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1.
J Prev Med Hyg ; 59(3): E187-E193, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30397674

ABSTRACT

OBJECTIVES: Tuscany region (Italy) recorded a rise in the number of meningococcal disease cases between January 2015 and February 2016, (52 cases) compared to 2014 (16 cases). The aim of this study was to describe the emergency meningococcal C (MenC) vaccination programme in Tuscany and the population's adherence to the activities performed in the Local Health Unit (LHU) of Florence. METHODS: The MenC vaccination programme and the planning of the prevention and communication activities were analysed in the LHU of Florence. As an indicator of population's adherence, the vaccination coverage (VC) during the emergency campaign was investigated and adverse drug reactions (ADR) surveillance was reported. RESULTS: The communication campaign included a dedicated toll-free telephone number, press releases (newspapers, radio, television, websites), and informative letters addressed to mayors, secondary schools, and sports associations. Citizens aged 11-20 years were the primary target of the campaign. Due to the high incidence of cases among older people, the vaccination was extended to subjects over 45 years. The population's adherence to the vaccination campaign was satisfactory: VC reached 47.1% for the primary target. The ADR reporting rate (3.1/10,000) on meningococcal vaccine in our study confirmed the safety of the vaccination. CONCLUSIONS: In 2017, only 10 cases of invasive meningococcal diseases (IMD) were reported, suggesting the effectiveness of the immunization campaign. Similar VC during emergency MenC vaccination programmes have been reached in other Italian regions and other EU countries, too. The achievement of greater vaccination coverage is restricted by a sentiment of hesitancy towards vaccines among the general population.


Subject(s)
Disease Outbreaks/prevention & control , Immunization Programs , Medication Adherence , Meningococcal Vaccines/administration & dosage , Adolescent , Adult , Child , Emergency Medical Services , Humans , Italy/epidemiology , Middle Aged , Population Surveillance , Young Adult
2.
Int J Neuropsychopharmacol ; 4(3): 219-22, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11602027

ABSTRACT

The effects of prenatal CO exposure (150 ppm from days 0 to 20 of pregnancy) on the postnatal development of hippocampal neuronal NO synthase (nNOS) and haem-oxygenase (HO-2) isoform activities in 15-, 30- and 90-d-old rats were investigated. Unlike HO-2, hippocampal nNOS activity increased from postnatal days 15-90 in controls. Prenatal CO produced a long-lasting decrease in either nNOS or HO-2. The results suggest that the altered developmental profile of hippocampal nNOS and HO-2 activities could be involved in cognitive deficits and long-term potentiation dysfunction exhibited by rats prenatally exposed to CO levels resulting in carboxyhaemoglobin (HbCO) levels equivalent to those observed in human cigarette smokers.


Subject(s)
Carbon Monoxide/toxicity , Heme Oxygenase (Decyclizing)/metabolism , Hippocampus/enzymology , Hippocampus/growth & development , Nitric Oxide Synthase/metabolism , Animals , Female , Hemoglobins/metabolism , Hippocampus/drug effects , Isoenzymes/metabolism , Nitric Oxide Synthase Type I , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Rats, Wistar
3.
Neuropsychopharmacology ; 24(6): 691-705, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11331149

ABSTRACT

The neurofunctional effects of developmental alcohol exposure (3% v/v solution from day 15 of gestation to day 7 after parturition) have been investigated in Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rat lines, selectively bred for opposite alcohol preference and consumption. Alcohol exposure significantly decreased the rate of ultrasonic emission in sP male pups; whereas, it did not affect this indicator of emotional reactivity in sNP animals. Perinatal alcohol intake did not influence either learning of an active avoidance task or hippocampal long-term potentiation in both offspring lines. Significant differences in time spent exploring novel objects were observed between control sP and sNP rats subjected to the novel exploration object test. Alcohol exposed sP rats, but not alcohol exposed sNP rats, apparently lost the capacity to discriminate between the novel and the familiar object, even though this difference is difficult to interpret because of the large differences in the respective responses to the novel objects. Neurochemical experiments have shown that basal levels of dopamine (DA) and homovanillic acid (HVA) were significantly higher in the nucleus accumbens (NAC) of sP rats with respect to sNP animals. Perinatal alcohol did not affect basal DA and HVA concentrations or amphetamine-induced DA increase and HVA decrease in the NAC of either sP or sNP offspring. These results suggest that subtle behavioral alterations induced by developmental exposure to low doses of alcohol, which do not cause malformations and/or overt neurotoxicity, may be associated with genetic factors, although not necessarily those responsible for differences in alcohol preference.


