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Biomedical subjects
A S Clark
Publications and source records attributed to A S Clark.
Anabolic-androgenic steroids and brain reward.
Anabolic-androgenic steroid (AAS) effects on brain reward were investigated in male rats with electrodes implanted in the lateral hypothalamus using the rate-frequency curve shift paradigm of brain stimulation reward. In the first experiment, treatment for 2 weeks with the AAS methandrostenolone had no effect on either the reward or performance components of intracranial self-stimulation. In the second experiment, treatment for 15 weeks with an AAS "cocktail" consisting of testosterone cypionate, nandrolone decanoate, and boldenone undecylenate did not alter brain reward but did produce a slight but significant change in bar press rate. In addition to the AAS treatment, animals in the second study were administered a single injection of d-amphetamine before and after 15 weeks of AAS exposure. The rate-frequency curve shift observed in response to a systemic injection of amphetamine was significantly greater in animals after 15 weeks of treatment with the AAS cocktail. Although AAS do not appear to alter the rewarding properties of brain stimulation, AAS may influence the sensitivity of brain reward systems.
Amphetamine↗
Comparison of the effects of 17 alpha-methyltestosterone, methandrostenolone, and nandrolone decanoate on the sexual behavior of castrated male rats.
In a series of 3 experiments, adult male Long-Evans rats were castrated and treated with 1 of 3 different anabolic-androgenic steroid (AAS) compounds (17 alpha-methyltestosterone, methandrostenolone, or nandrolone decanoate) for 6 weeks. In each experiment, subjects received daily injections of a high, medium, or low dose of AAS or the oil vehicle. The AAS effects on body weight in gonadectomized male rats were modest, and no effects on locomotor activity were observed. The AAS compounds administered at doses comparable with human abuse levels were not equipotent in maintaining male sexual behavior patterns (nandrolone decanoate > methandrostenolone > 17 alpha-methyltestosterone). In addition, the behavioral actions of AAS compounds did not parallel stimulation of sexual accessory glands. The authors reported that this study is the first to quantify the dose-response characteristics of individual AAS compounds with regard to these behavioral and endocrine measures.
Anabolic Agents↗
GABAA receptor-mediated responses in the ventromedial nucleus of the hypothalamus of female and male neonatal rats.
Perinatal exposure of the developing brain to gonadal steroids during a limited critical period induces permanent, organizational differences in neural structures between male and female animals. These differences are believed to underlie the manifestation of sexually dimorphic behaviors. Gamma-aminobutyric acid type A (GABAA) receptors expressed in the ventromedial nucleus (VMN) of the hypothalamus appear to be a key component underlying the expression of sexually dimorphic, and GABAA-mediated transmission within the VMN is critical for the expression of sexual behavior in female, but not male, rats. Here we report that analysis of VMN neurons from neonatal rats revealed significant sex-specific differences in GABAA receptor channel properties. Specifically, GABAA-mediated currents elicited by direct agonist application decayed more rapidly in VMN neurons from females than from males. Kinetic differences became more pronounced during the first 2 weeks of postnatal development. Analysis of small, spontaneous inhibitory postsynaptic currents recorded in intact slices indicated a trend towards slower responses in neurons from males than females, but the differences in decay kinetics were not significant. Sex-specific differences in GABAA receptor kinetics may arise from activation of receptors not receiving synaptic contacts in the slice preparation or may become apparent at intact synapses under conditions of increased activity and evoked release.
Adenosine Triphosphate↗
Anabolic-androgenic steroid and adrenal steroid effects on hippocampal plasticity.
Anabolic-androgenic steroids (AAS) are synthetic androgen-like compounds which are taken in high doses by athletes with the intention of enhancing muscular appearance, strength and/or athletic performance. Recent research indicates that high doses of AAS may influence the functions of the hippocampus. This evidence led us to explore the extent to which chronic AAS treatments influence spatial memory and the integrity of the hippocampus in the rat. Gonadally intact adult male Long-Evans rats were treated with either the AAS methandrostenolone, a steroid 'cocktail' (TNB; testosterone cypionate, boldenone undecylenate and nandrolone decanoate), or the oil vehicle daily for 12 weeks. A group of male rats treated with corticosterone (CORT; 10 mg/day) was also examined. Spatial memory was assessed in the Morris water maze after 10 weeks of hormone treatment. At 12 weeks, the animals were sacrificed, blood collected and the brain sectioned to assess hippocampal cell number. There were no impairments in the acquisition or retention of the Morris water maze in any hormone treatment group. Although serum testosterone levels were elevated in rats treated with TNB relative to the oil controls, neither the TNB or methandrostenolone treatments produced changes in hippocampal cell number. Serum CORT levels were significantly elevated in the rats treated with CORT and cell loss (15%) was detectable in the CA3b subfield in this group of animals. These results indicate that the AAS administered in the present study were not detrimental to hippocampal spatial memory or cell survival and that, while chronic CORT may produce mild hippocampal cell loss, this loss is not accompanied by deficits on a spatial memory task.
