Inhibition of cocaine intoxication by excitatory amino acid receptor antagonists.
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Animals↗
Biomedical subjects
I K Ho
Publications and source records attributed to I K Ho.
Effects of bicuculline on [3H]SR 95531 binding in discrete regions of rat brains.
Effects of bicuculline in vitro, and acute and chronic treatment of a subconvulsive dose of bicuculline on [3H]SR 95531 binding to discrete regions of rat brains were studied in Sprague-Dawley rats. Scatchard analysis of the binding isotherms exhibited two populations of binding sites for [3H]SR 95531 in frontal cortex, cerebellum, striatum and substantia nigra. The apparent KD for high-affinity sites was significantly increased in the frontal cortex and cerebellum in the presence of bicuculline (1 microM) with no change in Bmax. In contrast, the apparent affinity for low-affinity sites was not altered in the presence of bicuculline in these regions, whereas the Bmax was significantly decreased in the cerebellum. Following acute (2 mg/kg, i.p.) or chronic (2 mg/kg, i.p. for 10 days) bicuculline treatment, [3H]SR 95531 binding was also investigated in various regions of brains. The acute bicuculline treatment did not affect the [3H]SR 95531 binding in any of the regions studied. In contrast, apparent affinity for [3H]SR 95531 was significantly decreased in low-affinity sites of all regions studied in rats treated chronically with bicuculline. The Bmax values of high and low-affinity sites were significantly increased in the cerebellum with no change in the frontal cortex, striatum and substantia nigra. The present study demonstrates that chronic bicuculline treatment decreases apparent affinity of [3H]SR 95531 binding whereas the treatment increases apparent affinity of [3H]muscimol binding (1) in various brain regions. The results indicate that significant increase in Bmax of [3H]SR 95531 and [3H]muscimol binding in the cerebellum may be due to true up-regulation of GABA binding sites, involving increased de novo synthesis of receptor protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of pentobarbital tolerance and dependence on convulsant and GABAA receptor antagonist binding.
Experiments were performed which examined the effects of pentobarbital tolerance and dependence on GABAA receptor antagonist binding. In rats implanted with pentobarbital pellets for 7 days, followed by 24 hours of withdrawal, there was a significant decrease in the latency of TBPS-induced seizures and an increase in [35S]TBPS binding in the frontal cortex. The pentobarbital tolerant rats had a significant increase in the low affinity KD of [3H]SR95531 binding. Removal of the pellets for 24 hours caused a reversal of the effect on the low affinity KD and caused a decrease in the number of low affinity binding sites. In vitro addition of pentobarbital to binding assays produced a decrease in the number of high affinity [3H]SR95531 binding sites without changing low affinity binding. In the cerebellum, the binding in none of the treatment groups was significantly different from placebo. These observations suggest that pentobarbital tolerance and withdrawal cause changes in the properties of the GABAA receptor antagonist binding site which are different from those caused by in vitro exposure to the drug.
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Antagonism of the toxicity of cocaine by MK-801: differential effects in spontaneously hypertensive and Wistar-Kyoto rats.
A putative role for endogenous excitatory amino acid systems in the mediation of the cardiovascular and toxic responses to acute administration of cocaine, was examined in spontaneously hypertensive and normal Wistar-Kyoto rats. Conscious, restrained, male hypertensive and normal rats (12 weeks of age) received either the non-competitive excitatory amino acid receptor antagonist, MK-801 (0.01-10 mg/kg, i.v.) or vehicle, 30 min prior to initiation of infusion of cocaine hydrochloride (1.25 mg/kg min, i.v.). Administration of MK-801 produced increases in mean blood pressure and heart rate in both hypertensive and normal rats. Resting rectal temperature was reduced by MK-801 only at the largest dose tested (10 mg/kg). Infusion of cocaine caused convulsions and death at doses of 27.8 +/- 2.3 and 48.2 +/- 5.7 mg/kg, respectively in the normals, and 21.2 +/- 2.5 (P < 0.05) and 31.1 +/- 3.4 (P < 0.05) in the hypertensive rats. Pretreatment with MK-801 abolished the enhanced sensitivity of the hypertensive rats to the toxicity of cocaine. The doses of cocaine required to cause death were significantly increased, in the hypertensive rats at doses > or = 0.05 mg/kg, an effect which was not evident, at any dose, in the normals. The maximally effective dose of MK-801 (0.5 mg/kg) increased the dose of cocaine required to cause lethality by 272% (P < 0.05) in the hypertensive rats; the increase produced by MK-801 in the normals (163%) was not significant. Cocaine-induced convulsions were abolished in both hypertensive and control rats with doses of MK-801 > 0.1 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
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Behavioral and neurochemical effects of continuous infusion of cocaine in rats.