Subject(s)
Alcohol-Induced Disorders, Nervous System/congenital , Alcohol-Induced Disorders, Nervous System/physiopathology , Alcoholism/physiopathology , Brain/drug effects , Fetal Alcohol Spectrum Disorders/physiopathology , Food Preferences/physiology , Prenatal Exposure Delayed Effects , Amphetamine/pharmacology , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Brain/embryology , Brain/growth & development , Dopamine/metabolism , Ethanol/blood , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Female , Hippocampus/drug effects , Hippocampus/physiology , Long-Term Potentiation/drug effects , Long-Term Potentiation/physiology , Male , Motor Activity/drug effects , Motor Activity/physiology , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Pregnancy , Rats , Rats, Wistar , Vocalization, Animal/drug effects , Vocalization, Animal/physiology
4.
Neuroreport ; 11(16): 3637-9, 2000 Nov 09.
Article in English | MEDLINE | ID: mdl-11095534

ABSTRACT

In humans, nicotine is self administered by inhalation of tobacco smoke as opposed to animal models, where nicotine is administered via systemic injection. The aim of the present study was to clarify whether tobacco smoke inhalation would affect dopaminergic projections differently from the reported activation after the systemic administration of nicotine. For this purpose, tobacco smoke from cigarettes containing 1.0 or 0.1 mg nicotine was delivered by inhalation to rats, while recording from antidromically identified nigrostriatal and mesolimbic dopamine neurons. Smoke inhalation from 1.0 mg nicotine cigarettes caused a peculiar abrupt increase of discharge activity of mesolimbic dopamine neurons, while nigrostriatal cells were less responsive. This activation was promptly antagonized by mecamylamine (2.0 mg/kg, i.v.). In contrast, smoke delivered from 0.1 mg nicotine cigarettes was ineffective. These findings suggest that the boosting activation of mesolimbic dopamine neurons by inhaled nicotine might be relevant for the rewarding properties of tobacco smoking and also for the effectiveness of new treatments to stop smoking.


Subject(s)
Brain/physiology , Dopamine/physiology , Neurons/physiology , Nicotine/pharmacology , Smoking , Administration, Inhalation , Animals , Brain/drug effects , Corpus Striatum/drug effects , Corpus Striatum/physiology , Evoked Potentials/drug effects , Humans , Limbic System/drug effects , Limbic System/physiology , Mecamylamine/pharmacology , Neurons/drug effects , Nicotine/administration & dosage , Rats , Smoke , Substantia Nigra/drug effects , Substantia Nigra/physiology , Tobacco Smoke Pollution
5.
J Pharmacol Exp Ther ; 294(2): 728-34, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10900254

