Tiagabine reduces ethanol reward in C57BL/6 mice under acute and chronic administration regimens

Three experiments conducted on male C57BL/6 (B6) mice examined the effects of subcutaneous injections of the GABA uptake inhibitor, tiagabine, on appetitive (lever responding) and consummatory behavior (fountain contacts) of food restricted B6 mice for 12% ethanol and water rewards (Exp-1), and for food reward (Exp-2) delivered on a fixed ratio 4 schedule of reinforcement. Effects of acute injections (1,3,6,9 mgkg) and chronic administration (6,9 mg/kg) was examined. Exp-3 examined tiagabine effects on the voluntary consumption of continuously available 12% ethanol, and on the interactive effects of tiagabine and ethanol on motor activity of non-food restricted B6 mice. Results of Exp-1 and Exp-2 indicated that tiagabine can reduce appetitive behavior for ethanol reward with no evidence of tolerance upon chronic exposure. Tiagabine doses that reduced ethanol reward had less effect on behavior maintained by either water or food, and had no effect on motor activity. In contrast to the absence of tolerance to its effect on appetitive behavior for ethanol, mice rapidly developed tolerance to tiagabine's initial reduction of the consummatory response for ethanol (Exp-1), and the intake of freely available ethanol exceeded pre-tiagabine levels after several daily injections (Exp-3). Importantly, mice developed tolerance to tiagabine's sedative effect after three daily injections and its sedation was not enhanced when combined with ethanol, an effect consistent with the lack of a tiagabine + ethanol interaction previously reported for humans. The results of the experiments suggest that in addition to reducing alcohol withdrawal symptoms, tiagabine might also reduce the potency of ethanol-conditioned cues that drive appetitive behavior for ethanol.     

Swim-induced grooming in mice is mediated by a dopaminergic substrate

Summary Grooming induced in mice after a period of swimming was potently and dose-dependently blocked by neuroleptics. The order of potency of the neuroleptics was spiroperidol>haloperidol>cis-flupenthixol>pimozide>chlorpromazine>thioridazine. The trans isomer of flupenthixol was inactive at 40M/kg. The-adrenergic receptor antagonists, phentolamine and phenoxybenzamine, and the catecholamine synthesis inhibitor,-methyl-p-tyrosine were essentially without effect on the grooming behaviour. Amitriptyline inhibited grooming behaviour only in doses which severely affected the animals motor function. Fluoxetine was without effect. Cisflupenthixol was less active in inhibiting grooming in animals chronically treated with haloperidol than in control animals, indicating the presence of supersensitive dopamine receptors. The data indicate that swim-induced grooming in mice is mediated via dopaminergic systems.     

Mnesic imbalance: a cognitive theory about autism spectrum disorders

Background

Bupropion HCl is a widely used antidepressant that is known to cause seizures in a dose-dependent manner. Many patients taking antidepressants will consume alcohol, even when advised not to. Previous studies have not shown any interactions between bupropion HCl and alcohol. However, there have been no previous studies examining possible changes in seizure threshold induced by a combination of alcohol and bupropion HCl.

Methods

Experimentally naïve female Swiss albino mice (10 per group) received either single doses of bupropion HCl (ranging from 100 mg/kg to 120 mg/kg) or vehicle (0.9% NaCl) by intraperitoneal (IP) injection in a dose volume of 10 ml/kg, and single-dose ethanol alone (2.5 g/kg), or vehicle, 5 min prior to bupropion dosing. The presence or absence of seizures, the number of seizures, the onset, duration and the intensity of seizures were all recorded for 5 h following the administration of ethanol.

Results

The results show that administration of IP bupropion HCl alone induced seizures in mice in a dose-dependent manner, with the 120 mg/kg dose having the largest effect. The percentage of convulsing mice were 0%, 20%, 30% and 60% in the 0 (vehicle), 100, 110, and 120 mg/kg dose groups, respectively. Pretreatment with ethanol produced a larger bupropion HCl-induced convulsive effect at all the doses (70% each at 100, 110 and 120 mg/kg) and a 10% effect in the ethanol + vehicle only group. The convulsive dose of bupropion HCl required to induce seizures in 50% of mice (CD₅₀), was 116.72 mg/kg for bupropion HCl alone (CI: 107.95, 126.20) and 89.40 mg/kg for ethanol/bupropion HCl (CI: 64.92, 123.10).

