ABSTRACT
Chronic treatment of rats by sulbutiamine induced no change in density of N-methyl-D-aspartate (NMDA) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the cingular cortex, but a significant decrease of the kainate binding sites, as measured by quantitative autoradiography. In the same treated animals, an increase of D1 dopaminergic (DA) binding sites was measured both in the prefrontal and the cingular cortex, while no modification of the D2 binding sites was detected. Furthermore, an acute sulbutiamine administration induced a decrease of kainate binding sites but no change of the density of D1 and D2 DA receptors. Acute sulbutiamine injection led to a decrease of the DA levels in the prefrontal cortex and 3,4-dihydroxyphenylacetic acid levels in both the cingular and the prefrontal cortex. These observations are discussed in terms of a modulatory effect of sulbutiamine on both dopaminergic and glutamatergic cortical transmissions.
Subject(s)
Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Dopamine/physiology , Glutamic Acid/physiology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Thiamine/analogs & derivatives , Thiamine/pharmacology , Animals , Autoradiography , Binding Sites/drug effects , Brain Mapping , Injections, Intraperitoneal , Male , Rats , Rats, Sprague-Dawley , Thiamine/administration & dosageABSTRACT
A mouse model of barbital-induced narcosis was used to examine the effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761), an extract devoid of terpene trilactones (CP 205), and three terpene trilactone constituents of the extract (ginkgolides A and B, bilobalide). Administration of sodium barbital (180 mg/kg, IP) to the mice caused narcosis, measured as a loss in righting reflex. Single injections of EGb 761 (25 and 50 mg/kg), given 60 min prior to sodium barbital, significantly shortened barbital-induced sleeping time, whereas these same doses of CP 205 were ineffective. Single injections of ginkgolide B (1 mg/kg) and bilobalide (2 and 5 mg/kg) significantly shortened sleeping time, whereas ginkgolide A was ineffective. The effects of ginkgolide B and bilobalide were reflected as increases in latency to onset of sleep and those of EGb 761, ginkgolide B, and bilobalide were correlated with decreases in the number of mice that slept. At the behavioral level, these potent in vivo effects of EGb 761, ginkgolide B, and bilobalide resemble those of certain antidepressants. At the molecular level, it is hypothesized that interactions with the picrotoxinin/TBPT site of GABA-regulated Cl- channels of the CNS may be involved. This information appears useful in explaining the clinically observed "vigilance-enhancing" and "antidepressant-like" actions of EGb 761.
Subject(s)
Anesthesia , Diterpenes , Flavonoids/pharmacology , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Analysis of Variance , Animals , Barbital/pharmacology , Caffeine/pharmacology , Dose-Response Relationship, Drug , Ginkgo biloba , Ginkgolides , Injections, Intraperitoneal , Lactones/pharmacology , Male , Mice , Mice, Inbred Strains , Plant Extracts/chemistry , Sleep/drug effects , Time FactorsABSTRACT
Pretreatment of rats with the extract of Ginkgo biloba termed EGb761 reduced the behavioral sensitization induced by successive D-amphetamine administrations (0.5 mg/kg) as estimated by increasing values of locomotor activity. EGb761 pretreatment also prevented the reduced density of [3H]dexamethasone binding sites in the dentate gyrus and the CA1 hippocampal regions of D-amphetamine treated animals. These observations suggest that EGb761, by reducing glucocorticoid levels, could modulate the activity of the neuronal systems involved in the expression of the behavioral sensitization.
Subject(s)
Amphetamine/antagonists & inhibitors , Flavonoids/pharmacology , Ginkgo biloba , Hippocampus/drug effects , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Plants, Medicinal , Animals , Dentate Gyrus/drug effects , In Vitro Techniques , Male , Motor Activity/drug effects , Rats , Rats, Wistar , Receptors, Steroid/drug effectsABSTRACT
This study consists of two parts, first to compare the pharmacological profile of atropine and CEB-1957 substance toward muscarinic receptor subtypes. In various rat brain structures, binding properties were determined by competition experiments of [3H]pirenzepine, [3H]AF-DX 384, and [3H]4-DAMP in quantitative autoradiography of M1, M2, and M3 muscarinic receptor subtypes, respectively. Competition curves have shown that atropine presents similar nanomolar inhibition constants toward each subtype, while CEB-1957 has distinct affinities (Ki from 0.26 to 73 nM) with the following range order: M3 > or = M2 > M1. The second part is to compare atropine and CEB-1957 (in combination with pralidoxime) for their ability to protect against the lethality induced by 2 x LD50 of the acetylcholinesterase inhibitor sarin. CEB-1957 reduced the mortality at doses 10 times lower than atropine. Finally, from these results, it is proposed that a selective blockade of M2 and M3 receptor subtypes could play a pivotal role in the protective effect against sarin poisoning.