ABSTRACT

The aim of the present study was to investigate whether functional changes at CA3-CA1 synapses in the hippocampus could underlie learning and memory deficits produced in rat offspring by a prenatal exposure model simulating the carbon monoxide (CO) exposure observed in human cigarette smokers. Electrophysiological endpoints, including long-term potentiation, were examined in 15- to 30-day-old male rats whose mothers were exposed, from day 0 to day 20 of gestation, to 150 ppm of CO resulting in blood levels of carboxyhemoglobin comparable to those found in human cigarette smokers. Evoked field excitatory postsynaptic potentials were measured in the stratum radiatum in hippocampal slices. Results show that before tetanus, input/output functions, presynaptic volley, and paired-pulse facilitation were not affected in CO-exposed offspring, indicating that basal synaptic excitability and terminal Ca(2+) influx were not influenced by prenatal exposure to this gas. Conversely, evoked field excitatory postsynaptic potentials potentiation in response to tetanization was reduced by about 23% and decayed rapidly to baseline values in slices from CO-exposed animals. No changes between and within groups were observed in paired-pulse facilitation after tetanus. The selective impairment of long-term potentiation expression exhibited by CO-exposed rats was paralleled by a significant decrease in heme-oxygenase 2 and neuronal nitric-oxide synthase in the hippocampus. No changes in either enzymatic activity were found in frontal cortex and cerebellum. These electrophysiological and biochemical alterations might account for cognitive deficits previously observed in rats exposed prenatally to CO. Our findings could have clinical implications for the offspring of mothers who smoke during pregnancy.


Subject(s)
Carbon Monoxide/toxicity , Long-Term Potentiation/drug effects , Prenatal Exposure Delayed Effects , Pyramidal Cells/drug effects , Animals , Carboxyhemoglobin/metabolism , Cerebellum/drug effects , Cerebellum/enzymology , Excitatory Postsynaptic Potentials/drug effects , Female , Frontal Lobe/drug effects , Frontal Lobe/enzymology , Heme Oxygenase (Decyclizing)/metabolism , Male , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type I , Pregnancy , Pyramidal Cells/enzymology , Pyramidal Cells/physiology , Rats , Rats, Wistar , Synaptic Transmission/drug effects
6.
Brain Res ; 783(1): 127-32, 1998 Feb 02.
Article in English | MEDLINE | ID: mdl-9479061

ABSTRACT

A widely accepted theory postulates that chronic treatment with neuroleptics causes, in rats, the depolarization block of the majority of midbrain dopamine (DA) neurons. However, we reported that such treatment fails to reduce the number of spontaneously active DA neurons when the neuronal sampling is performed in the d-tubocurarine-paralyzed instead of chloral-hydrate anesthetized preparation. The present experiments were aimed at verifying whether the negative results might be due to the use of d-tubocurarine as paralyzing agent. Rats were chronically treated with haloperidol (0.5 mg kg-1 i.p., daily) for 3 to 4 weeks. Two to three hours after the last injection, the number of spontaneously active DA neurons in the ventral tegmental area (VTA) were sampled, and their discharging characteristics analyzed, both in animals under chloral hydrate anesthesia and in rats immobilized either with d-tubocurarine, gallamine or succinylcholine. The results indicate that chronic treatment with haloperidol reduced the number of spontaneously active VTA-DA neurons by about 65% in animals under chloral hydrate anesthesia, but failed to modify the number of spontaneously firing DA neurons in rats immobilized with d-tubocurarine, gallamine or succinylcholine. The results indicate that the depolarization block of DA neurons does not occur in the paralyzed preparation and raise doubts about the presence of this phenomenon in the intact non- anesthetized unrestrained animal.


Subject(s)
Antipsychotic Agents/pharmacology , Dopamine Antagonists/pharmacology , Haloperidol/pharmacology , Paralysis/chemically induced , Animals , Chloral Hydrate , Gallamine Triethiodide , Male , Membrane Potentials/drug effects , Neuromuscular Nondepolarizing Agents , Rats , Rats, Sprague-Dawley , Succinylcholine , Tubocurarine
8.
Neuroscience ; 77(4): 1029-36, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9130784