Conclusion

These results show that in mice alcohol lowers the seizure threshold for bupropion-induced seizures. Clinical implications are firstly that there may be an increased risk of seizures in patients consuming alcohol, and secondly that formulations that can release bupropion more readily in alcohol may present additional risks to patients.     

alpha2-gamma-Aminobutyric acid (GABA)A receptors are the molecular substrates mediating precipitation of narcosis but not of sedation by the combined use of diazepam and alcohol in vivo

Classical benzodiazepines such as diazepam are widely used tranquillisers and hypnotics in various neuropsychiatric diseases including alcohol-related disorders. One of the major drawbacks of benzodiazepine therapy, however, is an exacerbation of the sedative and hypnotic effects associated with alcohol intake, even at low doses. Even though the gamma-aminobutyric acid (GABA)A receptor complex is a common target for the actions of both classes of drugs, the molecular mechanisms underlying the enhanced pharmacological properties of the combined use of benzodiazepines and alcohol remain to be identified. The present experiments aimed at clarifying which of the GABAA receptor subtypes mediate the augmented hypnotic-like and sedative effects of combined diazepam and alcohol using the righting reflex and motor activity assays, respectively, in histidine-to-arginine point mutated mice that possess diazepam-insensitive alpha1-, alpha2-, alpha3- or alpha5-GABAA receptors. The combination of diazepam (2 or 3 mg/kg) and ethanol (3 g/kg) induced loss of righting reflex with a significantly dose-dependent increase of the latency to its full recovery in wild-type, alpha1(H101R), alpha3(H126R) and alpha5(H105R) but not in alpha2(H101R) mice. A combined treatment with diazepam (1 mg/kg) and ethanol (2.5 g/kg) precipitated motor inhibition similarly in wild-type and alpha2(H101R) mice. Responsiveness of the alpha2(H101R) mice to ethanol alone was similar to that of wild-type mice. These results demonstrate that induction of loss of righting reflex by combined diazepam and alcohol is closely dependent on the activation of the alpha2-GABAA receptors by the benzodiazepine whereas precipitation of sedation involves GABAA receptors other than the alpha2-GABAA receptors.     

Effects of dothiepin on delayed conduction produced by ventricular arrhythmia in the canine heart after myocardial infarction.

1. In order to clarify the arrhythmogenic effects of antidepressants, the authors examined the effects of dothiepin and amitriptyline on the ventricular activation time (VAT), effective refractory periods(ERP) and incidence of arrhythmias induced by programmed electrical stimulation(PES) in the dog heart in situ after myocardial infarction. 2. Myocardial infarction was produced by two-stage ligation of the left anterior descending coronary artery. Seven days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and normal zones to apply an electrical stimulation or record ventricular activation. An electrical stimulation with coupling interval 250 or 180 ms was applied on the ventricular surface, and AT was measured. 3. Dothiepin at doses of 1-3 mg/kg increased the heart rate. The VAT of coupling interval 180 ms in the infarcted zone was increased by the administration of 3 mg/kg dosulepin. Dothiepin at 3 mg/kg increased the incidence of ventricular arrhythmias induced by PES. 4. Amitriptyline, at doses of 1-3 mg/kg, significantly increased the heart rate. Amitriptyline increased the VAT dose- and frequency-dependently(2,3 mg/kg zone), and prolonged the ERP and QT c interval. Amitriptyline at doses of 1-3 mg/kg increased the incidence of ventricular arrhythmias by PES. 5. These results indicate that dothiepin, 1-3 mg/kg, has lesser effects on cardiac delayed conduction produced by ventricular arrhythmia than amitriptyline.     

Clonidine-induced sedation in rats: Evidence for mediation by postsynapticα 2-adrenoreceptors

Summary The effect of low doses of clonidine on exploration and motility was investigated in rats after destruction of central noradrenergic systems by 6-hydroxydopamine (6-OHDA) or DSP-4. In accordance with previous results, clonidine decreased exploration and motility in control animals. This sedative effect of clonidine was potentiated in animals that suffered selective and extensive depletions of brain NA as a result of neonatal treatment with 6-OHDA. Depletion of NA by administration of DSP-4 to adult animals did not influence clonidine's sedative effects. Yohimbine, but not phentolamine, antagonized clonidine-induced hypomotility both in control and in neonatal 6-OHDA treated groups. The results suggest that clonidineinduced sedation is mediated by postsynaptic ₂-adrenoreceptors.     