Subject(s)
Atropine/pharmacology , Brain/drug effects , Cholinesterase Inhibitors/poisoning , Muscarinic Antagonists/pharmacology , Sarin/poisoning , Thiophenes/therapeutic use , Animals , Atropine/metabolism , Autoradiography , Binding, Competitive , Brain/metabolism , Male , Muscarinic Antagonists/metabolism , Parasympatholytics/metabolism , Parasympatholytics/pharmacology , Piperidines/metabolism , Piperidines/pharmacology , Pirenzepine/analogs & derivatives , Pirenzepine/metabolism , Pirenzepine/pharmacology , Poisoning/drug therapy , Rats , Rats, Wistar , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/metabolism , Thiophenes/pharmacologyABSTRACT
The social interaction test was used to examine the effects of an extract of Ginkgo biloba (EGb 761) and its possible interactions with diazepam and ethyl beta-carboline-3-carboxylate (beta-CCE). Pairs of naive (unfamiliar) male Wistar AF rats subjected to the same treatment were placed in a novel test arena that was brightly illuminated, and the duration (in s) of social contact was observed over a 10 min period. Single injections of EGb 761 (8-16 mg/kg, i.p.), given 30 min prior to testing, or repeated oral administration of the extract (48 or 96 mg/kg/day) for 8 days, significantly decreased social contact under conditions that did not influence locomotor activity. Injection of diazepam (1 mg/kg, i.p.), 30 min before testing, significantly increased social contact. Injection of diazepam to animals that had received repeated oral treatment with EGb 761 (96 mg/kg/ day) increased social interaction to an extent greater than observed with diazepam alone. Injection of beta-CCE (2-16 mg/kg, i.p.), 15 min before testing, significantly decreased social contact. When the animals were treated with EGb 761 (48 or 96 mg/kg/day, p.o. for 8 days) and beta-CCE (4 mg/kg), both of which decreased social interaction when administered alone, the resulting level of social contact was similar to that of control animals. Interactions with certain sites of central GABAA/ benzodiazepine/Cl- channel receptor complexes could be involved in mediating these effects of EGb 761, diazepam and beta-CCE.
Subject(s)
Anti-Anxiety Agents/pharmacology , Carbolines/pharmacology , Diazepam/pharmacology , Plant Extracts/pharmacology , Social Behavior , Animals , Drug Interactions , Ginkgo biloba , Herb-Drug Interactions , Male , Motor Activity/drug effects , Rats , Rats, WistarABSTRACT
1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied in mice. 2. On the tests performed (antagonism of apomorphine- and oxotremorine-induced hypothermia, potentiation of yohimbine toxicity, L-5-HTP-induced head twitches and the learned-helplessness paradigm), T3 was active after subchronic treatment (1 injection per day for 3 days, ending 24 hours before testing). 3. In these tests T3 exhibited the same profile as antidepressant drugs in rodents. 4. The similar activity of beta-agonists in these tests and the ability of T3 to potentiate the effect of clenbuterol agree with the hypothesis that T3 can induce beta-adrenergic hypersensitivity. 5. Under the present experimental conditions these effects were obtained with doses of T3 which did not induce hyper-triiodothyroninemia. Thus, the lowest doses significantly affecting apomorphine- and oxotremorine-induced hypothermia were respectively .008 and .032 mg/kg/day. 6. Doses as low as .032 mg/kg/day were active in the yohimbine test. 7. L-5-HTP-induced head twitches were potentiated by a dose of .25 mg/kg/day and in the learned-helpless paradigm, the lowest effective dose was .06 mg/kg/day. 8. Plasma T3 values obtained in the same conditions were not significantly different from control at doses less than .5 mg/kg/day, and increased dramatically with higher doses, suggesting an accumulation of the hormone in plasma. 9. The doses inducing an hyper-triiodothyroninemia coincided with physiological signs of hyperthyroidism in the animals (i.e. loss of weight and slight hyperthermia). Thus, the active dose range of T3 was below the lowest dose required to produce a significant hyperthyroid state. 10. This results suggest that a clinical benefit could be obtained with low doses of T3 that do not significantly induce an hyperthyroidism.
Subject(s)
Antidepressive Agents , Hyperthyroidism/psychology , Triiodothyronine/pharmacology , 5-Hydroxytryptophan/pharmacology , Animals , Apomorphine/pharmacology , Avoidance Learning/drug effects , Body Temperature/drug effects , Body Weight/drug effects , Helplessness, Learned/psychology , Imipramine/pharmacology , Male , Mice , Oxotremorine/pharmacology , Rats , Triiodothyronine/blood , Yohimbine/pharmacologyABSTRACT
Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the properties of triiodothyronine (T3). In particular, it has an inhibitory effect on the thyreotropic axis, but its peripheral effects are reduced. Given the activity of T3 on psychopharmacological models of depression in rodents, we investigated the effects of TA3 on some pharmacological and behavioral tests in mice. TA3 antagonized apomorphine- and oxotremorine-induced hypothermia, potentiated yohimbine-induced toxicity and L-5-hydroxy-tryptophan-induced head twitches, but did not affect forced swimming-induced immobility or reserpine-induced hypothermia. Thus, TA3 was effective on the same psychopharmacological tests which have previously been used to demonstrate the antidepressant-like effects of T3. Moreover, TA3 under the same experimental conditions as T3 has little effect on the metabolic clearance rate parameters, and might, therefore, be preferable to T3 for clinical use in depression.