ABSTRACT

Dopamine neurons in midbrain coronal slices from adult rats (40-70 days old) discharged only in pacemaker-like mode. Irregular or bursting mode was never observed. In contrast, dopamine neurons in slices from immature rats (15-21 days old) exhibited not only pacemaker-like firing (53.4% of neurons), but also irregular and bursting patterns (28.3 and 18.3%, respectively). Glutamate and kainate increased the firing rate but failed to induce bursts in dopamine neurons from either adult or immature rats. N-Methyl-D-aspartate augmented the firing rate in all neurons from adult rats and produced a modest increase of bursts in only three out of 18 cells. In slices from immature rats, N-methyl-D-aspartate activated the discharge rate in all neurons and also induced bursts in 37 and 53% of pacemaker and irregular neurons, respectively, and increased the occurrence of spikes in bursts in 76% of spontaneously bursting neurons. The selective N-methyl-D-aspartate receptor antagonist (+/-)2-amino,5-phosphonopentanoic acid prevented N-methyl-D-aspartate-induced changes and also reduced spontaneous bursts, suggesting that bursting discharge is mediated by N-methyl-D-aspartate receptor activation. While pacemaker neurons from immature and from adult rats exhibited the same sensitivity to N-methyl-D-aspartate-induced stimulation of firing rate, spontaneously bursting neurons were more sensitive than pacemaker neurons from either immature or adult rats. The present study indicates that spontaneous bursting, dependent on N-methyl-D-aspartate receptor activation, is present, and may be induced, in dopamine neurons in slices from immature rats. Its absence from cells in slices from adult rats may reflect a reduced sensitivity of N-methyl-D-aspartate receptors on dopamine or the loss of the N-methyl-D-aspartate-activated burst generator.


Subject(s)
Dopamine/physiology , Mesencephalon/cytology , Neurons/physiology , Receptors, N-Methyl-D-Aspartate/physiology , 2-Amino-5-phosphonovalerate/pharmacology , Age Factors , Animals , Animals, Newborn , Electrophysiology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/pharmacology , Kainic Acid/pharmacology , Male , Mesencephalon/chemistry , N-Methylaspartate/pharmacology , Neurons/chemistry , Periodicity , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
9.
J Neurosci ; 15(2): 1144-9, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7869090

ABSTRACT

A widely accepted theory postulates that, in rats, chronic treatment with neuroleptics causes the depolarization inactivation of the majority of midbrain dopamine (DA) neurons. The present study was aimed to verify whether general anesthesia and/or other factors might contribute to the depolarization inactivation of A9 and A10 DA neurons. To investigate on the possible role played by DA receptor subtypes, three representatives DA antagonists were used: haloperidol (a mixed D1/D2), (-)-sulpiride (a selective D2) and SCH 23390 (a selective D1). In agreement with previous studies, where neuronal sampling was carried out in animals under chloral hydrate anesthesia, chronic treatment with haloperidol (0.5 mg/kg daily for 21-28 d) produced a profound reduction (about 80%) in the number of spontaneously active A9 DA neurons. However, when neuronal sampling was performed in unanesthetized rats, the single administration of haloperidol, (-)-sulpiride, or SCH 23390 (0.5, 25, and 0.3 mg/kg respectively 2-3 hr beforehand) increased the number of spontaneously active A9 and A10 DA neurons and their firing rate, whereas the chronic administration of these drugs (daily for 21-28 d) failed to reduce the number of spontaneously active A9 and A10 DA neurons. The inhibitory effect of apomorphine on the firing rate of A9 and A10 DA neurons was prevented 3-4 hr after the acute or last injection of chronic haloperidol or (-)-sulpiride. However, the inhibitory effect was potentiated 24 hr after the last administration of the chronic regimen with these neuroleptics, but it was not influenced by either acute or chronic treatment with SCH 23390.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Dopamine/physiology , Electrophysiology , Neurons/physiology , Animals , Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Artifacts , Haloperidol/pharmacology , Male , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Time Factors
10.
Eur J Pharmacol ; 264(3): 449-53, 1994 Nov 03.
Article in English | MEDLINE | ID: mdl-7698187

ABSTRACT

Chronic treatment with neuroleptics has been reported to induce a status of depolarization inactivation of the majority of midbrain dopamine neurons. The present study was aimed at determining whether general anesthesia might be a contributory cause of depolarization inactivation of substantia nigra dopamine neurons. In agreement with previous studies, where neuronal sampling was carried out in animals under chloral hydrate anesthesia, chronic treatment with haloperidol (0.5 mg/kg daily for 21-28 days) produced a marked reduction (about 80%) in the number of spontaneously active dopamine neurons. However, when neuronal sampling was performed in unanesthetized rats, chronic administration of haloperidol (daily for 21-28 days) failed to reduce the incidence of active dopaminergic neurons. The results suggest that depolarization inactivation of dopamine neurons is not present in the intact animal but is probably produced during the neuronal sampling procedure as a consequence of neuroleptic-induced hyperexcitability of dopamine neurons combined with their stimulation by general anesthetics.