The sedative but not the memory-blocking properties of ethanol are modulated by α5-subunit-containing γ-aminobutyric acid type A receptors

The precise mechanisms underlying the memory-blocking properties of ethanol are unknown, in part because ethanol targets a wide array of neurotransmitter receptors and transporters. The aim of this study was to determine whether the memory loss caused by ethanol is mediated, in part, by α5 subunit-containing γ-aminobutyric acid subtype A receptors. These receptors have been implicated in learning and memory processes and are targets for a variety of neurodepressive drugs. Also, since these receptors generate a tonic inhibitory current in hippocampal pyramidal neurons, we examined whether concentrations of ethanol that block memory in vivo increased the tonic current using whole-cell patch-clamp recordings in hippocampal neurons. Null mutant mice lacking the α5 subunit (Gabra5-/-) and wild-type mice were equally impaired in contextual fear conditioning by moderate (1mg/kg) and high (1.5mg/kg) doses of ethanol. The higher dose of ethanol also reduced auditory delay fear conditioning to the same extent in the two genotypes. Interestingly, wild-type mice were more sensitive than Gabra5-/- mice to the sedative effects of low (0.5mg/kg) and moderate (1mg/kg) doses of ethanol in the open-field task. Concentrations of ethanol that impaired memory performance in vivo did not increase the amplitude of the tonic current. Together, the results suggest that the α5-subunit containing γ-aminobutyric acid subtype A receptors are not direct targets for positive modulation by ethanol nor do they contribute to ethanol-induced memory loss. In contrast, these receptors may contribute to the sedative properties of ethanol.     

Intravenous sedation for dental patients with intellectual disability

Background The poor quality of oral health care for people with intellectual disability (ID) has been recognized, and the strong fears about dental treatment suggested as a major reason for disturbances of visits to dentists by such patients. Intravenous sedation is a useful method for relieving the anxiety and fear of such patients about dental treatment, and is frequently essential for ID patients undergoing dental treatment. However, decision regarding the dose of sedative required to be administered for an adequate level of sedation is difficult because the effect of sedation cannot be adequately assessed in patients with severe ID. As an appropriate sedative dose for dental patients with ID has not been fully established, we investigated sedative doses required and the effect of sedation in patients with ID, compared with other dental patients. Methods We reviewed the anaesthetic records of dental patients with ID (73 cases) and other dental patients (19 cases) aged between 20 and 29 years who had undergone intravenous sedation with midazolam and propofol in Okayama University Dental Hospital, from January 2000 to December 2000. Intravenous sedation was induced with a bolus intravenous administration of midazolam (2–3 mg) and maintained with a continuous infusion of propofol. The dose of propofol was titrated to achieve an adequate level of sedation: asleep but responding to painful stimulation. The efficacy of sedation, the required doses of propofol, and the wake‐up times were investigated for all subjects. The efficacy of sedation was evaluated by judging whether the patient became cooperative and allowed the dental treatment to be carried out or not. The complications induced by intravenous sedation were also evaluated in each subject. Differences in variables between subjects with ID and other subjects were analysed using the Mann–Whitney U‐test. Results Intravenous sedation was effective for dental treatment in all subjects with or without ID. The required dose of propofol in subjects with ID was 4.74 mg/kg/h (2.63–10.33 mg/kg/h), significantly higher than that required for other subjects (3.31, 1.72–4.80 mg/kg/h). Wake‐up times of subjects with ID were similar to those of the other subjects. Severe complications were not seen during or after intravenous sedation. Conclusion The results of this study show that intravenous sedation is a useful method for dental patients with ID as well as for other dental patients, but indicate that dental patients with ID need higher doses of sedative to obtain an adequate level of sedation.     

