Biomedical subjects

Elisabetta Cagetti

Publications and source records attributed to Elisabetta Cagetti.

7 recordsLinked to original sources

PubMed2006

Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors.

Alcohol withdrawal syndrome (AWS) symptoms include hyperexcitability, anxiety, and sleep disorders. Chronic intermittent ethanol (CIE) treatment of rats with subsequent withdrawal of ethanol (EtOH) reproduced AWS symptoms in behavioral assays, which included tolerance to the sleep-inducing effect of acute EtOH and its maintained anxiolytic effect. Electrophysiological assays demonstrated a CIE-induced long-term loss of extrasynaptic GABAA receptor (GABAAR) responsiveness and a gain of synaptic GABAAR responsiveness of CA1 pyramidal and dentate granule neurons to EtOH that we were able to relate to behavioral effects. After CIE treatment, the alpha4 subunit-preferring GABAAR ligands 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol, La3+, and Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5alpha][1,4]benzodiazepine-3-carboxylate) exerted decreased effects on extrasynaptic currents but had increased effects on synaptic currents. Electron microscopy revealed an increase in central synaptic localization of alpha4 but not delta subunits within GABAergic synapses on the dentate granule cells of CIE rats. Recordings in dentate granule cells from delta subunit-deficient mice revealed that this subunit is not required for synaptic GABAAR sensitivity to low [EtOH]. The profound alterations in EtOH sensitivity and alpha4 subunit localization at hippocampal GABAARs of CIE rats suggest that such changes in these and other relevant brain circuits may contribute to the development of tolerance to the sleep-inducing effects and long-term dependence on alcohol.

Animals↗

PubMed2005

Plasticity of GABAA receptors in brains of rats treated with chronic intermittent ethanol.

The study of alcohol dependence mechanisms has been aided by work in rodents, where regimens of intermittent chronic administration with repeated episodes of intoxication and withdrawal can be coupled with controlled timing of in vitro studies and the possibility of relating them to behavior. The chronic intermittent ethanol (CIE) model in the rat has been found to be a good model of human alcohol dependence, showing persistent signs of withdrawal and self-administration. Studies in CIE rats suggest that plastic changes in GABA-mediated inhibition involving the GABAA receptor system may be responsible for the behavioral alterations. Here we summarize a combination of evidence that the alcoholic rat CIE model demonstrates changes in GABAA receptor subunit levels, in receptor localization, and in physiology and pharmacology, leading to alterations in behavior that contribute to the hyperexcitable alcohol withdrawal state (anxiety, insomnia, seizure susceptibility) and alcohol dependence.

Animals↗

PubMed2004

Altered pharmacology of synaptic and extrasynaptic GABAA receptors on CA1 hippocampal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence.

Previously, we reported (Cagetti, Liang, Spigelman, and Olsen, 2003) that chronic intermittent ethanol (CIE) treatment leads to signs of alcohol dependence, including anxiety and hyperactivity, accompanied by reduced synaptic gamma-aminobutyric acid (A) receptor (GABAAR) function and altered sensitivity to its allosteric modulators consistent with a measured switch in subunit composition. In this study, we separated the synaptic and extrasynaptic components of GABAAR activation in recordings from pyramidal CA1 cells of hippocampal slices and demonstrated marked differences in the responsiveness of synaptic and extrasynaptic GABAARs to agonists and allosteric modulators in control rats, and in the way they are altered following CIE treatment. Notably, tonic inhibition mediated by extrasynaptic GABAARs was differentially sensitive to the partial agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; THIP) and the allosteric modulator zolpidem, compared with the miniature inhibitory synaptic currents (mIPSCs) in the same cells from saline-treated rats. After CIE treatment, potentiation of tonic currents by diazepam and zolpidem was lost, whereas potentiation by the alpha4 subunit-preferring benzodiazepine Ro15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxylate) and THIP was only partially reduced. Potentiation of synaptic GABAAR currents by zolpidem was eliminated after CIE, whereas THIP slightly inhibited mIPSCs from control rats and greatly enhanced them after CIE treatment. These results are consistent with alpha1 subunit decreases at synaptic and extrasynaptic GABAARs, whereas alpha4 subunits are increased at synaptic and decreased at extrasynaptic GABAARs. Behaviorally, THIP was active as a hypnotic and anxiolytic but not as an anti-convulsant against pentylenetetrazol seizures in control rats. Only slight tolerance was observed to the sleep time, but not to the anxiolytic, effect of THIP after CIE. Thus, differential alterations in synaptic and extrasynaptic GABAARs appear to play an important role in the brain plasticity of alcohol dependence, and withdrawal signs may be profitably treated with GABAergic drugs such as THIP, which does not show cross-tolerance with ethanol.

Alcoholism↗

PubMed2004

Topiramate attenuates withdrawal signs after chronic intermittent ethanol in rats.

Topiramate, a novel anticonvulsant drug, has CNS depressant activity including enhancement of GABAergic inhibitory synaptic transmission. Drugs of this pharmacological spectrum might have utility in assuaging drug addiction. This study analyzes the ability of TPM to reduce withdrawal signs in the kindling model of ethanol dependence: chronic intermittent ethanol (CIE) rats. After CIE, persistent withdrawal signs are shown by an increased seizure susceptibility to the convulsant drug pentylenetetrazol and increased anxiety measured on the elevated plus-maze. Topiramate increased significantly the PTZ seizure threshold in CIE but not in control rats. On the elevated plus-maze, Topiramate was markedly more effective in CIE rats than in controls. Topiramate may have a therapeutic efficacy in treating alcohol withdrawal symptoms.

