Participation of the nucleus paragigantocellularis (PGi) in mediation of opioid withdrawal was examined in conscious, unrestrained, non-opioid-dependent rats, using electrical stimulation of the PGi. A characteristic series of behaviors, which resembled those seen during naloxone-precipitated withdrawal from dependence on the opioid agonist, butorphanol, was elicited during 30 min of PGi stimulation. Thus, the behavioral syndrome has been termed opioid withdrawal-like. Simultaneous microdialysis measurement of glutamate within the locus ceruleus indicated a positive correlation between extracellular glutamate concentrations and behavioral responses. Behavioral responses were inhibited by 50% during reverse dialysis perfusion of the locus ceruleus with the glutamate receptor antagonist, kynurenic acid, without any effect on glutamate concentrations. Thus, increases in locus ceruleus glutamate partially mediate opioid withdrawal-like behavior. Intracerebroventricular (i.c.v.) injections of the opioid antagonist, naloxone, or of the mu-selective (beta-funaltrexamine) or the delta-selective (naltrindole) opioid antagonists decreased, but did not abolish, stimulation-induced behavioral responses. Similar i.c.v. injections of the kappa-selective antagonist, nor-binaltorphimine, had no effect on behavioral responses to PGi stimulation. Activation of the PGi by electrical stimulation can elicit behaviors similar to those observed during opioid withdrawal. Moreover, additional levels of complexity are evident in the neuropharmacology of PGi stimulation-induced opioid withdrawal-like behavior.

Animals↗

PubMedDate not supplied

Effects of single or repeated dermal exposure to methyl parathion on behavior and blood cholinesterase activity in rats.

The effects of a single or repeated dermal administration of methyl parathion on motor function, learning and memory were investigated in adult female rats and correlated with blood cholinesterase activity. Exposure to a single dose of 50 mg/kg methyl parathion (75% of the dermal LD(50)) resulted in an 88% inhibition of blood cholinesterase activity and was associated with severe acute toxicity. Spontaneous locomotor activity and neuromuscular coordination were also depressed. Rats treated with a lower dose of methyl parathion, i.e. 6.25 or 12.5 mg/kg, displayed minimal signs of acute toxicity. Blood cholinesterase activity and motor function, however, were depressed initially but recovered fully within 1-3 weeks. There were no delayed effects of a single dose of methyl parathion on learning acquisition or memory as assessed by a step-down inhibitory avoidance learning task. Repeated treatment with 1 mg/kg/day methyl parathion resulted in a 50% inhibition of blood cholinesterase activity. A decrease in locomotor activity and impairment of memory were also observed after 28 days of repeated treatment. Thus, a single dermal exposure of rats to doses of methyl parathion which are lower than those that elicit acute toxicity can cause decrements in both cholinesterase activity and motor function which are reversible. In contrast, repeated low-dose dermal treatment results in a sustained inhibition of cholinesterase activity and impairment of both motor function and memory.

Administration, Cutaneous↗

PubMedDate not supplied

Age-induced differentiation of morphine's effect on cyclic nucleotide metabolism.

Male ICR mice, immature (25 days old), mature adult (3 months old) and aged (22 months old), were injected with morphine sulfate (10 mg/kg, SC) or were implanted with morphine pellets (75 mg). Age-matched controls received saline injections or placebo pellets. One hour after injections and 72 hours after pellet implantation (when tolerance to morphine had occurred), the mice were decapitated and the frontal cortex and cerebellum were removed. Basal activities of adenylate cyclase, guanylate cyclase, cyclic AMP phosphodiesterase and cyclic GMP phosphodiesterase were determined in both brain regions. Results showed that there are age- and region-differentiated effects of morphine on these enzymes.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

Effects of acute barbiturate administration, tolerance and dependence on brain 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 review attempts to summarize the evidence available 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 presented. 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.

Animals↗

PubMedDate not supplied

Opiate receptor characteristics in brains from young, mature and aged mice.

