240 nM icv) did not show any seizure-like activity. PS given at LD84, together with NMDA (at the LD16), increased the hippocampal concentration of alanine, and enhanced local metabolism of dopamine in a period immediately preceding the onset of seizures significantly stronger than did NMDA alone. These and other data indicate that the enhancement by PS of hippocampal levels of alanine may contribute to the seizures development as this amino acid is a precursor of glutamate, and a co-agonist of the NMDA receptors. On the other hand, simultaneously occurring stimulation of hippocampal dopaminergic system may be considered a compensatory phenomenon, limiting seizures propagation through the limbic forebrain. Summarizing, our results show that PS-induced potentiation of NMDA seizures is accompanied by selective changes in hippocampal dopamine turnover and alanine concentration.
Pharmacology Biochemistry and Behavior 09/2004; 78(4):781-6. · 2.53 Impact Factor
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ABSTRACT: The effects of an intracerebroventricular (i.c.v.) administration of a non-selective full benzodiazepine receptor agonist, midazolam, and a neuroactive steroid, allopregnanolone, on picrotoxin-induced seizures and striatal dopamine metabolism, were studied in mice. It was found that acute i.c.v. injections of midazolam (ED50=38.25 nmol) and allopregnanolone (ED50=26.34 nmol) blocked picrotoxin-induced seizures to a similar extent. After repeated administration at the ED(85) doses (midazolam-56.6 nmol, allopregnanolone-94.2 nmol; once or twice daily for 5 days) tolerance developed to the anticonvulsant activity of midazolam (ED50=94.14 nmol) and allopregnanolone (ED50=186.70 nmol). Acute i.c.v. injections of midazolam and allopregnanolone (at the ED50 doses established in the model of picrotoxin seizures: 38.25 and 26.34 nmol, respectively), significantly decreased the concentration of dopamine metabolites: 3-methoxytyramine and 3,4-dihydroxyphenylacetic acid, as well as the dopamine turnover rate (homovanilic acid/dopamine ratio; by about 20%), in the mouse striatum. These findings together with the recently published data on the potentiation by midazolam and allopregnanolone of ethanol-induced sleep [Pharmacol. Biochem. Behav. 67 (2000) 345] indicate a very similar central effect profile of benzodiazepines and neurosteroids. Moreover, similar efficacy of allopregnanolone and midazolam at the GABA(A) receptors has been found. Overall, the results of the present study, along with the possibility of neurosteroid conversion in the brain into other steroid hormones (testosterone, estradiol, aldosterone), add to the accumulating evidence suggesting a less favorable pharmacological profile for this class of drugs than was previously thought.
European Journal of Pharmacology 09/2001; 425(2):121-7. · 2.52 Impact Factor
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ABSTRACT: Rat behavior in the open field and conditioned fear response test was correlated with specific binding of dopamine D1 receptor antagonist [3H]SCH 23390 within different brain structures assayed with autoradiography. A significant positive correlation was found between the ligand binding in the substantia nigra pars reticulata and both animal motor activity (r = 0.67, p < 0.05) and the number of entries into the central sector of the open field (r = 0.59, p < 0.05). On the other hand, rat motility and the central entries were negatively correlated with [3H]SCH 23390 binding within the caudate putamen (r = -0.64, p < 0.05 and r = -0.61 p <0.05, respectively). No correlation was revealed between the ligand binding in the examined brain areas and freezing reaction in the contextual fear conditioning test. The present data indicate for the first time a significant, structure-dependent correlation between rat motor behavior and the dopamine D1 receptor ligand binding within the nigrostriatal system.