Animals↗

PubMed2004

Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function.

The administration of ethanol on a chronic intermittent regimen (CIE) involving multiple withdrawal episodes is a model for ethanol dependence. After CIE, rats exhibited reduced seizure threshold, increased anxiety, tolerance to GABAergic sedative-hypnotic drugs, and changes in GABA(A) receptor function and subunit composition in hippocampus. Previous studies have shown that acute and chronic ethanol may induce changes in the levels of the neurosteroid 3alpha-hydroxysteroid-5alpha-pregnan-20-one (3alpha, 5alpha-THP) in the brain. Therefore, the current study analyses the correlation between chronic intermittent ethanol effects on the level of 3alpha, 5alpha-THP in hippocampus of CIE rats and the behavioral changes in sensitivity to neurosteroids. After CIE, the levels for 3alpha, 5alpha-THP were significantly reduced in hippocampus of rats. The mRNA levels for the enzymes 5alpha-reductase and 3alpha-HSD in hippocampus were also reduced. In vivo, (in contrast to a tolerance to the hypnotic effect of steroids), CIE rats showed increased sensitivity to the anticonvulsant and to the anxiolytic effect of the steroid alphaxalone. Perhaps, this is a response to lowered levels of endogenous neuroactive steroids. CIE rats also showed impairment of hippocampus-dependent memory function. These results suggest that changes in neurosteroids level and in vivo sensitivity to these compounds are involved in the development of ethanol dependence in the CIE model.

Animals↗

PubMed2003

Reduced inhibition and sensitivity to neurosteroids in hippocampus of mice lacking the GABA(A) receptor delta subunit.

The delta subunit of the gamma-aminobutyric acid (A) receptor (GABA(A)R) is expressed postnatally mostly in the cerebellum, thalamus, and dentate gyrus. Previous studies in mice with a targeted disruption of the delta subunit revealed a considerable attenuation of behavioral responses to neuroactive steroids but not to other neuromodulatory drugs. Here we show that delta subunit loss leads to a concomitant reduction in hippocampal alpha4 subunit levels. These changes were accompanied by faster decay of evoked inhibitory postsynaptic potentials (IPSPs) in dentate granule neurons of -/- mutants (decay tau = 25 ms) compared with +/+ controls (tau = 50 ms). Furthermore, the GABA(A)R-mediated miniature inhibitory postsynaptic currents (mIPSCs) also decayed faster in delta-mutants (tau = 6.3 ms) than controls (tau = 7.2 ms) and had decreased frequency (controls, 10.5 Hz; mutants, 6.6 Hz). Prolongation of mIPSCs by the neuroactive steroid anesthetic, alphaxalone (1-10 microM), was smaller in delta-mutants (at 10 microM, 65% increase) compared with +/+ littermates (308% increase). In competition binding experiments, alphaxalone (0.03-1 microM) modulation of [35S]t-butylbicyclophosphorothionate binding was reduced in delta-mutant brain homogenates, indicating that the decreased alphaxalone effects on mIPSCs were due to changes in the GABA(A)R protein. Faster decay of evoked IPSPs and mIPSCs in delta-mutants suggests presence of the delta subunit at both synaptic and extrasynaptic GABA(A)Rs. Decreased synaptic and extrasynaptic inhibition likely contributes to the pro-epileptic phenotype of delta-mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. While the simplest explanation is that delta subunit-containing GABA(A)Rs represent the actual target of neurosteroids, it is possible that the behavioral and physiological sensitivity to neuroactive steroids is indirectly altered in the delta -/- mice.

Anesthetics↗

PubMed2003

Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors.

One of the pharmacological targets of ethanol is the GABAA receptor (GABAR), whose function and expression are altered after chronic administration of ethanol. The details of the changes differ between experimental models. In the chronic intermittent ethanol (CIE) model for alcohol dependence, rats are exposed to intermittent episodes of intoxicating ethanol and withdrawal, leading to a kindling-like state of behavioral excitability. This is accompanied by presumably causal changes in GABAR expression and physiology. The present study investigates further the effect of CIE on GABAR function and expression. CIE is validated as a model for human alcohol withdrawal syndrome (AWS) by demonstrating increased level of anxiety; diazepam improved performance in the test. In addition, CIE rats showed remarkably reduced hypnotic response to a benzodiazepine and a steroid anesthetic, reduced sensitivity to a barbiturate, but not propofol. Immunoblotting revealed decrease in alpha1 and delta expression and increase in gamma2 and alpha4 subunits in hippocampus of CIE rats, confirmed by an increase in diazepam-insensitive binding for ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-alpha)(1,4)benzodiazepine-3-carboxylate (Ro15-4513). Elevated mRNA levels were shown for the gamma2S and gamma1 subunits. Recordings in hippocampal slices from CIE rats revealed that the decay time of GABAR-mediated miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal cells was decreased, and potentiation of mIPCSs by positive modulators of GABAR was also reduced compared with control rats. However, mIPSC potentiation by the alpha4-preferring benzodiazepine ligands bretazenil and Ro15-4513 was maintained, and increased, respectively. These data suggest that specific alterations in GABAR occur after CIE and may underlie the development of hyperexcitability and ethanol dependence.

Affinity Labels↗