Allosteric modulation of [35S]TBPS-binding in the cerebral cortex of the rat during postnatal development

Giorgi, Osvaldo; Cancedda, E; Lecca, Daniele; Orlandi, M; Corda, Maria Giuseppa

doi:10.1016/0165-3806(94)90091-4

Cited by 8 publications

(14 citation statements)

References 36 publications

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“…In agreement with the existing literature on outbred rats [7,9,45,58], the present study confirms that there is a high density of [35S]TBPS binding sites in numerous brain regions including the cerebral cortex, anterior hypo thalamic nucleus and amygdaloid complex. As compared with LAD rats, HAD rat brains contain fewer [35S]TBPS binding sites of GABAa receptors in the central medial thalamic, lateral and anterior hypothalamic nuclei and amygdaloid nuclei (the central, basolateral and basome dial amygdaloid nuclei).…”

Section: Discussionsupporting

confidence: 81%

“…This is possibly due to the fact that alcohol treatment alters [35S]TBPS binding affinities without changing its binding densities [44], although in vivo administration of diazepam changes the [35S]TBPS binding density without any effect on its binding affinity. In addition, it is also possible that the effect of ethanol on [35S]TBS binding is associated with endogenous differences in the molecular composition of GABAa receptors [9,20,27] which are formed by different receptor subunits [47,48] in various parts of the brain. This can be appreciated from the stud ies showing that the chronic ethanol treatment upregulates GABA receptor ß-subunit expression in the cerebral cortex [31], but downregulates a-subunits in the cerebral cortex and on cerebellar granule cells [30,32,33], Because of the high-affinity-binding property of TBPS to the GABAa receptor-gated chloride channel complex, [35S]TBPS has become one of the most attractive ligands of choice for autoradiographic studies [7] and in vitro studies [27,39,46,48] to assess the function of the GABAA-receptor-coupled chloride channel.…”

mentioning

confidence: 99%

“…Introduction receptor complex (GABAa receptors) and has been widely used as a pharmacological tool to assess GABAa receptors [3,7,9,44], [35S]TBPS has also been used to study the chronic effects of ethanol on the GABAA-receptor-coupled chloride channel [39,46,56]. Interestingly, ethanol can inhibit [35S]TBPS binding in vitro [56], but chronic treatment with ethanol does not alter [35S]TBPS binding [39].…”

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confidence: 99%

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Quantitative Autoradiography on [^35S]TBPS Binding Sites of Gamma- Aminobutyric AcidA Receptors in Discrete Brain Regions of High- Alcohol-Drinking and Low-Alcohol- Drinking Rats Selectively Bred for High- and Low-Alcohol Preference

Hwang¹,

Kunkler²,

Lumeng³

1997

J Biomed Sci

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It has been documented that ethanol can potentiate brain y-aminobutyric acid (GABA)ergic function, and there is a close link between the GABA(A) receptor complex and effects of ethanol, including reinforcement of alcohol which is a fundamental element of alcohol preference. However, it is unknown in what discrete brain regions GABA(A) receptors might be associated with alcohol preference. In the present study, [^35S]t-butylbicyclophosphorothionate ([^35S]TBPS) was used to localize GABA(A) receptors in high-alcohol-drinking (HAD) rats and low-alcohol-drinking (LAD) rats which were selectively bred for high and low alcohol preference, respectively. Initial qualitative observations indicated that [^35S]TBPS binding sites were abundant in many brain areas including the cerebral cortex, hypothalamus and amygdala of HAD and LAD rats. Furthermore, the quantitative autoradiographic analysis revealed fewer [^35S]TBPS binding sites of GABAa receptors in the amygdaloid complex, central medial thalamic nucleus, lateral hypothalamic nucleus and anterior hypothalamic nucleus of HAD rats than LAD rats. Collectively, this study has indicated that HAD rats selectively bred for high alcohol preference possess lower [^35S]TBPS binding in the brain. Since lower TBPS binding has been proposed to reflect enhanced GABAergic function, as evidenced in rats with seizure or under alcohol withdrawal, the results from the present study suggest that HAD rats might have an enhanced GABAergic function. It is thus likely that enhanced GABAergic function in the brain might be related to high alcohol preference which is characteristic in HAD rats. In addition, the present result showing no difference of [^35S]TBPS binding in the nucleus accumbens is also in agreement with a notion that [^35S]TBPS binding may represent only a small spectrum of the GABAa receptor complex which is constituted of a sophisticated subunit combination whose functional compositions are still unknown. In conclusion, the present study supports the working hypothesis that GABAa receptors are involved in alcohol preference in HAD rats.