Subject(s)
Dopamine/metabolism , Haloperidol/toxicity , Neurons/drug effects , Substantia Nigra/cytology , Analysis of Variance , Anesthesia/adverse effects , Animals , Disease Models, Animal , Haloperidol/administration & dosage , Haloperidol/therapeutic use , Male , Microelectrodes , Neurons/cytology , Neurons/physiology , Rats , Rats, Sprague-Dawley , Schizophrenia/drug therapy , Substantia Nigra/drug effects , Substantia Nigra/physiology
13.
Brain Res ; 566(1-2): 208-11, 1991 Dec 06.
Article in English | MEDLINE | ID: mdl-1814536

ABSTRACT

In unanesthetized rats the intravenous (i.v.) administration of gamma-hydroxybutyric acid (GHB) at the doses of 50-400 mg/kg produced a dose-related stimulation (10-56%) of the firing rate of dopaminergic (DA) neurons in the pars compacta of the substantia nigra. Doses of 1000 and 1500 mg/kg inhibited the firing rate almost completely. In unanesthetized rats the intraperitoneal injection of GHB at the dose of 750 mg/kg produced a brief initial stimulation (23%) followed by a modest reduction in the firing rate (29%). On the other hand, in chloral hydrate-anesthetized rats the i.v. administration of GHB at cumulative doses of up to 200 mg/kg failed to modify the firing rate of DA neurons, while a cumulative dose of 400 mg/kg suppressed neuronal firing. The results indicate that sub-anesthetic doses of GHB stimulate the firing rate of DA neurons in unanesthetized rats.


Subject(s)
Dopamine/physiology , Neurons/physiology , Sodium Oxybate/pharmacology , Substantia Nigra/physiology , Anesthesia, General , Animals , Dose-Response Relationship, Drug , Injections, Intraperitoneal , Injections, Intravenous , Kinetics , Male , Neurons/drug effects , Rats , Rats, Inbred Strains , Sodium Oxybate/administration & dosage , Substantia Nigra/drug effects , Wakefulness
14.
J Neurosci ; 11(5): 1359-66, 1991 May.
Article in English | MEDLINE | ID: mdl-1674003

ABSTRACT

Although dopamine (DA)-containing neurons participate in a number of important cerebral functions, the physiology of their synaptic connections is poorly understood. By using whole-cell patch-clamp recording in thin slices of rat mesencephalon, we have investigated the biophysical properties of synaptic events and the nature of neurotransmitter(s) and receptors involved in the synaptic input to DA neurons in substantia nigra. The histological and electrophysiological characteristics of these cells were consistent with those described by recent in vivo and in vitro studies, thus allowing their unequivocal identification. Under appropriate experimental conditions, intranigral stimulation produced excitatory synaptic inputs in DA neurons. By voltage-clamp analysis, most of these excitatory postsynaptic currents (EPSCs) had a rise time of about 1.0 msec and a decay phase that could be fit by the sum of two exponential curves so that a fast and a slow component could be distinguished. The slow component was enhanced by glycine, by removing Mg2+ from the bath medium, or by membrane depolarization. Moreover, the slow component was consistently decreased by selective antagonists of NMDA receptors, whereas an antagonist for the non-NMDA receptors abolished the fast component slightly affecting the slow component and reduced peak EPSC amplitude. The results indicate that both NMDA-sensitive and non-NMDA-sensitive glutamate receptors contribute to EPSCs of DA neurons. Therefore, it is suggested that these receptors may play a critical role in the physiology (control of excitability, pacemaker firing, and dendritic DA release) as well as pathology (neuronal death in Parkinson's disease, psychosis, and mechanism of action of drugs of abuse, such as ethanol) related to DA neurons.