Animals↗
Antitumor imidazotetrazines. 32. Synthesis of novel imidazotetrazinones and related bicyclic heterocycles to probe the mode of action of the antitumor drug temozolomide.
A series of new imidazo[5,1-d]-1,2,3,5-tetrazinones with additional hydrogen-bonding or ionic substituents at the 8-carboxamide position of the antitumor drugs temozolomide (1) and mitozolomide (2) has been prepared. None of these compounds were significantly more cytotoxic in vitro against the mouse TLX5 lymphoma than the lead structures. Molecular modeling techniques have been used to design benzo- and pyrazolo[4,3-d]-1,2,3-triazinones bearing carboxamide groups in appropriate positions which are isosteric with temozolomide and mitozolamide but which cannot ring open to alkylating species. As predicted, these compounds have no inhibitory properties against human GM892A or Raji cell lines in vitro. Temozolomide and the spermidine-temozolomide conjugate 28 preferentially methylate guanines within guanine-rich sequences in DNA, but no experimental evidence has been found to support the hypothesis that such regions are involved in catalyzing the ring opening of the imidazotetrazinone prodrugs to their active forms.
Animals↗
Sleep during the week before labor: relationships to labor outcomes.
This correlational study was conducted to examine the relationship between maternal sleep during the nights prior to the onset of labor and labor outcomes of length, type of delivery, and maternal perceptions of labor. Subjects (N = 99) were drawn from childbirth education classes at a women's hospital in the southeastern United States. Subjects completed the Visual Analog Sleep Scale each morning, beginning two weeks prior to their due dates. Following delivery, subjects completed the Perception of Labor and Delivery Scale, and researchers gathered data about their labors. These women reported poor sleep effectiveness coupled with high sleep disturbance; however, there were no significant correlations between sleep quality and length of labor or maternal perceptions of labor for either the night, or the week, prior to the onset of labor. This finding leads us to question the view that disturbed prenatal sleep will interfere with the progress of labor and lead to more cesarean sections.
Adolescent↗
Aromatase in the cerebral cortex, hippocampus, and mid-brain: ontogeny and developmental implications.
Aromatase activity was measured in explant cultures from the newborn mouse and rat brain and in homogenates of regions of the rat brain sampled between birth and 51 days of age. Conversion of 19-[3H]hydroxy-androstenedione to estradiol and estrone was detected in explant cultures from the mouse preoptic/septal region, anterior cingulate cortex, and midbrain, as well as from the rat preoptic area, septum, hippocampus, anterior cingulate cortex, and midbrain central grey. No detectable estrogen biosynthesis was observed in explants from the cerebellum and spinal cord of either species. Measurements of aromatase in tissue homogenates using 1 beta[3H]androstenedione as substrate revealed detectable enzyme activity in the hypothalamus + preoptic area, amygdala, hippocampus, anterior cingulate cortex, and midbrain, from birth onward. Aromatase activity per milligram of tissue protein was highest in the hypothalamus-preoptic area and amygdala, followed by the hippocampus, midbrain, and cingulate cortex. In all brain regions, aromatase activity was markedly higher at Postnatal Days 1 and 7 than later in life. In both the cingulate cortex and the hippocampus, aromatase was barely detectable above the assay blank in adult (51 day) animals. These results demonstrate that regions of the developing rodent neo- and archicortex have the capacity to convert androgen to estrogen, consistent with a role for local estrogen biosynthesis in the sexual differentiation of higher brain functions.
Aging↗
Anabolic-androgenic steroids and aggression in castrated male rats.
The resident-intruder paradigm of aggression was utilized to evaluate the aggression-inducing properties of two anabolic-androgenic steroid (AAS) compounds, methyltestosterone and stanozolol, in castrated male rats. Three weekly tests were conducted. On test week three, castrated males treated with methyltestosterone displayed levels of aggression equivalent to the levels displayed by castrated males treated with testosterone propionate on most of the behavioral indices assessed. In contrast, treatment with stanozolol at the dose used in this study was completely ineffective in eliciting aggressive behavior. AAS effects on aggression were mirrored by their ability to stimulate seminal vesicle growth. There were no effects of AAS treatments on the levels of locomotor activity. These findings highlight the heterogeneity of AAS effects on the nervous system and behavior and indicate that the psychological effects reported by human AAS abusers may depend upon the distinct chemical structures of the abused steroids.