The ability of continuous intravenous infusion of cocaine (60 mg/kg per day for 11 or 12 days; by osmotic minipump) to alter responses to acute injection of cocaine (20 mg/kg, i.p.; given 24 hr after termination of the infusion by minipump) was tested in conscious, tethered Sprague-Dawley rats. Extracellular levels of cocaine, dopamine and metabolites of dopamine in the striatum were determined by in vivo microdialysis. Locomotor activity and stereotyped behavior were evaluated simultaneously during dialysis sampling. Prior infusion of cocaine blunted the ability of acute challenge with cocaine to increase the efflux of dopamine in the striatum, locomotor activity and stereotypy. Increases in extracellular levels of homovanillic acid in the striatum were significantly greater in cocaine-infused rats than vehicle-infused controls, both prior to and after acute injections of cocaine. However, no differences between these two groups were observed in levels of cocaine in the striatum after acute challenge. Extracellular levels of dopamine in the striatum correlated significantly (P less than 0.05) with stereotypy in both groups but with locomotor activity only in cocaine-infused rats. The results indicate that behavioral tolerance occurred after continuous intravenous infusions of cocaine, that this was correlated with neurochemical tolerance to acute cocaine challenge and that alterations in the metabolism of cocaine did not account for the observed behavioral responses.
3,4-Dihydroxyphenylacetic Acid↗
Effects of beta-funaltrexamine on butorphanol dependence.
The present experiments were performed to investigate the effects of the selective mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on the physical dependence liability of butorphanol (a mixed agonist/antagonist opioid analgesic). Butorphanol (26 nmol/microliter/h) was continuously infused via osmotic minipumps into the lateral cerebral ventricle of male Sprague-Dawley rats for 72 h. beta-FNA (12, 24, and 48 nmol/5 microliter/rat) was administered ICV 3 h prior to and 48 h after initiation of the butorphanol infusion. Treatment with beta-FNA significantly diminished naloxone-induced escape behavior, hypothermia, and loss of body weight in a dose-dependent manner, while naloxone-induced teeth-chattering, forepaw tremors, and urination were also reduced, but in a dose-independent manner. These results suggest that the mu opioid receptor is partially involved in the development of physical dependence upon butorphanol.
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Cocaine elevates striatal dopamine efflux in spontaneously hypertensive and Wistar-Kyoto rats.
The effects of acute cocaine administration on central dopaminergic systems were examined in the striata of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats with the use of an in vivo microdialysis technique. Increased extracellular levels of dopamine were observed for 45 to 75 minutes following acute cocaine administration in both halothane-anesthetized and conscious SHR and WKY. However, no significant differences were noted between anesthetized and conscious SHR and WKY in either baseline levels or cocaine-induced changes in extracellular levels of dopamine and its metabolites. A positive, linear correlation between extracellular levels of dopamine and cocaine was demonstrated for the 60-min period following acute cocaine administration in both SHR and WKY. The slopes of the linear regression plots obtained from the data of each 15-min sample was slightly, but significantly, higher in conscious SHR than in conscious WKY. The present results suggest a transient and dose-related stimulation of striatal dopamine release following acute cocaine administration and a linear relationship between striatal extracellular levels of dopamine and cocaine in both SHR and WKY.
3,4-Dihydroxyphenylacetic Acid↗
Effects of acute pentobarbital administration on GABAA receptor-regulated chloride uptake in rat brain synaptoneurosomes.