Some effects of chronic antidepressant treatments on rat brain monoaminergic systems

Summary A range of established and putative antidepressant therapies were studied for the effect of their long-term administration on two facets of presynaptic monoaminergic functioning in rat brain, namely NE, DA, and 5-HT turnover and alpha₂-adrenoceptor sensitivity. Unless stated otherwise drugs (10 mg/kg) were injected i.p. twice daily for 14 days. ECT (100 mA for 1 s) was applied once daily for 10 days.Changes in turnover were indirectly assessed by measuring levels of metabolites. Brain levels of MHPG-SO₄ were unchanged by chronic amitriptyline, imipramine, nisoxetine (20 mg/kg), nortriptyline, salbutamol (5 mg/kg), and ECT. Amitriptyline elicited a slight, but significant, increase in brain DOPAC content. Brain levels of 5-HIAA were increased by amitriptyline, imipramine, salbutamol, and ECT. An overall view of the results indicates that no common pattern of change was elicited by the range of antidepressant therapies studied.Central alpha₂-adrenoceptor sensitivity was assessed by investigating the effect of various therapies on the ability of clonidine (25g/kg i.p.) to decrease rat brain MHPG-SO₄ content. The clonidine-induced fall was attenuated by desipramine, imipramine, and ECT. Amitriptyline, iprindole, mianserin, nisoxetine, nortriptyline, Org 6582 (10 mg/kg once daily), pargyline (25 mg/kg once daily), salbutamol, and trazodone were ineffective.The following chronic antidepressant therapies were investigated for their effect on rat frontal cortex³H-clonidine binding: amitriptyline, desipramine, imipramine, iprindole, mianserin, nisoxetine, nortriptyline, pargyline, salbutamol, and ECT. Chronic, but not acute, pargyline decreased³H-clonidine binding and this was due to a diminished number of binding sites.The induction of subsensitive presynaptic alpha₂-adrenoceptors in rat brain is not a property common to all forms of antidepressant therapies. Hence it cannot be the fundamental mode of action of antidepressants. No correlation exists between the changes in rat cortical³H-clonidine binding and the observed changes in the sensitivity of central presynaptic alpha₂- adrenoceptors.     

Ethanol-induced locomotor activity: involvement of central nicotinic acetylcholine receptors?

Ethanol and nicotine have many psychopharmacological effects in common, which could explain why coadministration of these compounds often is observed in individuals. In the present study in mice, low doses of nicotine in a complex manner altered the locomotor activity (LMA) stimulatory effect of different doses of ethanol, whereas the quaternary nicotine analog tetramethylammonium did not. The blood-brain-barrier-penetrating nicotine antagonist mecamylamine (2.0 and 4.0 mg/kg), but not the quaternary nicotine antagonist hexamethonium (4.0 and 8.0 mg/kg), partly counteracted the LMA stimulatory effect of ethanol (3.0 g/kg) in doses having no LMA reducing effects per se. Furthermore, the dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) quotient increase in mouse brain after ethanol 3.0 g/kg was partly antagonized by mecamylamine 2.0 and 4.0 mg/kg. These results suggest that part of the LMA and DA turnover-increasing effect of ethanol is mediated via activation of central nicotinic acetylcholine receptors.     

Gender specific effects of ethanol in mice, lacking CCK2 receptors

Neuropeptide cholecystokinin (CCK) has been reported to suppress ethanol intake, but there is contradictory evidence about the role of CCK(2) receptors. In the present study anxiolytic, hypolocomotor and sedative effects of acute ethanol administration, but also voluntary ethanol consumption were studied in male and female mice, lacking CCK(2) receptors (-/-). Ethanol (1.0 and 2.0 g/kg) induced a significant reduction of anxiety-related behaviours in the elevated plus-maze, but this effect was statistically significant only in female homozygous mice (-/-). In male mice, lacking CCK(2) receptors (-/-), but not in their wild-type littermates (+/+), the suppression of vertical locomotor activity was caused by ethanol at a dose 0.5 g/kg. The highest dose of ethanol (2.0 g/kg) produced statistically significant reduction of horizontal locomotor activity only in female wild-type (+/+) mice, but this effect was related to increased basal activity when compared to female mutant (-/-) mice. Duration of the loss of righting reflex was not significantly affected by genotype or gender, but blood ethanol levels at regain of righting reflex were significantly lower in female homozygous mice (-/-) compared to their wild-type (+/+) littermates, indicating increased sensitivity to the sedative effect of ethanol. Ethanol intake, but not preference, at concentration 10% was significantly increased in female mice, lacking CCK(2) receptors (-/-). The present study revealed an altered response to the acute effects of ethanol in CCK(2) receptor deficient mice (-/-). These changes are gender-specific and could be attributed to the altered activity of dopaminergic system in male mice and increased activity of GABA-ergic system in female mice as established in our previous studies.     