Aggression↗
Antitumor imidazotetrazines. 25. Crystal structure of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) and structural comparisons with the related drugs mitozolomide and DTIC.
The antitumor imidazotetrazinone, temozolomide (5), C6H6N6O2, forms crystals with unit cell dimensions a = 17.332 (3), b = 7.351 (2), c = 13.247 (1), beta = 109.56 (1) degree and space group P21/c. A doubly hydrogen-bonded dimer constitutes the asymmetric unit. One carboxamide group forms an additional intermolecular NH...O hydrogen bond; in both molecules the carboxamide group is coplanar with the heterocycle and its NH2 group interacts with the imidazole nitrogen atom N(7). Molecular orbital calculations show the carbonyl carbon C(4) to be the most electron deficient atom, with relatively weak N(3)-C(4) and C(4)-N(5) bonds confirming that temozolomide should ring-open at this position in solution. The energy barrier to carboxamide group rotation of approximately 20 kJ mol-1 should permit interconversion between rotamers. In temozolomide and the related drug mitozolomide (4), N(7) is more negatively charged than N(1), which favors the formation of hydrogen bonds to the former atom in spite of their poor geometry. The relevance of these structural features to the action of temozolomide as a major-groove-directed prodrug of the alkylating agent MTIC (3) is discussed.
Antineoplastic Agents↗
Adrenal hormone effects on hippocampal excitatory amino acid binding.
The influence of short-term adrenalectomy or corticosterone treatment on the binding of glutamate receptor subtypes in the rat hippocampus was explored using the technique of in vitro autoradiography. Analysis of NMDA, kainate and AMPA binding in the hippocampus was conducted on the brains of control, adrenalectomized, and adrenalectomized animals given corticosterone treatment. In addition, serum corticosterone levels were determined by RIA. No striking effects of acute adrenalectomy on the distribution or density of any glutamate receptor subtype were observed in the hippocampus. Adrenalectomy had a small but significant effect on kainate binding in the stratum lucidum and stratum radiatum of CA3 in the first experiment, but no effect in follow-up experiments. Short-term treatment with stress levels of corticosterone had no effect on the binding of NMDA or kainate in any hippocampal subfield. However, a small effect of high doses of corticosterone (CORT) was observed on AMPA binding in one subregion. Although the hippocampus is a target for glucocorticoids and uses excitatory amino acids as a primary neurotransmitter, transient manipulation of adrenal hormone levels did not directly modulate excitatory amino acid receptor binding.
Adrenal Cortex Hormones↗
In vitro autoradiography of hippocampal excitatory amino acid binding in aged Fischer 344 rats: relationship to performance on the Morris water maze.
Young and aged Fischer 344 rats were tested on the place and cue versions of the Morris water maze task. Although all of the young animals reached criterion within the 8-day testing period, the aged animals could be divided into two groups on the basis of their performance to criterion: achievers and nonachievers. Upon completion of the water maze testing, the animals were sacrificed, and their brains were processed for in vitro autoradiography of hippocampal excitatory amino acid receptors. Significant differences were found between the young and old rats in the levels of N-methyl-D-aspartate, CPP, kainate, and AMPA binding in subregions of the hippocampus. Despite the age-related decline in hippocampal glutamate receptors, no relationship was observed between the density or distribution of excitatory amino acid receptors and performance on the water maze task in the aged rats.
Aging↗
Free text databases in an Integrated Academic Information System (IAIMS) at Columbia Presbyterian Medical Center.
The use of Folio Views, a PC DOS based product for free text databases, is explored in three applications in an Integrated Academic Information System (IAIMS): (1) a telephone directory, (2) a grants and contracts newsletter, and (3) nursing care plans.
Databases, Factual↗
Modulation by norepinephrine of neural responses to estradiol.
Pharmacological studies have suggested that neurotransmitter activity impinging on steroid-concentrating cells can affect the steroid receptor system within those cells, modifying behavioral responses to the hormone. The present experiments revealed that the alpha 1-noradrenergic antagonist prazosin, administered to ovariectomized rats at the time of each of two pulses of estradiol, inhibited the appearance of sexual receptivity. Prazosin also substantially reduced the levels of estrogen receptors within hypothalamic cell nuclei following an injection of estradiol. Manipulation of noradrenergic inputs into the hypothalamus by lesioning brain stem norepinephrine cell groups with 6-hydroxydopamine (6OHDA) also reduced the level of nuclear estrogen receptors following an injection of estradiol. Although this effect of 6OHDA lesions was observed in two separate experiments, in other experiments 6OHDA had no effect on estrogen receptors. In some instances, there was a positive correlation between nuclear estrogen receptor levels in the hypothalamus and the levels of norepinephrine. The results are consistent with the hypothesis that brain stem inputs to the hypothalamus are able to modulate neural responses to steroids and specifically that noradrenergic inputs are able to modulate neural responses to estradiol. However, there are additional undiscovered variables that preclude statements of a simple relationship between norepinephrine levels and estrogen receptor levels.