Neuroreport 12/2000; 11(18):3953-6. · 1.66 Impact Factor
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ABSTRACT: The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) administered neurosteroids [allopregnanolone (AP); 5beta-tetrahydrodeoxycorticosterone (5beta-THDOC); dehydroepiandrosterone sulfate (DHEAS); pregnenolone sulfate (PS)] and their precursors [progesterone (PROG), pregnanedione (PREG)] on N-methyl-D-aspartic acid (NMDA)-, picrotoxin (PTX)- and bicuculline (BIC)-induced seizures and ethanol-induced sleep were studied in mice. It was found that IP injections of (+)MK-801 most potently antagonized NMDA-, PTX- and BIC-induced seizures, as compared to diazepam (DZP), PROG and PREG. Both precursors of neurosteroids appeared only marginally active in the applied models of convulsions. ICV injections of AP selectively blocked PTX- and BIC-induced seizures, whereas 5beta-THDOC and (+)MK-801 also antagonized NMDA-induced convulsions. ICV administered DHEAS induced seizures in a dose-dependent way. ICV injections of AP and midazolam shortened the latency and prolonged the duration of sleep induced by IP injections of ethanol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the hypnotic-like effect of ethanol. The obtained results suggest that neurosteroids may modulate in an agonistic (AP, 5beta-THDOC), or antagonistic way (PS, DHEAS), the GABA(A) receptor complex functions. Some of them (5beta-THDOC) also interact with NMDA receptors. AP appeared to be the most selectively acting compound, with its profile of action fully comparable to that of midazolam. AP also enhanced the hypnotic effect of ethanol, pointing out to the propensity to interact with centrally depressant agents. These findings, together with the possibility of conversion of some neurosteroids in the brain to other steroid hormones (testosterone, estradiol and aldosterone), indicate the limitations of their use for the treatment of neurological and psychiatric disorders.
Pharmacology Biochemistry and Behavior 11/2000; 67(2):345-53. · 2.53 Impact Factor
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ABSTRACT: The effects of 5-HT(1A) receptor agonist buspirone, a nonselective (diazepam), and a selective (zolpidem) GABA(A) receptor agonist were compared in the open field test of neophobia. Unhabituated rats were pretreated with the drugs once, prior to a first exposure to the open field, and their behavior was recorded both during this test and during a second trial 24 h later. It has been hypothesized that the decrease in exploratory activity observed during the second test session may be considered an adaptive reaction to the first day aversive experience (neophobia). If so, a selective modulation of 5-HT and GABA systems activity during the test could bring about significant changes in animal behavior on the retest. Buspirone at the lowest dose of 0.3 mg/kg revealed anxiolytic-like properties on the first day, whereas the action of diazepam and zolpidem was modulated by the dose-related sedative effect. At the dose of 2.4 mg/kg buspirone elicited delayed in time anxiolytic-like action, i.e., produced the antithigmotactic effect during the retrial 24 h later. Diazepam and zolpidem failed to exhibit similar profile of action. Autoradiography of [3H]muscimol binding after pretreatment of rats with buspirone showed a significant increase in the selective radioligand binding within the frontal cortex and a similar, near-significant tendency in the dentate gyrus of the hippocampus. The behavioral data validate buspirone as important drug for the treatment of anxiety disorders, devoid of disruptive influence on motor and cognitive processes. The open field test, as modified by us, appeared sensitive in distinguishing the behavioral profiles of action of different anxiolytic compounds, including 5-HT(1A) receptor agonist. The present results support the assumption that reduced turnover of 5-HT due to stimulation of 5-HT(1A) autoreceptors, may bring about changes in GABA(A) receptor system activity, in some brain structures, leading to the anxiolytic effect.
Pharmacology Biochemistry and Behavior 08/2000; 66(3):645-51. · 2.53 Impact Factor
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ABSTRACT: The aim of the study was to analyse in a well-established model of neophobia the effects of peripheral and central (ICV) administration of a prototypical and easily penetrating to the brain acetylcholinesterase inhibitor (AChE-I)--physostigmine, hemicholinium, a selective blocker of the high affinity choline uptake sites, as well as muscarinic and nicotinic receptor ligands. Thus, an attempt was made to address the question whether anxiolytic-like effects of AChE-I, reported in the clinic, are directly related to the anti-emotional action. The effects of peripherally and centrally administrated cholinergic ligands on novelty-induced decrease in exploratory behaviour were examined in rats. It was found that in a limited dose-range physostigmine and nicotine given peripherally or ICV selectively disinhibited rat exploration in the open field, whereas scopolamine stimulated animal motor activity and increased thigmotaxis. Locomotor effects of physostigmine and nicotine appeared at the higher doses and could be easily separated from their anti-neophobic action. The rat's exploratory behaviour tended to be attenuated by central administration of hemicholinium (a choline uptake blocker), and it was significantly inhibited by mecamylamine (a nicotinic receptor antagonist), and pirenzepine (a selective M1 receptor antagonist). Gallamine, a selective M2 receptor antagonist, did not influence on animal novelty-induced anxiety-related behaviour. It is concluded that AChE-I can selectively affect brain emotional processes evoked by neophobia-related stimuli. Probably both nicotinic and M1 cholinergic receptors mediate such an action of AChE-I.