Effects of acute pentobarbital administration on GABAA receptor-regulated muscimol-stimulated, pentobarbital-stimulated, or flunitrazepam-enhanced, muscimol-stimulated chloride uptake were studied in the brains of Sprague-Dawley rats. Animals received sodium pentobarbital, 60 mg/kg IP, and cerebral cortical and cerebellar synaptoneurosomes were isolated at 10 min, 1 h, and when animals had awakened. The basal uptake of chloride was not changed in either cerebral cortex or cerebellum at different time periods after pentobarbital administration. Ten minutes after sodium pentobarbital administration, muscimol-stimulated chloride uptake was significantly reduced in cerebellum when the muscimol concentration was 2.5, 5, or 20 microM and in cerebral cortex when the concentration of muscimol was 5 or 10 microM (p less than 0.05, Duncan multiple-range test). One hour after pentobarbital administration or after animals had awakened, chloride uptake in brains from pentobarbital-treated animals was less at low concentration of muscimol (2.5 microM). No significant difference was found in either cerebral cortex or cerebellum in pentobarbital-(125-1,000 microM) stimulated or flunitrazepam-(2.5-20 microM) enhanced, muscimol-(3 microM) stimulated chloride uptake at different time periods after pentobarbital administration. Saline treatment had no effects on the basal or muscimol-stimulated chloride uptake in cerebellar synaptoneurosomes when compared with naive animals. The results demonstrate that GABAA receptor-regulated chloride uptake is decreased after acute pentobarbital administration, an effect that is reversible.
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Amitriptyline prevents N-methyl-D-aspartate (NMDA)-induced toxicity, does not prevent NMDA-induced elevations of extracellular glutamate, but augments kainate-induced elevations of glutamate.
The effect of amitriptyline on kainate- and N-methyl-D-aspartate (NMDA)-induced toxicity and release of amino acids from cerebellar granule neurons was studied. The ED50 for amitriptyline, imipramine, and nortriptyline protection against NMDA-induced toxicity was 6.9, 6.5, and 1.3 microM, respectively. None of these compounds protected against kainate-induced toxicity. Even though amitriptyline was protective against NMDA-induced toxicity, it had no effect on the NMDA-induced increase in extracellular levels of glutamate or aspartate from these cells, indicating a dissociation between NMDA receptor activation (as indicated by glutamate content elevations) and NMDA-induced toxicity. However, kainate and quisqualate treatment resulted in elevations of glutamate and taurine levels that were further augmented in the presence of 25 microM amitriptyline. These findings confirm the reports of others that tricyclic antidepressants have neuroprotective effects related to the NMDA receptor and expand on these reports by showing that even though there is protection against toxicity, the NMDA receptor is nevertheless activated, suggesting an involvement of these compounds at sites removed from the receptor. Furthermore, this is the first report showing an interaction of tricyclic antidepressants with the function of non-NMDA receptors.
Amitriptyline↗
The physical dependence liability of butorphanol: a comparative study with morphine.
In these studies, the physical dependence liability of butorphanol, a mixed 'agonist/antagonist' opioid analgesic, was compared to that of morphine. Male, Sprague-Dawley rats received i.c.v. infusions of saline (1 microliter/h), or an equimolar dose of butorphanol or morphine (52.3 nmol/h) for 3 days. The physical dependence liabilities of these two compounds were then compared by assessing both behavioral withdrawal signs and weight loss following naloxone-precipitated withdrawal. Body weight loss was also evaluated following abrupt (cessation of infusion) withdrawal from butorphanol or morphine. In animals receiving i.c.v. infusions of butorphanol or morphine, naloxone administration (5 mg/kg s.c.) induced an equivalent degree of body weight loss compared to saline-treated animals. In addition, the ED50 of naloxone to produce wet shakes, escape behavior, teeth chattering, urination and defecation was equivalent in rats receiving butorphanol or morphine. Infusions of butorphanol or morphine also produced an equivalent degree of weight loss in animals undergoing abrupt withdrawal. These results demonstrate then that a substantial degree of physical dependence had developed in rats which received a large dose of butorphanol.
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Effects of pentobarbital tolerance to and dependence on GABAB receptor-binding.