Subject(s)
Antidepressive Agents , Behavior, Animal/drug effects , Triiodothyronine/analogs & derivatives , Animals , Apomorphine/pharmacology , Body Temperature/drug effects , Body Weight/drug effects , Drug Interactions , Male , Mice , Motor Activity/drug effects , Oxotremorine/pharmacology , Reserpine/pharmacology , Triiodothyronine/pharmacology , Yohimbine/pharmacologyABSTRACT
Several clinical investigations have suggested that a special relationship exists between thyroid function and affective disorders and/or therapeutic response to antidepressants. The present report describes that the reversal by antidepressants (imipramine, desipramine, and nomifensine) of depressive-like behavior in rats (escape deficits produced by previous exposure to uncontrollable stress) was significantly hastened in animals given daily triiodothyronine (T3). The learned helplessness paradigm might be a useful model for approaching in animals the neurohormonal correlates of affective disorders and the neurobiochemical bases of the reported T3 enhancement of antidepressants.
Subject(s)
Desipramine/pharmacology , Helplessness, Learned/psychology , Imipramine/pharmacology , Nomifensine/pharmacology , Triiodothyronine/pharmacology , Animals , Avoidance Learning/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Escape Reaction/drug effects , Male , Rats , Rats, Inbred StrainsABSTRACT
Clenbuterol, isoproterenol and salbutamol increased the latency in the licking response of mice on the hot plate at 56.5 degrees C. This effect was dose-related and obtained after IP administration. Clenbuterol was active at lower doses than isoproterenol and salbutamol, a result which is consistent with its better penetration in the central nervous system. Moreover, the effect of clenbuterol was stereospecific, the (-)-isomer being the active form. Our results suggest the implication of central beta-adrenoceptors in the modulation of the response to a painful stimulation.
Subject(s)
Central Nervous System/physiopathology , Pain/physiopathology , Receptors, Adrenergic, beta/physiology , Albuterol , Animals , Clenbuterol , Isoproterenol , Male , Mice , Reaction Time/physiology , StereoisomerismABSTRACT
Several studies have indicated that alpha-adrenergic systems are implicated in the anticonvulsant activity of diphenylhydantoin. We now report that in mice prazosin (0.125 mg/kg), a blocker of alpha 1-adrenoceptors, reverses the effects exerted by diphenylhydantoin (256 mg/kg) in tests which are predictive of antidepressant activity: reserpine-induced ptosis and immobility which are caused by inescapable, aversive situations. These date indicate that alpha-adrenoceptors are not only involved in the anticonvulsant action of diphenylhydantoin, but also in its antidepressant-like effects.
Subject(s)
Antidepressive Agents , Phenytoin/pharmacology , Receptors, Adrenergic, alpha/physiology , Animals , Blepharoptosis/chemically induced , Helplessness, Learned , In Vitro Techniques , Male , Mice , Prazosin/pharmacology , Reserpine/pharmacologyABSTRACT
The effects of the enantiomers of clenbuterol were compared in four psychopharmacological tests in which beta-adrenergic agonists are known to be active. In mice (+/-)-clenbuterol 0.06 mg/kg decreased motor activity and antagonized the hypothermia induced by 16 mg/kg of apomorphine; at 0.5 mg/kg it increased head-twitches and tremors induced by 1-5-hydroxytryptophan (4 mg/kg) and decreased the number of bites of a food pellet by mice which had been maintained on a water only diet for 24-27 h ('Tantale' test). The present results show that the (-) form is responsible for this activity and that the (+) form has no effect per se and does not antagonize the (-) enantiomer.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Behavior, Animal/drug effects , Clenbuterol/pharmacology , Ethanolamines/pharmacology , 5-Hydroxytryptophan/antagonists & inhibitors , Animals , Apomorphine/antagonists & inhibitors , Body Temperature/drug effects , Male , Mice , Motor Activity/drug effects , Stereoisomerism , Tremor/chemically inducedSubject(s)
Helplessness, Learned , Triiodothyronine/therapeutic use , Animals , Brain/physiopathology , Depressive Disorder/physiopathology , Electroshock , Humans , Male , Norepinephrine/physiology , Rats , Rats, Inbred Strains , Serotonin/physiology , Synaptic Transmission , Thyroid Gland/physiopathologyABSTRACT
Daily injection of triiodothyronine (T3) for 3 consecutive days dose dependently enhanced 1-5-HTP (4 mg/kg)-induced head twitches in mice. This effect was blocked by 1-penbutolol. Pretreatment with a sub-effective dose of T3 (0.06 mg/kg) markedly enhanced the ability of clenbuterol but not indalpine to potentiate the response to 1-5-HTP. Likewise, the effects of T3 were more pronounced on the desipramine- or maprotiline-induced potentiation of head-twitches than on the action of citalopram or clomipramine. These data suggest that the increased responsiveness to 1-5-HTP caused by T3 involves an indirect (noradrenalin-mediated) rather than a direct effect on serotonergic processes.