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Biomedical subjects

C Pesold

Publications and source records attributed to C Pesold.

30 records · Page 2Linked to original sources
PubMed1997

Tolerance to diazepam and changes in GABA(A) receptor subunit expression in rat neocortical areas.

Long-term treatment with diazepam, a full allosteric modulator of the GABA(A) receptor, results in tolerance to its anticonvulsant effects, whereas an equipotent treatment with the partial allosteric modulator imidazenil does not produce tolerance. Use of subunit-specific antibodies linked to gold particles allowed an immunocytochemical estimation of the expression density of the alpha1, alpha2, alpha3, alpha5, gamma(2L&S) and beta(2/3) subunits of the GABA(A) receptor in the frontoparietal motor and frontoparietal somatosensory cortices of rats that received long-term treatment with vehicle, diazepam (three times daily for 14 days, doses increasing from 17.6 to 70.4 micromol/kg), or imidazenil (three times daily for 14 days, doses increasing from 2.5 to 10.0 micromol/kg). In this study, tolerance to diazepam was associated with a selective decrease (37%) in the expression of the alpha1 subunit in layers III-IV of the frontoparietal motor cortex, and a concomitant increase in the expression of the alpha5 (150%), gamma(2L&S) and beta(2/3) subunits (48%); an increase in alpha5 subunits was measured in all cortical layers. In the frontoparietal somatosensory cortex, diazepam-tolerant rats had a 221% increase in the expression of alpha5 subunits in all cortical layers, as well as a 35% increase in the expression of alpha3 subunits restricted to layers V-VI. Western blot analysis substantiated that these diazepam-induced changes reflected the expression of full subunit molecules. Rats that received equipotent treatment with imidazenil did not become tolerant to its anticonvulsant properties, and did not show significant changes in the expression of any of the GABA(A) receptor subunits studied, with the exception of a small decrease in alpha2 subunits in cortical layers V-VI of the frontoparietal somatosensory cortex. The results of this study suggest that tolerance to benzodiazepines may be associated with select changes in subunit abundance, leading to the expression of different GABA(A) receptor subtypes in specific brain areas. These changes might be mediated by a unique homeostatic mechanism regulating the expression of GABA(A) receptor subtypes that maintain specific functional features of GABAergic function in cortical cell layers.

Animals↗
PubMed1996

The neuroanatomical specificity of the anxiolytic effects of intra-septal infusions of midazolam.

Microinfusions of the benzodiazepine anxiolytic midazolam into the lateral but not the medial septum suppressed fear reactions in two test of rat 'anxiety'. Midazolam infusions into the lateral septal nuclei increased open-arm exploration in the elevated plus-maze test, and blocked burying behavior in the shock-probe test, whereas midazolam infusions into the medial septum produced neither of these anxiolytic effects. The anxiolytic effects of midazolam in the lateral septum were partially blocked by pre-infusion of the benzodiazepine receptor antagonist Ro15-1788, which had no intrinsic effects by itself. These results suggest that the anxiolytic effects of intra-septal midazolam occur, at least in part, at GABAA-benzodiazepine receptor sites located in the lateral septal nuclei.

Animals↗
PubMed1996

Modifications of gamma-aminobutyric acidA receptor subunit expression in rat neocortex during tolerance to diazepam.

We evaluated whether tolerance to the antagonism of bicuculine-induced seizures by diazepam is associated with changes (i) in the content of mRNAs encoding for gamma-aminobutyric acidA (GABAA) receptor subunits, (ii) in the expression density of these subunits, and (iii) in the 1,4-benzodiazepine binding site characteristics in discrete neocortical structures. We found that in diazepam-tolerant rats, the content of the mRNA encoding for the alpha 1 subunit of the GABAA receptor decreased in the frontoparietal motor (FrPaM) cortex and in the hippocampus (42% and 20%, respectively) but not in the frontoparietal somatosensory (FrPaSS) cortex, striatum, olfactory bulb, and cerebellum. In the FrPaM cortex, gamma 2S and gamma 2L subunit mRNA contents were also decreased (48% and 30%, respectively), whereas that of alpha 5 was increased (30%). In the FrPaM and FrPaSS cortices as well as in cerebellum of diazepam-tolerant rats, the content of alpha 2, alpha 3, alpha 6, beta 2, and delta subunit mRNA was unchanged, as was the content of alpha 2, alpha 5, gamma 1, and gamma 2S subunit mRNA in the hippocampus. Furthermore, the reduction in alpha 1 subunit mRNA content in the FrPaM cortex and the anticonvulsant tolerance to diazepam returned to control values 72 hr after termination of the protracted diazepam treatment. Rats receiving a treatment with imidazenil in doses equipotent and with a schedule identical to that of diazepam failed to exhibit tolerance to the anticonvulsant action of this drug or cross-tolerance to diazepam. In these rats, the content of mRNA encoding for alpha 1, alpha 2, alpha 3, alpha 5, alpha 6, gamma 1, gamma 2S, gamma 2L, and delta GABAA receptor subunits failed to change in the FrPaM and FrPaSS cortices, in the hippocampus, and in the other brain areas that were studied in diazepam-tolerant rats. Although the density and affinity of [3H]flumazenil and [3H]imidazenil binding failed to change in the FrPaM and FrPaSS cortices of diazepam-tolerant rats, the expression density of alpha 1 subunit immunogold labeling decreased by 37%, whereas that of alpha 5, gamma 2L/S, and beta 2/3 increased by 158%, 50%, and 47%, respectively, in the FrPaM cortex, and the density of the alpha 5 subunit selectively increased (209%) in the FrPaSS cortex. In contrast, the immunogold labeling density of the alpha 1, alpha 5, gamma 2L/S, and beta 2/3 subunits failed to change in either the FrPaM or FrPaSS cortex of rats receiving protracted imidazenil treatment.

