Publisher Summary This chapter discusses separate pools of CNS zinc, which are, vesicular zinc, free zinc, and protein-bound zinc Vesicular zinc is the one which is sequestered in the presynaptic vesicles of a special class of neurons, the zinc-containing neurons, which are found primarily in limbic, cerebrocortical, and corticofugal systems This vesicular zinc can be selectively stained by several histochemical procedures and is, therefore, accessible to histological and histoanalytical studies The second pool, free zinc, is an entirely hypothetical pool of ionic Zn +2 in the cytosol or interstitial fluid that may or may not be present in normal, healthy brain tissue The third pool of zinc is that which is bound firmly into the structure of the many zinc-containing enzymes in the brain The enzymatic zinc is, therefore, a stable pool, involved only in the specific function of the zinc-containing enzymes Zinc metalloenzymes are essential to the normal biology of brain cells, and any experimental treatment that is extreme enough to affect the metalloenzymes, such as prolonged zinc undernutrition or administration of chelators, can disrupt brain function through metalloenzymatic effects

Neurobiology of zinc and zinc-containing neurons.

The major inhibitory neurotransmitter in mammalian brain, y-aminobutyric acid (GABA), exerts its effects through increased postsynaptic membrane permeability to chloride ions (McBurney and Barker, 1978; Nistri et a]., 1980). The GABA receptor and associated chloride ion channel appear to be part of a protein complex containing receptor sites for GABA, benzodiazepines, and picrotoxininl barbiturates, as well as the chloride ionophore (Fig. 1). The three types of drug receptor sites studied by radioactive ligand binding have been thoroughly characterized to show their relevance to in vivo actions of the drugs that bind to the receptor sites in v i m . Various lines of evidence support the hypothesis that modulation of the postsynaptic response to GABA is involved in many of the actions of both the benzodiazepines (Haefely et a]., 1979; Costa and Guidotti, 1979) and the barbiturates and related central nervous system depressants (Nicoll et al., 1975; Haefely et a]., 1979; Macdonald and Barker, 1979). This article reviews the recent evidence for in v i m interactions between the three categories of drug receptors; the evidence supports the model for a complex as depicted in Fig. 1 and thus the relevance of GABA to the actions of the other drugs.

GABA‐Benzodiazepine‐Barbiturate Receptor Interactions

The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligand-gated ion channels. Functional receptors of this family comprise five subunits and ...

Molecular Structure and Function of the Glycine Receptor Chloride Channel

Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats.

Several new lines of evidence suggest the existence of two or more distinct types of benzodiazepine receptors, in contrast to earlier results suggesting the presence of only one class of receptors. Appropriate thermoinactivation experiments indicate two receptors with different thermostabilities. Several triazolopyridazines, with some of the pharmacological properties of anxiolytics have recently been shown to displace 3H-diazepam and 3H-flunitrazepam with Ki values in the 6 to 100 nanomolar range. These new substances are active in conflict tests in rats and monkeys and prevent metrazol induced seizures in vivo, but strikingly lack the ataxia and sedative properties of the benzodiazepines. Hill analyses of dose-response curves for some of these substances yields Hill coefficients in the range of 0.4--0.6, suggesting that these compounds may be able to discriminate between several types of benzodiazepine receptors.

Some properties of brain specific benzodiazepine receptors: New evidence for multiple receptors

SummaryThe effects of anions and cations on the specific binding of 3H-diazepam to rat brain were determined. Crude synaptic membranes from whole rat brain were prepared by differential centrifugation followed by hypo-osmotic shock and freezing. The monovalent cations (as their chloride salts) Li+, Na+, K+, and NH4+ produced very slight enhancements of binding whereas Cs+ did not have any effect. The monovalent anions (as their sodium salts) F- and I- were inhibitory whereas Br- produced a very slight enhancement. Divalent cations (as their chloride salts) produced marked enhancements of binding. Ni2+ caused the greatest increase which reached 86% at 5 mM. This increased binding was the result of enhanced affinity for the binding site; the total number of sites was not altered. The rank order of potency for stimulating binding at 0.1 mM cation concentration was Ni2+, Hg2+ > Cu2+, Zn2+ > Co2+ > Ba2+, Mg2+, Ca2+, Mn2+, Ni2+ did not affect the specific binding to brain homogenates of 3H-strychnine or of 3H-q...

Effects of cations and anions on the binding of 3H-diazepam to rat brain.