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Section: Discussionsupporting

confidence: 81%

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confidence: 99%

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confidence: 99%

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Quantitative Autoradiography on [^35S]TBPS Binding Sites of Gamma- Aminobutyric AcidA Receptors in Discrete Brain Regions of High- Alcohol-Drinking and Low-Alcohol- Drinking Rats Selectively Bred for High- and Low-Alcohol Preference

Hwang¹,

Kunkler²,

Lumeng³

1997

J Biomed Sci

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“…However, our simulations show that potentiation is unlikely in the presence of substantial receptor activation by endogenous GABA release. The role of endogenous GABA should be considered in allosteric modulation of convulsant binding (26). This suggests that the principal factor preventing potentiation of the response to TGB by MDL may be the presence of endogenous GABA release.…”

Section: Figmentioning

confidence: 99%

Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal Transduction

Jonker¹,

Vermeij²,

Edelbroek³

et al. 2003

Epilepsia

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Summary:Purpose: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the ␥-aminobutyric acid subtype A (GABA A ) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake.Methods: The in vivo concentration-response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5-to 30-Hz frequency band was used as the pharmacodynamic end point.Results: Infusion of MDL resulted in a mean steady-state plasma concentration of 66 ± 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 ± 7 ml/min/kg from the original value of 89 ± 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration-EEG relation of TGB was described by the sigmoid-E max model. The pharmacodynamic parameter estimates of TGB were: E max ‫ס‬ 327 ± 10 V, EC 50 ‫ס‬ 392 ± 20 ng/ml, and n H ‫ס‬ 3.1 ± 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism.Conclusions: We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage.

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“…35 S]-TBPS is an ideal ligand for autoradiographic studies, because of its high specific activity, low non-specific binding, high resolution in autoradiographic analysis (Giorgi et al, 1994;Atack et al, 2007) and convenient quantification using commercially available standards. Second, modulation of […”

Section: Discussionmentioning

confidence: 99%

MODULATION OF THE GABA<sub>A</sub> RECEPTOR BY SRIF IN RAT THALAMUS

Chigr¹

2012

American Journal of Neuroscience

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Somatostatin has been reported to modulate GABA A receptor complex in many brain structures. This study was conducted to investigate somatostatin modulation of the GABA A receptor binding in several rat diencephalic structures, focusing primarily on the thalamus, as this structure plays important roles. Animals were assigned to control conditions. Changes in specific binding of GABA A receptor as labelled with [35 S]tButylbicyclophosphorothionate (TBPS) were assessed by in vitro quantitative autoradiography with the aid of a computer assisted image analysis system. Our results reveal the presence of higher densities in several thalamic structures located principally in the part of thalamus. We demonstrate for the first time the presence of a modulatory effect of somatostatin on the GABA A receptor complex in this brain region in rats. Indeed, the peptide affected in a concentration-dependent manner; the binding of

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Allosteric modulation of [35S]TBPS-binding in the cerebral cortex of the rat during postnatal development

Cited by 8 publications

References 36 publications

Quantitative Autoradiography on [^35S]TBPS Binding Sites of Gamma- Aminobutyric AcidA Receptors in Discrete Brain Regions of High- Alcohol-Drinking and Low-Alcohol- Drinking Rats Selectively Bred for High- and Low-Alcohol Preference

Quantitative Autoradiography on [^35S]TBPS Binding Sites of Gamma- Aminobutyric AcidA Receptors in Discrete Brain Regions of High- Alcohol-Drinking and Low-Alcohol- Drinking Rats Selectively Bred for High- and Low-Alcohol Preference

Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal Transduction

MODULATION OF THE GABA<sub>A</sub> RECEPTOR BY SRIF IN RAT THALAMUS

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