Age-related differences in opiate receptors were determined using young (1 month old), mature (3 and 8 months old) and aged (20 months old) mice. 3H-Dihydromorphine binding to mu-receptors in brain synaptic membranes consisted of two components: one with high affinity and one with low affinity. High affinity mu binding sites in membranes from young and aged mice had significantly less receptor densities and higher affinities than the mature mice. In the membranes from aged mouse brain, the affinity of low affinity binding sites for 3H-dihydromorphine was also significantly increased when compared to those in membranes from the 8-month-old group. Membranes from the young and aged groups revealed significantly higher affinity for binding of the kappa ligand, 3H-(-)ethylketocylazocine, than mature mice, which was not accompanied by any change in the density of the receptors. There was no change in either the number or affinity of the binding sites for 3H-(D-Ser2-Leu5)-enkephalinyl-Thr, the delta receptor ligand, among young mature and aged groups.

Aging↗

PubMedDate not supplied

Induction of hepatic mixed function oxidases by photomirex.

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Animals↗

PubMedDate not supplied

Effects of morphine and aging on brain calmodulin levels in mice.

Calmodulin levels were determined in brain areas (cerebellum, cortex, diencephalon, medulla + pons and striatum) of immature, mature and old mice one hour after they were injected with morphine (10 mg/kg, s.c.) and 3 days after morphine pellet (75 mg) implantation (during tolerance). Acutely, morphine caused significant (two-fold) increases in calmodulin in striatal regions from immature and old mice, and increased calmodulin after morphine administration to mature mice occurred only in the cerebellum. After tolerance to morphine had developed, calmodulin levels in all brain regions were the same as those from placebo-implanted mice.

Aging↗

PubMedDate not supplied

Neurochemical evaluation of chlordecone toxicity in the mouse.

Plasma and brain levels of chlordecone in chlordecone-induced motor impairment, lethal levels of chlordecone, and cumulative LD50 of chlordecone in the mouse are presented. In terms of biochemical events, the possible contributory role of neurotransmitters in chlordecone-induced neurotoxicity is also discussed. On the basis of the data obtained so far, it is suggested that the dopaminergic pathway and its interaction with other neurotransmitter systems in the basal ganglia may be primarily involved in chlordecone-induced neurotoxicity.

Animals↗

PubMedDate not supplied

Possible molecular mechanism of mirex-induced hepatobiliary dysfunction.

Male Sprague-Dawley rats were treated with mirex, po, at 0, 5, 10, and 50 mg/kg/day in 0.4 ml of corn oil for 3 days. Forty-eight hours after the last treatment, the biliary excretion of exogenously provided polar metabolites of 14C-imipramine was suppressed at all levels of mirex in a dose-dependent manner. Biliary excretion of phenolphthalein glucuronide was suppressed at high doses of mirex. These effects of impaired biliary excretion were accompanied by increased bile flow. Persistence of the mirex-induced biliary excretory dysfunction toward otherwise readily excretable, preformed metabolites suggests aberration of transport of these substances from the liver to bile. Whereas mitochondrial Mg++-ATPase and microsomal Na+-K+-ATPase activities were both inhibited by exposure to mirex in a dose-dependent manner, the latter activity was consistently inhibited to a higher degree. These results are suggestive of mirex-induced interference with energy production and utilization in the manifestation of hepatobiliary dysfunction.

Adenosine Triphosphatases↗

PubMedDate not supplied

Interaction of rubratoxin B and pentobarbital in mice.

Rubratoxin B, a metabolite of Penicillium rubrum, is a potent mycotoxin that produces hepatic mid-zonal necrosis. Using propylene glycol as the solvent, the acute LD50 (i.p.) in male mice was estimated at 1.42 mg/kg. Pretreatment with s.c. pellets of pentobarbital reduced this toxicity approximately 42 percent, while castration and SKF 525A pretreatment enhanced toxicity approximately 20 percent and 60 percent, respectively. These studies also demonstrated that rubratoxin B potentiated pentobarbital-induced narcosis and enhanced pentobarbital hypothermia. The effect of SKF-525A and pentobarbital on the LD50 value of rubratoxin B suggests that the toxicity of this mycotoxin in mice does not arise from a toxic metabolite but from the parent compound.

Animals↗