Two crude oils, differing in viscosity (V) and nitrogen (N) and sulfur (S) content, were evaluated for pre- and postnatal developmental toxicity. In Crude I (low V, low N, low S) studies, the material was applied neat to the clipped backs of pregnant rats at dose levels ofO, 125, 500, WOO (postnatal only), and 2000 (prenatal only) mg/kg. In Crude II (high V, high N, moderate S) studies, the oil was applied similarly but at dose levels of 0, 30, 125, and 500 mg/kg. Rats were exposed to the crude oils on gestation days (CD) 0-19; application sites were not covered. “Prenatal” rats were killed on CD 20. “Postnatal” rats were allowed to deliver naturally; surviving dams and litters were killed 3-4 wk postpar- turn. Both crude oils produced maternal and developmental toxicity. Adverse fetal effects included increased in utero death, decreased body weight, and reduced ossification of skeletal elements. Parturition was delayed in Crude II dams at 500 mg/kg. The 4-d viability index was decreased in all C...

Developmental toxicity of dermally applied crude oils in rats

Exposure to crude oil and certain petroleum products can be a serious health hazard. Clarified slurry oil (CSO) is a complex mixture of hydrocarbons derived from the process-ing of crude oil, and is a known systemic and developmental toxicant, mutagen, and carcinogen. In the present study, CSO and two crude oils, Belridge heavy crude oil (BHCO) and Lost Hills light crude oil (LHLCO), were examined for their estrogenic and antiestrogenic properties in a human breast-cancer cell (MCF-7) assay. The MCF-7 focus assay is based on postconfluent cell growth and tissue restructuring, measured as the postconfluent development of multicellular nodules or foci. The mutagenicity indices of BHCO and LHLCO also were determined in a modified Ames Salmonella assay. Oil samples were prepared in dimethyl sulfoxide, resulting in extraction of virtually all of the aromatic compounds including the sulfur- and nitrogen-substituted three- to seven-ring polycyclic aromatic compounds comprising 62.2% of the CSO, 9% of the BHCO, and 2% of the LHLCO by total weight. None of the three samples was estrogenic in the MCF-7 focus assay. In contrast, all of the samples were antiestrogenic; that is, they inbibited the development of foci induced by 1 nM 17β-estradiol (E 2 ). The potencies of the oil samples for both antiestrogenicity and mutagenicity were correlated with the percent of polycyclic aromatic compounds they contained. Two potential mechanisms for the observed antiestrogenicity were examined. Radiometric analysis of the catabolism of [ 3 H]E 2 in MCF-7 cell cultures demonstrated that all three samples increased catabolism of E 2 . Results from a whole-cell estrogen-receptor (ER) binding assay suggested that metabolites of compounds in the oil samples might have competed with [ 3 H]E 2 for ER in the MCF-7 cultures. Thus the antiestrogenicity of the oil samples may occur through at least two mechanisms, increased catabolism of E 2 and antagonistic binding to ER.

Antiestrogenicity of clarified slurry oil and two crude oils in a human breast-cancer cell assay.

Effects of clofibrate, in vitro, on mitochondrial respiration and oxidative phosphorylation

Clarified slurry oil (CSO), syntower bottoms (STB), and distillate aromatic extract (DAE) are refinery streams produced by processing crude oil. Each of these refinery streams is rich in both hydrocarbons having carbon numbers of C20 or greater and polycyclic aromatic compounds. Available data indicate that some refinery streams are developmentally toxic (manifested primarily as increased embryolethality and growth retardation) by the dermal route of exposure. However, there is no conclusive evidence for their being teratogenic. The present studies were designed to further explore the suspected teratogenic potency of refinery streams while at the same time limiting embryolethality. To profile teratogenic effects as a function of gestation day, pregnant rats received a single oral dose (2000 mg/kg) of CSO, STB, or DAE on one of gestation days (GD) 11–14; DAE and STB were also administered on GD 15. To profile effects as a dose response function, rats received a single oral dose of CSO, DAE, or STB on GD 12...

Carl R. Mackerer

Papers

Effects of cations and anions on the binding of 3H-diazepam to rat brain.

Developmental toxicity of dermally applied crude oils in rats

Antiestrogenicity of clarified slurry oil and two crude oils in a human breast-cancer cell assay.

Effects of clofibrate, in vitro, on mitochondrial respiration and oxidative phosphorylation

Developmental toxicity of clarified slurry oil, syntower bottoms, and distillate aromatic extract administered as a single oral dose to pregnant rats.