Chronic ethanol exposure during adolescence alters the behavioral responsiveness to ethanol in adult mice

Alcohol exposure during early adolescence is believed to durably alter the behavioral properties of ethanol, increasing the likelihood of later alcohol-related disorders. The aim of the present experiments was to characterize changes in the behavioral effects of ethanol in adult female Swiss mice after a chronic ethanol exposure during adolescence, extending from postnatal day 28 to postnatal day 42. After a chronic ethanol exposure during adolescence (daily injections of 0, 2.5 or 4 g/kg ethanol for 14 consecutive days), adult mice were tested at postnatal day 63. The locomotor stimulant effects of ethanol, together with ethanol sensitization were tested in experiment 1. In experiment 2, the sedative effects of ethanol were assessed with the loss of righting reflex procedure. Finally, in experiment 3, the anxiolytic effects of ethanol were tested with the light/dark box test. Adult mice chronically exposed to ethanol during adolescence showed a lower basal locomotor activity, but higher locomotor stimulant effects of ethanol than non-exposed mice. Additionally, these adult mice developed higher rates of ethanol sensitization after chronic re-exposure to ethanol in adulthood. Adult mice exposed to ethanol during adolescence also had a stronger tolerance to the sedative effects of high ethanol doses, although they showed no evidence of changes in the anxiolytic effects of ethanol. These results are in agreement with the thesis that chronic alcohol consumption during adolescence, especially in high amounts, increases the risk of later alcohol-related disorders.     

Pregnenolone sulfate,dehydroepiandrosterone sulfate and allotetrahydrodeoxycorticosterone affect rapid tolerance to the hypothermic effect of ethanol

Our previous study showed that the neurosteroids pregnenolone sulfate (PS) and epipregnanolone stimulated and blocked, respectively, the demonstration of chronic tolerance to the incoordinating effect of ethanol. The aim of the present study was to investigate the influence of three neurosteroids on the demonstration of tolerance to ethanol-induced hypothermia in mice using the rapid tolerance paradigm. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to ethanol-induced hypothermia. In the second, the influence of pretreatment of mice with PS (0.08 or 0.15 mg/kg, i.p.) or dehydroepiandrosterone sulfate (DHEAS; 0.15 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance was studied. The third experiment examined the effect of allotetrahydrodeoxicorticosterone (ALLOT; 0.10 or 0.20 mg/kg, i.p.) before ethanol (4.0 g/kg, i.p.) on rapid tolerance. Results showed that pretreatment with PS or with DHEAS significantly facilitated the demonstration of rapid tolerance, whereas pretreatment with ALLOT interfered with the demonstration of tolerance to the hypothermic effect.     

Prolactin releasing effect of sulpiride isomers in rats and man

Summary Sulpiride, an antipsychotic drug of the benzamide class, reportedly displaces stereospecifically [³H]-butyrophenones from putative dopamine (DA) binding sites in rat striatum. To evaluate if sulpiride displays the same stereospecificity in the inhibition of pituitary DA receptors, the effect of the two (-)- and (+)-sulpiride isomers was tested with regard to their ability to stimulate prolactin (PRL) secretion in rats and man and to displace [³H]-spiroperidol bound to rat anterior pituitary receptors.In male rats, (–)-sulpiride at doses of 0.1 and 1.0 mg/kg i.p., induced a maximum PRL-releasing effect, not different from that evoked by a dose of 10 mg/kg of the compound. (+)-Sulpiride was active only at the dose of 10 mg/kg i.p., and its PRL-releasing effect was superimposable to that evoked by the same dose of (–)-sulpiride. Similarly, in 8 normal subjects (4 men and 4 women) only (–)-sulpiride was active as PRL releaser when the low dose of 0.25 mg i.v. was used; when the higher dose of sulpiride was used (4.0 mg i.v.), it induced a rise in plasma PRL of the same entity for both isomers at early post-injection times (15–30 min) but greater with the (–)-isomer at the following time intervals (45–120 min). (–)-Sulpiride displaced [³H]-spiroperidol bound to rat anterior pituitary homogenates with a potency about 100 times as greater as that showed by (+)-sulpiride. In all, these data indicate that sulpiride isomers display at the level of pituitary DA receptors for PRL control the same stereospecificity exhibited on a population of striatal DA receptors.Supported in part by C.N.R. project Biology of Reproduction, Rome and by a Grant from Ministry of Education.     