Animals↗
PubMed1996

Semiquantitative immunocytochemical analysis of GABAA receptor subunit expression in the rat neostriatum.

A semiquantitative immunogold technique was used to investigate the levels of expression of specific GABAA receptor subunits in different regions (dorsolateral, dorsomedial and ventromedial regions) of the rat striatum. The results indicate that the subunits studied can be classified into three groups on the basis of their labelling density in the striatum: alpha 1 and alpha 3 (labelling density of less than 100 gold particles per 1000 microns2), gamma 2 and delta (between 100 and 200 particles per 1000 microns2), and alpha 2 and beta 2/3 (more than 300 particles per 1000 microns2). The alpha 1 and alpha 3 subunits are about 35% more abundant in the dorsal than in the ventral striatum, while the beta 2/3 and gamma 2 subunits are about 40% more abundant in the medial than in the lateral striatum. The alpha 2 and delta subunits did not show significant regional differences in abundance. The present data are consistent with the possibility that there are regional variations in the relative abundances of different GABAA receptor subtypes in the rat striatum.

Animals↗
PubMed1995

The central and basolateral amygdala differentially mediate the anxiolytic effects of benzodiazepines.

Microinfusions of the benzodiazepine anxiolytic midazolam into the central or basolateral amygdaloid nuclei produced different anxiolytic effects in two tests of rat 'anxiety'. Infusions into the basolateral nucleus impaired open-arm avoidance in the elevated plus-maze test, but did not impair shock-probe avoidance in the shock-probe burying test. In contrast, infusions into the central nucleus impaired shock-probe avoidance, but did not impair open-arm avoidance. Both of these site-specific, midazolam-induced anxiolytic effects were blocked by a pre-infusion of the benzodiazepine receptor antagonist Ro 15-1788 (flumazenil). None of the treatments affected defensive burying. These results suggest that benzodiazepine receptors in the central and basolateral amygdaloid nuclei differentially mediate the anti-anxiety effects of benzodiazepine anxiolytics.

Amygdala↗
PubMed1994

The septum and amygdala differentially mediate the anxiolytic effects of benzodiazepines.

Microinfusions of a benzodiazepine anxiolytic (midazolam) into the septum or the amygdala suppressed different fear reactions in two tests of rat "anxiety". Septal infusions increased open-arm activity in the plus-maze test and decreased burying behavior in the shock-probe test whereas amygdaloid infusions produced neither of these antianxiety effects. Amygdaloid infusions, however, dramatically impaired shock-probe avoidance, an antianxiety effect not produced by the septal infusions. Infusions of the benzodiazepine receptor antagonist Ro 15-1788 (flumazenil) blocked each of these specific, anti-fear effects of midazolam without producing intrinsic effects by itself. These results suggest that benzodiazepine receptor systems within the amygdala and the septum differentially mediate specific fear reactions.

Amygdala↗
PubMed1993

Anxiolytic effects of serotonergic interventions in the shock-probe burying test and the elevated plus-maze test.

Although serotonergic neural systems have been implicated in the control of anxiety for a number of years, evidence in favour of this role is controversial. The present experiments were designed to further characterize the putative role of serotonin (5-HT) in anxiety, using two pharmacologically validated animal models: the elevated plus-maze and the shock-probe burying tests. If the integrity of 5-HT neural systems is necessary for the expression of 'anxious' behaviors, then disruption of 5-HT systems should produce effects in the plus-maze and shock-probe tests that are similar to those of anxiolytic drugs. In the present experiments, serotonergic function was disrupted in rats, either by chemical depletion using the synthesis inhibitor p-CPA, by inhibitory autoreceptor activation using the selective 5-HT1A receptor ligand 8-OH-DPAT, or by electrolytic lesions of the serotonin-containing, dorsal raphe nucleus. p-CPA and dorsal raphe lesions produced robust anxiolytic effects in the elevated plus-maze and the shock-probe burying tests, whereas 8-OH-DPAT produced anxiolytic effects only in the shock-probe burying test, and 'anxiogenic' effects in the elevated plus-maze test. Although these results generally support the view that serotonin plays a role in the expression of 'anxious' behavior, the opposite effects of 8-OH-DPAT in the two behavioral paradigms suggest that the 5-HT1A receptor subtype exerts differential control over different types of experimental anxiety.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Dissociating the anti-fear effects of septal and amygdaloid lesions using two pharmacologically validated models of rat anxiety.