Acta Neurovegetativa 02/2000; 107(12):1403-12. · 2.73 Impact Factor
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ABSTRACT: The effects of ICV administration of metabolites of progesterone and deoxycorticosterone [i.e., neurosteroids: AP (3alpha-hydroxy-5alpha-pregnan-20-one, allopregnanolone), 5alpha(-THDOC (3alphat-21-dihydroxy-5alpha-pregnan-20-one, 5alpha-tetrahydrodeoxycorticosterone), 5beta-THDOC (3alpha-21-dihydroxy-5beta-pregnan-20-one, 5beta-tetrahydrodeoxycorticosterone), and PS (3beta-hydroxy-5-pregnen-20-one sulfate, pregnenolone sulfate] were studied in the open-field test of neophobia and Vogel's test of conflict behavior in rats. The influence of in vivo administered 5beta-THDOC, a positive allosteric modulator of the GABA(A) receptor complex, on 3H-muscimol binding in different brain structures, was also studied with the help of quantitative autoradiography. The presented data did not reveal any anxioselective effects for a range of centrally active neurosteroids, in the ethologically orientated and conflict models of anxiety, after intracerebral drug administration. Their central effects appeared secondary to changes in rat gross behavior. It is possible that high local concentration of neurosteroids after ICV injection and production of a narrower range of behavioral effects than that of benzodiazepines, precluded manifestation of the antianxiety effects of AP, 5alpha-THDOC and 5beta-THDOC. Autoradiography did not reveal any significant changes in the specific binding of 3H-muscimol in brain structures after in vivo ICV administration of 5beta-THDOC at the behaviorally active dose. Thus, the possibility that neuroactive neurosteroids may provide a novel potential site for therapeutic interventions in anxiety disorders is not supported. The part of the experiment with 5beta-THDOC is interpreted as contributing to other results, suggesting the existence of a new category of neurosteroids acting as partial agonists of the GABA(A) receptor.
Pharmacology Biochemistry and Behavior 09/1999; 63(4):639-46. · 2.53 Impact Factor
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ABSTRACT: The effects of an intrahippocampal administering of a nonselective full (midazolam), a partial benzodiazepine (BDZ) receptor agonist (bretazenil), and a BDZ1 selective (zolpidem) receptor ligand were examined in the open field test (OFT) of neophobia and Vogel's test (VT) of conflict behavior in rats. Moreover, the influence of local injections of a noncompetitive GABA(A) receptor antagonist, picrotoxin, on the anxiolytic-like effect of serotonin (5-HT) depletion (p-chlorophenylalanine, p-CPA) in the Vogel test was studied. It was found that in the OFT only midazolam (0.1 microg/site) given to the hippocampus (HP) disinhibited rat exploratory behavior, whereas all the examined compounds inhibited animal motor activity when injected locally at 10.0 microg/site, the highest dose used in the tests. In the VT, again, only midazolam disinhibited rat conflict behavior on a dose-dependent basis. Picrotoxin administered to the HP produced a tendency to increase locomotor activity in rats, and significantly attenuated the anti-conflict action of serotonin depletion without changing the pain threshold and spontaneous drinking of the animals. p-CPA induced potent, dose-dependent and selective 5-HT and 5-hydroxyindoleacetic acid decrease in the HP after administering the dose used in the behavioral experiment. Thus, the present data provide evidence for the lack of selective anxiolytic activity of a partial non-selective agonist and a full selective agonist at the BDZ1 receptor after their administration to the HP. The model of intra-HP drug injections appeared effective in discriminating the anxiolytic spectrum of activity of new psychotropic compounds. Moreover, the obtained results indicate that the dorsal HP is one of the central sites important for GABA/5-HT interaction that modulates rat emotional behavior.