Antagonism of morphine-induced central stimulation in mice by small doses of catecholamine-receptor agonists

Summary The morphine (75 mg/kg i.p.) induced stimulation of motor activity in mice was significantly suppressed by small doses of central catecholamine (CA) receptor agonists, apomorphine (0.2 mg/kg) and clonidine (0.05 mg/kg). In the same dose, and at the same time interval as the behavioural stimulation was obtained, morphine did not significantly affect thein vivo rate of tyrosine hydroxylation in two dopamine (DA)-rich mouse brain regions, the corpus striatum and the limbic system, or in the noradrenaline (NA)-rich, but DA-poor hemispheres, measured as the Dopa-accumulation during 30 min after inhibition of aromatic amino-acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015) 150 mg/kg. The apomorphine induced reduction in Dopa accumulation in the DA-rich brain regions was not significantly affected by morphine. The disappearance rate of brain NA after inhibition of tyrosine hydroxylase by-methyltyrosine methylester (250 mg/kg), the utilization of NA, was accelerated by morphine, whereas that of DA was not affected. Clonidine (0.05 mg/kg) retarded selectively brain NA utilization, and also suppressed the morphine-induced increase in NA utilization.In conclusion, morphine's stimulation of motor activity in mice, an effect which previously has been found to be correlated with its dependence producing action, could be inhibited by apomorphine or clonidine in small doses which inhibit brain DA- and NA-neurons, respectively. Thus, we have now shown the psychomotor stimulation by two euphoriant and dependenceproducing drugs, ethanol and morphine, to be suppressed by CA autoreceptor activation.     

Effects of ethanol on nicotine-induced conditioned place preference in C57BL/6J mice

It has been shown that small doses of ethanol (相似文献   

Ethanol and pentobarbital have different behavioral effects in the rat

Stimulus control was established in rats with 600 mg/kg ethanol and saline by employing a two-lever response choice task and an FR10 schedule of food reinforcement. Once trained, rats were tested with lower doses of ethanol (300 and 450 mg/kg) and with pentobarbital (0.75 - 4.0 mg/kg). The 3.0 and 4.0 mg/kg doses of pentobarbital were observed to produce ethanol-like responding and decreasing doses of both ethanol and pentobarbital produced dose-related effects upon discriminative performance. The ED50 for ethanol was 372 mg/kg and for pentobarbital was 1.09 mg/kg. Graphic representation of the dose-response relationships suggested that these drugs possess different sites and/or mechanisms of action.     

High Ethanol and Acetaldehyde Inhibit Glutamatergic Transmission in the Hippocampus of Aldh2-Knockout and C57BL/6N Mice: an In Vivo and Ex Vivo Analysis

We aimed to investigate whether ethanol (EtOH) and acetaldehyde (AcH) can affect glutamate and its receptors GluN1 and GluA1 in the hippocampus of Aldh2-knockout (Aldh2-KO) and C57BL/6N (wild-type (WT)) mice. To do this, we first examined the effect of local administration of EtOH (100 mM, 200 mM, and 500 mM) and AcH (100 μM, 200 μM, and 500 μM) on extracellular glutamate levels in freely moving mice. Retrodialysis of 200 mM and 500 mM EtOH into the hippocampus of WT and Aldh2-KO mice produced significant decreases in extracellular glutamate levels (p?<?0.05). A dose of 500 mM EtOH induced a greater decrease in Aldh2-KO mice (p?<?0.05) than in WT mice, indicating the action of AcH. Similarly, perfusion of 200 μM and 500 μM AcH decreased glutamate in Aldh2-KO mice (p?<?0.05), but this decrease was not seen in WT mice at any AcH dose. Second, we tested whether the EtOH- and AcH-induced decrease in glutamate was associated with decreases in GluN1 and GluA1 expression, as measured by real-time PCR and Western blot. We found a significant decrease in GluN1 (p?<?0.05) and GluA1 (p?<?0.05) subunits after a high dose of EtOH (4.0 g/kg) and AcH (200 mg/kg) in WT mice. However, a 2.0 g/kg dose of EtOH did not produce a consistent decrease in GluN1 or GluA1 between messenger RNA and protein. In Aldh2-KO mice, all three doses of EtOH (1.0 g/kg, 2.0 g/kg, and 4.0 g/kg) and AcH (50 mg/kg, 100 mg/kg, and 200 mg/kg) decreased GluN1 expression (p?<?0.05), while moderate-to-high doses of EtOH (2.0 g/kg and 4.0 g/kg) and AcH (100 mg/kg and 200 mg/kg) decreased GluA1 expression (p?<?0.05). Together, these in vivo and ex vivo data suggest that EtOH and AcH decrease extracellular glutamate in the hippocampus of mice with a concomitant decrease in GluN1 and GluA1 subunits, but these effects require relatively high concentrations and may, therefore, explain the consequences of EtOH intoxication.