Effects of pentobarbital pellet implantation on [3H]baclofen binding in the frontal cortex of cerebellum of rat brains were examined. In the frontal cortex, pentobarbital tolerance caused an increase in the number of binding sites (Bmax) without changing their affinity (KD). Twenty-four hours after withdrawal of the pentobarbital pellets, there was a significant increase in the KD and Bmax values. Cerebellar binding, in contrast, was not significantly changed in any of the treatment groups. Addition of 1 mM of pentobarbital directly to binding assays using cortical membrane produced as increase in KD without a change in Bmax. In vitro, pentobarbital affected neither the KD nor the Bmax in the cerebellar [3H]baclofen binding. These results suggest that like the GABAA receptor, [3H]baclofen binding to the GABAB receptor in rat frontal cortex was affected by pentobarbital tolerance and dependence, and that there are regional differences in the properties of the GABAB receptor.
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Severe hypoxia produced by concomitant intoxication with sublethal doses of carbon monoxide and cyanide.
It has long been known that a number of tissue hypoxicants are generated in the fire scenario. However, until recently few investigators have undertaken to correlate smoke inhalation deaths with the simultaneous exposure to histotoxic hypoxicants. Carbon monoxide and hydrogen cyanide are two histotoxic hypoxicants that are generated in nearly every fire. Prior studies performed in our laboratory have demonstrated that death can result from concomitant exposure to otherwise sublethal concentrations of carbon monoxide and cyanide. Since most smoke inhalation victims exhibit acid/base anomalies, we sought to investigate whether the death associated with simultaneous exposure to these two hypoxicants, at concentrations widely held to be nonlethal, could be explained by acid/base imbalances. Male ICR mice were exposed to 0.35% carbon monoxide immediately after having been injected ip with potassium cyanide solution, or were challenged with either agent alone. Animals challenged with cyanide or carbon monoxide alone demonstrated significant hypoxia. However, animals challenged with both agents demonstrated much greater hypoxia than could be explained by an additive effect alone. Controls demonstrated no alteration in acid/base homeostasis. Blood pH perturbations were found to be due to severe lactic acidosis coupled with inadequate respiratory compensation. Thus, it appears that the synergistic lethal effect of simultaneous administration of carbon monoxide and cyanide are related to a precipitous decrease in blood pH, the tissue hypoxia and its resulting complications.
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Dopamine receptors mediate cocaine-induced temperature responses in spontaneously hypertensive and Wistar-Kyoto rats.
The involvement of dopaminergic receptors in the responses of conscious, restrained spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats to cocaine was examined using antagonists selective for DA-1 (SCH 23390) or DA-2 (sulpiride) dopamine receptors. Following pretreatment with saline vehicle, SCH 23390 (50 mg/kg, SC), sulpiride (50 mg/kg, IP) or SCH 23390 and sulpiride, cocaine was infused (1.25 mg/kg.min, IV) until death. Cocaine caused an initial pressor and tachycardiac response, which was followed by a progressively developing secondary pressor response. Combined (DA-1 and DA-2) antagonist pretreatment abolished the initial tachycardic response to cocaine. Rectal temperature during cocaine infusion increased in 38.5% of vehicle-treated SHR (designated SHRH), but decreased in the remaining SHR (SHRL) and all vehicle-treated WKY. The time-to-onset of cocaine-induced convulsions (Tc) was reduced in vehicle-treated SHRH compared to vehicle-treated SHRL and WKY. Sulpiride elevated rectal temperature in response to cocaine in SHR and WKY but reduced Tc only in SHR. SCH 23390 abolished hyperthermic responses to cocaine in SHR without altering toxicity in SHR or WKY. Combined pretreatment virtually abolished temperature responses to cocaine in SHR and WKY, but increased the Tc only in WKY. Dopamine receptors, particularly the DA-1 subtype, are involved in cocaine-induced hyperthermia.
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Trihexyphenidyl enhances physostigmine prophylaxis against soman poisoning in guinea pigs.