Acta Neurovegetativa 02/1999; 106(5-6):369-81. · 2.73 Impact Factor
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ABSTRACT: The influence of p-chlorophenylalanine (p-CPA) and 5,7-dihydroxytryptamine (5,7-DHT)-induced serotonin depletion on rat behavior as well as on zolpidem's the behavioral effects and binding to some brain areas of zolpidem, was examined with the help of Vogel's punished drinking test and autoradiography, respectively. Moreover, changes in the serotonin levels and turnover rate were studied in the forebrain and brainstem of rats pretreated with various ligands at the benzodiazepine (BDZ) receptors (midazolam, bretazenil, abecarnil, zolpidem). These drugs were given at doses shown previously to significantly disinhibit animal behavior suppressed by punishment in the Vogel test (Nazar et al., 1997). It was found that serotonin decrease in the frontal cortex and hippocampus after p-CPA significantly and inversely correlated with rat behavior controlled by fear in the VT. p-CPA produced an anticonflict activity in the absence of effect on spontaneous drinking, pain threshold and motility of animals. All applied benzodiazepine receptor ligands decreased the 5-HT turnover rate in the frontal cortex and hippocampus, whereas in the brainstem only abecarnil and zolpidem diminished 5-hydroxyindoleacetic acid levels. This part of the study replicated earlier data with neurotoxins and indicated that the anxiolytic-like effect of 5-HT depletion in some models of anxiety did not depend on changes in animal appetitive behavior or stimulus control. Moreover, the fact that all nonselective and selective (zolpidem) agonists of the type 1 benzodiazepine receptors seemed to produce the same anticonflict effect and decreasing 5-HT turnover indicates that this subtype of benzodiazepine receptor may be important for the interaction between brain 5-HT and GABA/BDZ systems. Accordingly, it was found that serotonin decrease enhanced the anticonflict effect of zolpidem in the Vogel test and increased 3H-zolpidem binding to the occipital cortex and substantia nigra. Altogether, the present study provides more arguments for the role of changes in the activity of brain 5-HT innervation in the control of emotional processes. Moreover, it points to the BDZ1 receptor subtype as a possible target of interaction between brain 5-HT and GABA(A)/BDZ systems.
Acta Neurovegetativa 02/1999; 106(5-6):355-68. · 2.73 Impact Factor
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ABSTRACT: The effect of serotonin depletion (p-chlorophenylalanine pretreatment) on habituation of exploratory motor activity, and on cortical and hippocampal [3H]muscimol binding in vitro, was examined in rats. It appeared that the very strong decrease in serotonin concentration abolished motor habituation in the open field and decreased [3H]muscimol binding to cortical and hippocampal brain slices. The GABA(A) receptor down-regulation was due to a decrease in the apparent affinity of the radioligand for the receptors. p-Chlorophenylalanine-induced biochemical changes were selective and most probably secondary to serotonin depletion, as the serotonin synthesis inhibitor did not displace [3H]muscimol from its binding sites in neural membranes taken from the occipital cortex. It is concluded that there is a functional interaction between brain serotonin and GABA (gamma-aminobutyric acid) systems, both at behavioral and biochemical levels, that is involved in the motor activity habituation process.
European Journal of Pharmacology 08/1998; 353(1):5-12. · 2.52 Impact Factor
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ABSTRACT: Imipramine, amitriptyline, citalopram, and maprotiline were examined in different models of a nociceptive reaction after single-dose, and 21-day long administration, in rats. Animals' behavior in the Porsolt and open-field tests was also studied to compare analgesic and antidepressant-like action of drugs and to check the contribution of changes in the rats' gross behavior to animals' reactions to the nociceptive stimuli. The time- and dose-dependent fluctuations in the blood and brain concentrations of imipramine were evaluated in another group of animals. Imipramine, amitriptyline, citalopram, and maprotiline were shown to exert analgesic activity in some tests only. The most unequivocal analgesic effects were observed in the writhing test (2% acetic acid solution I.P.). The antinociceptive action of antidepressants in this test was probably not due to their local anaesthetic activity, because it was also present after intragastric drugs administration. Alterations in the open-field behavior of rats subjected to the treatment with antidepressant drugs did not correlate with animals' behavior in the writhing test. In the Porsolt test, the antidespair effects of antidepressants were not observed after acute drugs administration at the doses effective in the writhing test. Moreover, in contrary to the writhing reaction, the antiimmobility effect was potently enhanced after repeated administration of tricyclic drugs. Additionally, no association was found between the blood and brain concentrations of chronically administered imipramine and its effects in the writhing test. The obtained results indicate: (a) disparate sensitivity to antidepressant treatment of differently evoked behavioral reactions to the nociceptive stimuli; (b) the most potent effects of administered antidepressants in the model of visceral pain; (c) a better correlation of the brain concentration of imipramine with its antiimmobility than analgesic effect: (d) the lack of relationship between the analgesic and antidepressant-like effects of examined antidepressants compounds.