     

α2-Adrenoceptor antagonists potentiate the anticonflict and the rotarod impairing effects of benzodiazepines

Summary Putative interactions between the specific ₂-adrenoceptor antagonist idazoxan and benzodiazepines (BDZs) were examined in two different rat conflict models; Vogel's drinking conflict test (VT) and Montgomery's conflict test (MT) (the elevated +-maze). In the MT, idazoxan (0.031mg/kg) produced anxiogenic-like effects, which were counteracted both by the triazolo-BDZ alprazolam (APZ; 0.2mg/kg) and the conventional BDZ diazepam (DIZ; 0.2mg/ kg). In fact, the anxiolytic-like effects of APZ were significantly potentiated when co-administering idazoxan. A tendency to such a phenomenon was seen also in rats treated with DIZ and idazoxan. In the VT, the anxiolytic-like effects both of APZ (1.0 mg/kg) and DIZ (4.0 mg/kg) were significantly enhanced when co-administering idazoxan (1.0 mg/kg) in a dose not affecting the behaviorper se. Similar potentiating phenomena by behaviorally inert doses of ₂-adrenoceptor antagonists (idazoxan 1.0 mg/kg; yohimbine 2.0 mg/kg) were seen with regard to the ataxic/sedative effects of the BDZs (APZ 0.25 mg/kg; DIZ 1.5 mg/ kg). The present results provide further support for the notion that the anxiolytic-like effects of BDZs are not related to attenuation of Locus Coeruleus activity. In addition, it is suggested that the potentiation caused by the ₂-adrenoceptor antagonist is mediated via a noradrenaline induced increase in signal-to-noise ratio in target neurons of the brain noradrenergic system.     

The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes

The present study attempted to identify an alpha-2 agonist that could improve working memory in aged nonhuman primates without the marked hypotensive and sedative side effects produced by clonidine. Toward this end, the hypotensive, sedative, and memory-altering properties of the alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed by a variable delay, spatial delayed response paradigm that requires the animal to remember information over short temporal intervals and to update this information on every trial. B-HT920 was found to produce a dose-response profile qualitatively similar to, but weaker than, clonidine: low doses impaired memory and began to lower blood pressure and produce sedation, while high doses improved memory. In contrast, guanfacine produced a dose-response profile opposite to that seen with clonidine: low doses improved memory without inducing hypotension or sedation, while the memory-impairing, hypotensive, and sedating properties of the drug were observed at higher doses. The potency of the 3 agonists to lower blood pressure was clonidine = B-HT920 greater than guanfacine; sedation was affected in the order clonidine greater than B-HT920 greater than guanfacine; for memory impairment, as measured by performance on the delayed response task, the rank order potency was clonidine greater than B-HT920 greater than guanfacine, while for memory improvement it was guanfacine greater than clonidine greater than B-HT920. These differences in rank order potency are consistent with the recent proposal of alpha-2 receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine greater than B-HT920 greater than guanfacine and a rauwolscine-insensitive site (Ri) that binds guanfacine greater than clonidine greater than B-HT920 (Boyajian and Leslie, 1987). The data suggest that the hypotensive, sedating, and memory-impairing effects of alpha-2 agonists may be due to actions at one subtype of receptor (Rs), while the memory-enhancing effects of these drugs may result from actions at another alpha-2 receptor subtype, the Ri site. The ability of low doses of guanfacine to improve memory without inducing hypotension or sedation indicates that this agonist may be an excellent candidate for treating memory disorders in man.