Subject(s)
Dopamine/pharmacology , Mesencephalon/physiology , Neurons/physiology , Receptors, Neurotransmitter/physiology , Synapses/physiology , 2-Amino-5-phosphonovalerate/pharmacology , 6-Cyano-7-nitroquinoxaline-2,3-dione , Action Potentials/drug effects , Animals , Evoked Potentials/drug effects , Glutamates/physiology , In Vitro Techniques , Kynurenic Acid/analogs & derivatives , Kynurenic Acid/pharmacology , Mecamylamine/pharmacology , Neurons/drug effects , Picrotoxin/pharmacology , Quinoxalines/pharmacology , Rats , Receptors, Glutamate , Receptors, Neurotransmitter/drug effects , Synapses/drug effects
15.
Epilepsy Res ; 6(3): 205-10, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2272344

ABSTRACT

Diphenylhydantoin (DPH) has recently been reported to produce dopaminergic (DA) supersensitivity in animals. These results have suggested that the dyskinesias observed in humans after DPH, although rare, might be regarded as a neuroleptic-like effect. Indeed dyskinesias would be induced by an inactivation of post-synaptic DAergic receptors, operated by DPH, and therefore reminiscent of that observable in neuroleptic treatment. In order to investigate this matter, we studied the effects of i.v. DPH on the extracellular single unit activity of DAergic cells located in mid-brain areas of rats. DPH was injected alone or in combination with DA antagonists such as L-sulpiride (L-SULP) and haloperidol (HAL), or the DAergic agonist apomorphine (APO). Our results show that DPH did not affect spontaneous DAergic firing rate and also failed to modify the known action of the DA agonists and antagonists which were tested on these neurons.


Subject(s)
Dopamine/physiology , Mesencephalon/drug effects , Neurons/drug effects , Phenytoin/pharmacology , Action Potentials/drug effects , Animals , Male , Mesencephalon/physiology , Rats , Rats, Inbred Strains
16.
Eur J Pharmacol ; 179(3): 339-45, 1990 Apr 25.
Article in English | MEDLINE | ID: mdl-1973107

ABSTRACT

Zolpidem and alpidem, two imidazopyridines with high affinity for the type I benzodiazepine recognition site, have recently been proposed as preferential hypnotic (zolpidem) and anxiolytic (alpidem) drugs notable for the minor incidence of side-effects. To further characterize the molecular mechanism involved in the action of these drugs, we studied their effects in comparison with those of diazepam on the spontaneous electrical activity of substantia nigra pars reticulata (SNR) neurons. These cells have been shown to be extremely sensitive to various positive and negative modulators of GABAergic transmission. All three drugs consistently produced a dose-dependent (0.03-8.0 mg/kg i.v.) inhibition of the firing of SNR cells when administered as a single bolus. However, zolpidem was more potent and efficacious than diazepam or alpidem. The ID50s were 0.076, 0.492 and 0.821 mg/kg, respectively. When the drugs were injected in exponentially (ratio 2) increasing doses up to 8.0 mg/kg, the rank order for tachyphylaxis was zolpidem much greater than diazepam greater than alpidem. Since the effects of the drugs were abolished and prevented by a small dose (0.5 mg/kg i.v.) of flumazenil (Ro 15-1788), it is likely that the effects were mediated through activation of benzodiazepine receptors. The results indicate that the hypnotic, zolpidem, has a more potent inhibitory action on SNR cell activity than the anxiolytics, alpidem and diazepam.