Effects of septal and amygdaloid lesions were compared in 2 models of rat "anxiety." Septal lesions decreased burying behavior in the "shock-probe burying test" and increased open-arm exploration in the "elevated plus-maze test," whereas amygdaloid lesions produced neither of these anxiolytic effects. However, amygdaloid lesions increased rats' contacts of the electrified probe, an anxiolytic effect not produced by septal lesions. Each of these distinct, anxiolytic effects of septal or amygdaloid lesions were displayed together in animals with lesions of both structures. Furthermore, the magnitude of these anxiolytic effects after combined lesions was comparable to their magnitude after individual lesions. Taken together, these results suggest the amygdala and the septum independently control the expression of different fear-related behaviors.

Amygdala↗
PubMed1993

Noninteractive effects of diazepam and amygdaloid lesions in two animal models of anxiety.

The role of the amygdala in mediating the anxiolytic effects of diazepam was examined in two models of rat anxiety. As in our previous experiments, amygdaloid lesions by themselves did not increase rats' exploration of the open arms of the elevated plus-maze or decrease rats' burying of an electrified probe in the shock-probe burying test. However, amygdaloid lesions did increase rats' shock-probe contacts. Diazepam (2 mg/kg) increased open-arm activity and decreased burying behavior to an equal extent in sham-lesioned and amygdala-lesioned rats and had no significant effect on the facilitation of probe contacts induced by amygdaloid lesions. These results suggest that many of the anxiolytic effects of benzodiazepines are not mediated by the amygdala.

Amygdala↗
PubMed1992

Excitotoxic lesions of the septum produce anxiolytic effects in the elevated plus-maze and the shock-probe burying tests.

Our previous research has shown that electrolytic lesions of the posterior septum result in dramatic, antianxiety effects in two different animal models of anxiolytic drug action, i.e., a selective increase in open-arm activity in the elevated plus-maze test, and a selective abolition of defensive burying in the shock-probe burying test. Although these results suggest that posterior regions of the septum play an important role in the expression of anxiety in these tests, it is unclear whether destruction of septal nuclei themselves mediated these effects, since electrolytic lesions also destroy fibers of passage. Accordingly, in the present experiments, the anxiolytic effects of electrolytic lesions of the septum were compared to those of excitotoxic lesions, which preferentially destroy cell bodies, leaving fibers of passage intact. In the first experiment, both electrolytic and kainic acid lesions of the posterior septum produced complete anxiolytic effects in the elevated plus-maze (an increase in the percentage of open-arm entries and percentage of time in open arms), and partial anxiolytic effects in the shock-probe test (an increase in contact-induced probe shocks), compared to sham-lesioned controls. These antianxiety effects could not be attributed to an increase in general activity, or a decrease in reactivity to shock. In the second experiment, excitotoxic lesions of the posterior septum were produced by a more selective agent, quisqualic acid. Quisqualic acid, like electrolytic lesions, produced clear, anxiolytic effects in both the plus-maze and the shock-probe tests, compared to sham-lesioned control. Taken together, these results strongly suggest that cells originating in posterior regions of the septum mediate anxiety-related responses.

Animals↗
PubMed1990

Septal lesions inhibit fear reactions in two animal models of anxiolytic drug action.

The role of the septum in anxiety was studied using two different animal models of antianxiety drug action; i.e., the shock probe-burying test and the elevated plus maze test. Antianxiety effects were observed in both paradigms (i.e., a decrease in probe burying, and an increase in open arm activity) after lesions of the entire septum, compared to sham-lesioned controls (Experiment 1). No differences between lesioned and sham-lesioned rats were found in general activity, shock reactivity, or handling reactivity at the time of the antianxiety tests. A second experiment showed that the antianxiety effects observed in the two paradigms were anatomically specific, since lesions of the posterior septum decreased both indices of anxiety (probe burying and open arm avoidance), whereas lesions of the anterior septum resulted in levels of anxiety that were comparable to those displayed by sham-lesioned controls. Taken together, these results provide convergent evidence that posterior regions of the septum play an important role in the control of anxiety in the rat.

Agonistic Behavior↗