The protective effects of simultaneous and continuous administration of physostigmine and trihexyphenidyl against soman-induced toxicity were studied in guinea pigs. Not only did trihexyphenidyl reduce physostigmine-induced toxicity when it was administered continuously to the animals along with physostigmine, the combination afforded greater protection from soman lethality than did either agent administered alone. The combination pretreatment also gave better protection against soman-induced body weight loss and decreased water consumption and attenuated the down-regulation of cholinergic receptors which occurred when physostigmine alone was used. The onsets of other soman-induced toxicity signs were delayed significantly by the combination pretreatment regimen. These results suggest that simultaneous administration of the combination of physostigmine and trihexyphenidyl may be more useful than physostigmine alone as prophylaxis against soman poisoning.
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Glutamate receptor antagonists block cocaine-induced convulsions and death.
The involvement of excitatory amino acid (EAA) receptors in mediation of the toxic effects of cocaine was studied in male ICR mice. Cocaine HCl (90 mg/kg, IP) induced seizures in 95% and death within 24 h in 68% (n = 135) of the animals. There was a significant correlation (r = .54) between the time to onset of convulsions and the time to death in mice which died within 30 min of injection (n = 84). Pretreatment with selected EAA receptor antagonists 15 min prior to cocaine differentially blocked cocaine toxicity. Selective N-methyl-D-aspartic acid (NMDA) receptor antagonists (MK-801, dextrorphan, CPP) decreased both the incidence of seizures and mortality. A nonselective EAA antagonist, kynurenic acid, decreased lethality in doses which did not reduce convulsions. A similar action was observed following pretreatment with the selective kainic acid/AMPA receptor antagonist, GDEE. Antagonists at EAA receptors can provide significant protection against cocaine-induced toxicity. Moreover, the data provide evidence for the involvement of both NMDA and non-NMDA receptor subtypes in aspects of cocaine toxicity.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Effects of haloperidol on motor and cognitive functioning in aged mice.
The effects of haloperidol on motor and functioning and cognitive functioning were studied in young (3-5 months old) and aged (20-22 months old) male mice by examining haloperidol-induced catalepsy and haloperidol-induced decrements in performance on a radial arm maze. The aged mice were much more sensitive to these adverse effects of haloperidol than were the young mice. Studies of the distribution of radioactivity from [3H]haloperidol to the brain indicated that the differences in sensitivity to this drug were not due to pharmacokinetic differences. The results demonstrate that mice are suitable for studies of aging-induced changes in the behavioral effects of neuroleptic agents.
Aging↗
Comparisons of cocaine receptors in brain regions from WKY and SHR.
Both high- and low-affinity sites for [3H]cocaine binding were present in the striatum, hippocampus, olfactory tubercle, and hypothalamus of WKY and SHR. In the striatum, Kd values of both sites and the Bmax value of the high-affinity site were lower in SHR than in WKY rats. In the hippocampus, only the Kd value of the high-affinity site was lower in SHR than in WKY rats. However, there were no differences in Kd or Bmax values between strains in the olfactory tubercle or hypothalamus. The differences in characteristics of [3H]cocaine binding in WKY and SHR may provide a neurochemical basis for the different responses of the two strains to cocaine administration.
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Effects of barbiturates on GABA system: comparison to alcohol and benzodiazepines.
Central nervous system depressants, e.g. barbiturates, alcohol and benzodiazepines, have a wide spectrum of activity in humans and animals. Evidence accumulated suggests that some of the pharmacological actions exerted by these agents may be mediated through GABA system by mimicking GABAergic transmission. This proceeding briefly summarizes the evidence presented in our previous review (Yu S and Ho Ik: Alcohol 7: 261, 1990) as to how the GABA system plays a part in the barbiturate actions and the development of tolerance to and physical dependence on barbiturates. The comparisons of the effects of alcohol, barbiturates and benzodiazepines at different steps of GABA synapse are also discussed. Furthermore, the results which have been reported in the literature are inconsistent. This may be due to differences in (a) animal models used; (b) brain regions used; (c) protocols (dose, duration, form and route of administration, etc.) used in treating animals and/or (d) techniques (pharmacological, biochemical, physiological, etc.) used.
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