Adrenergic Antagonists↗
Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA.
The structural and electronic properties of the major groove-binding anti-tumour imidazotetrazinones, mitozolomide and temozolomide were studied using molecular orbital techniques. Structure-activity relationships of mitozolomide derivatives emphasized the importance of a hydrogen bond donor on the C8-substituent and showed that good activity would be expected for derivatives carrying a small C8-substituent with restricted negative potential. The coplanarity of the carboxamide substituent in mitozolomide is unlikely to be disrupted by hydrogen bonding in the major groove. Semi-empirical M.O. calculations gave a very high partial positive charge on C4, indicating an enhanced susceptibility to nucleophilic attack leading to ring opening at this position and the formation of a triazene alkylating agent.
Antineoplastic Agents↗
Gonadal hormones influence the emergence of cortical function in nonhuman primates.
The role of gonadal hormones in the maturation of the orbital prefrontal cortex (ORB) was studied in normal male and female rhesus monkeys, monkeys given ORB lesions at 50 days of age, and female monkeys given androgen at different ages. Monkeys were tested on an object discrimination reversal task at 75 days of age. Gender influenced the performance of monkeys on the task during normal development and after ORB lesions. Normal males made fewer errors than did normal females. Females treated with androgen performed similarly to normal male monkeys. ORB lesions produced deficits in male monkeys and in females given androgen during late prenatal or early postnatal life, but not in normal females. These findings suggest that gonadal hormones may play an inductive role in the differentiation of higher cortical function in nonhuman primates.
Animals↗
Androgen binding and metabolism in the cerebral cortex of the developing rhesus monkey.
The influence of gonadal steroids on the maturation of the cerebral cortex and their possible influence on cortical function are not well understood. The present study examines androgen binding and metabolism in regions of the cerebral cortex and several subcortical structures at different time points during the development of the rhesus monkey. Androgen binding and metabolism were assessed in selected cortical and subcortical regions from neonatal, juvenile, and adult rhesus monkeys. Specific high affinity androgen-binding sites (apparent equilibrium dissociation constants for [3H]R1881, 0.04-0.3 nM) were observed in many areas of the rhesus monkey brain. These areas included (but were not limited to) the hypothalamus, amygdala, dorsolateral prefrontal cortex, orbital prefrontal cortex, visual and somatosensory cortex, and corpus callosum. Although the highest level of androgen binding was observed in the hypothalamus (8-20 fmol/mg protein), cortical samples also had measurable levels of binding (1-5 fmol/mg protein). No apparent regional or developmental differences in the number or affinity of androgen-binding sites were detected in animals ranging from 1 week to 8 yr in age. Androgen metabolism via aromatization and 5 alpha-reduction was observed in all regions of the neocortex examined, although at lower levels than in the hypothalamus and amygdala. Overall production of estrogens and 5 alpha-reduced androgens declined approximately 10-fold from prenatal to early postnatal life in both cortical and subcortical structures. The presence of androgen binding and metabolism in the monkey cerebral cortex indicates that steroid hormones may have considerable impact on cortical function in primates at postnatal as well as prenatal ages.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
A highly sensitive chromogenic microtiter plate assay for plasminogen activators which quantitatively discriminates between the urokinase and tissue-type activators.
A simple and highly sensitive chromogenic microtiter plate assay for plasminogen activators is described. The assay is based on plasmin cleavage of the synthetic tripeptide plasmin substrate H-D-norleucyl-hexahydrotyrosyl-lysine p-nitroaniline, which yields the yellow chromophore p-nitroanilide. Production of the latter compound is then quantitated spectrophotometrically at 405 nm on an ELISA plate reader. Linearity of the assay can be achieved over at least four orders of magnitude in a single experiment (0.01-100 milliPloug units) with appropriate incubation times. Capitalizing on tissue-type plasminogen activator's dependence on fibrin for enzymatic activity, the selective use of soluble fibrin products allows discrimination between urokinase and tissue-type activator. The utility of this aspect of the assay for the analysis of complex samples containing both types of plasminogen activators is demonstrated.
Aniline Compounds↗