Pharmacology Biochemistry and Behavior 03/1998; 59(2):331-8. · 2.53 Impact Factor
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ABSTRACT: The effects of an agonist (S-AMPA, i.c.v.), as well as competitive (CNQX, NBQX, DNQX, i.p.), and noncompetitive antagonists (GYKI 52466, i.p.) at the AMPA/kainate receptors were examined in the open field and the Vogel tests of anxiety. It was found that both kinds of antagonists inhibited rat exploratory behavior in a dose-dependent manner, at the dose range exhibiting a clear-cut tendency to decrease rat locomotor activity. They appeared inactive in the Vogel test over an examined dose-range. S-AMPA, whereas not changing in a significant way rat behavior in the open field, significantly enhanced the suppressive influence of a shock on drinking in the Vogel test. The drug administered at the dose of 2 micrograms/5 microliters, i.c.v., revealed also a tendency to decrease the motor activity followed by prodromal symptoms of epileptic-like activity in some subjects. It is concluded that AMPA/kainate receptors probably are not directly involved in the control of rat emotional behavior. Thus, their primary role as putative neuroprotective and anticonvulsant agents is indirectly confirmed.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 10/1997; 48(3):479-88. · 2.27 Impact Factor
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ABSTRACT: The influence of serotonin (5-HT) depletion (5,7-dihydroxytryptamine, 5,7-DHT, 250.0 micrograms, ICV), on behavioral effects of non-competitive (MK-801) and competitive (CGP 37849) NMDA antagonists, was examined in rats. 5,7-DHT induced very potent and long lasting decrease in the 5-HT concentration in the brainstem and limbic forebrain. One week after 5,7-DHT administration, dopamine metabolism was found enhanced in the brainstem. The lesion did not change rat baseline motor and exploratory activity, but it significantly disinhibited animals' behavior suppressed by shock, in the Vogel test. Serotonin depletion revealed locomotor stimulating effect of MK-801, administered IP at the doses of 0.05 and 0.2 mg/kg. However, no change in striatal dopamine metabolism was detected in rats injected with the same dose of MK-801 (0.2 mg/kg), and examined one week after serotonergic denervation. Serotonergic lesions antagonized both enhancements of exploratory behavior, and motor suppression produced by the dose of 1.0 and 10.0 mg/kg of CGP 37849, respectively. Thus, 5,7-DHT-induced lesions influenced in a complex way the effects of NMDA antagonists. It is reasoned, that enhancement of motor stimulating effects of MK-801 in neurotoxin pretreated animals, reflects synergistic disinhibition of activity of dopaminergic neurons by MK-801 and serotonin depletion. On the other hand, antagonism of CGP 37849-caused motor depression can be explained by the lowering influence of 5,7-DHT on serotonin content. It is known that the release of serotonin is strongly stimulated by higher doses of CGP 37849, and takes part in the expression of some symptoms of the serotonin-like syndrome, including motor disturbances.
Pharmacology Biochemistry and Behavior 10/1997; 58(1):159-66. · 2.53 Impact Factor
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ABSTRACT: In the present study, the actions of several compounds with different intrinsic activities and BDZ receptor selectivity were examined in two well established animal models of anxiety: the open field test (OFT) and Vogel's punished drinking text (VT). Full agonists at the BDZ GABAA receptor (midazolam and diazepam) showed anxiolytic-like effects in both tests; however, the doses necessary to disinhibit animal behavior controlled by fear were higher in the VT than in the OFT. None of the partial BDZ receptor agonists studied (bretazenil, Ro 19-8022 and abecarnil) diminished neophobia-like behavior of rats in the OFT, and their sedative influence on gross behavior prevailed. On the other hand, all three drugs produced a clear-cut anxiolytic effect in the VT. A selective BDZ, receptor subtype full agonist (zolpidem) had a similar profile of action to that of partial agonists with an even stronger sedative effect in the OFT. Alpidem (a selective BDZ1 receptor partial agonist) did not reveal any anxiolytic action in either test. Flumazenil (an antagonist at the BDZ-GABAA receptors) also produced no effect in the OFT, or the VT. An inverse BDZ receptor agonist, beta-carboline-3-carboxylate methyl ester (beta-CCM), evoked an anxiogenic-like response in the OFT, but not in the VT. In summary, it appeared that partial agonists and selective ligands at BDZ1 receptors revealed less advantageous anxiolytic-like action than did full allosteric GABAA receptor modulators. This study also indicates the test dependent profiles of action of BDZ-GABAA receptor ligands. It also indirectly suggests a different neurobiological background underlying the applied tests.
Acta Neurovegetativa 02/1997; 104(6-7):733-46. · 2.73 Impact Factor