Subject(s)
Anti-Anxiety Agents/pharmacology , Hypnotics and Sedatives/pharmacology , Imidazoles/pharmacology , Neurons/drug effects , Pyridines/pharmacology , Receptors, GABA-A/drug effects , Reticular Formation/physiology , Action Potentials , Animals , Diazepam/pharmacology , Flumazenil/pharmacology , Male , Neurons/physiology , Rats , Rats, Inbred Strains , Reticular Formation/cytology , Reticular Formation/drug effects , Zolpidem
19.
Synapse ; 3(2): 117-28, 1989.
Article in English | MEDLINE | ID: mdl-2538942

ABSTRACT

Ethanol (ETH) and general anesthetics have been reported to facilitate the chloride channel opening, possibly, or at least partly, through an interaction with the GABA-benzodiazepine (BZ) receptor-gated chloride ionophore "supramolecular complex". Recently Ro 15-4513, a novel BZ ligand, has been indicated as a potent and selective antagonist of various ETH-induced behavioral and biochemical effects. However, since its precise characterization is still a matter of debate, we have tested and compared the effect of Ro 15-4513, as well as its antagonism against ETH, in two objective electrophysiological parameters, i.e., the electroencephalograph (EEG) pattern in freely moving rats and single unit activity of reticulata neurons. Ro 15-4513 produced an EEG state of alertness and antagonized the behavioral impairment and the EEG deterioration by ETH. However, while its protective action was consistent against moderate doses (2 g/kg) of ETH, it was much less evident versus higher doses (4 and 8 g/kg). On reticulata cells, Ro 15-4513 potently stimulated their spontaneous firing and reversed the depression by both ETH and Na-pentobarbital. Moreover, the beta-carboline DMCM also had similar effects. The "pure" BZ antagonist Ro 15-1788 was completely inefective against ETH, yet fully cancelled the reversing actions of Ro 15-4513 and DMCM upon ETH or Na-pentobarbital effects. It is concluded that Ro 15-4513 behaves as a BZ inverse agonist, so that its opposition to ETH and Na-pentobarbital is probably the result of its "negative" coupling with the BZ recognition site that triggers the closing of chloride channels. It suggests that BZ inverse agonists might constitute, in the near future, a new class of analeptic drugs.


Subject(s)
Azides/pharmacology , Benzodiazepines/pharmacology , Brain/physiology , Ethanol/pharmacology , Receptors, GABA-A/physiology , Substantia Nigra/physiology , Action Potentials/drug effects , Animals , Behavior, Animal/drug effects , Brain/drug effects , Diazepam/pharmacology , Dose-Response Relationship, Drug , Electroencephalography , Male , Rats , Rats, Inbred Strains , Receptors, GABA-A/drug effects , Substantia Nigra/drug effects
20.
Life Sci ; 43(25): 2151-8, 1988.
Article in English | MEDLINE | ID: mdl-2850426

ABSTRACT

The aim of the present study was to compare the ability of Ro 15-4513 and FG 7142, two inverse agonists for benzodiazepine recognition sites, to antagonize the EEG effects of ethanol in freely moving rats. Ethanol (2.5 g/kg, p.o.) induced sedation and ataxia associated with a progressive suppression of the fast cortical activities and an enhancement of low frequencies in both cortical and hippocampal tracings. In contrast, Ro 15-4513 (2 mg/kg, i.p.) and FG 7142 (10 mg/kg, i.p.) both caused a state of alertness associated with desynchronized cortical activity and theta hippocampal rhythm as well as spiking activity which was predominantly observed in the cortical tracings. When rats were treated with FG 7142 or RO 15-4513 either before or after ethanol, a reciprocal antagonism of the behavioral and EEG effects of ethanol and of the partial inverse agonists was observed. These data support the view that the anti-ethanol effects of Ro 15-4513 may be related to its partial inverse agonist properties.


Subject(s)
Azides/pharmacology , Benzodiazepines/pharmacology , Brain/physiology , Carbolines/pharmacology , Ethanol/antagonists & inhibitors , Receptors, GABA-A/drug effects , Animals , Appetite Depressants/pharmacology , Brain/drug effects , Electroencephalography , Ethanol/pharmacology , Male , Rats , Rats, Inbred Strains , Reference Values
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