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Biomedical subjects

R L Singhal

Publications and source records attributed to R L Singhal.

At least 37 records · Page 2Linked to original sources
PubMed1984

Comparison of the changes in central catecholamine systems following short- and long-term lithium treatment and the consequences of lithium withdrawal.

The effects of treatment with and withdrawal from lithium (Li, 2 mmol/kg) on central catecholamine systems in rat brain were investigated. Synthetic parameters were found to be unchanged after treatment, but abrupt withdrawal resulted in enhanced activity of tyrosine hydroxylase. Noradrenaline levels in most brain regions examined were depressed following both short- and long-term Li administration, with a further decrease in content in the pons but enhanced cortical levels on withdrawal. Li administration resulted in elevated 3,4-dihydroxyphenylacetic acid levels, whereas withdrawal caused an enhancement of homovanillic acid content and depression of 3-methoxy-4-hydroxyphenyl glycol levels. It appears that the changes in central catecholamine systems are qualitatively the same following both short- and long-term Li treatment, as are the consequences of abrupt Li withdrawal. It is suggested that Li administration results in a disruption of catecholamine storage processes, while withdrawal from Li does not result in a simple return towards normal states.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Studies on glutathione metabolism in ventral prostate and chemically induced prostatic carcinoma in rats.

Glutathione content and the activity of glutathione reductase were examined in ventral prostate and chemically induced 11095 squamous-cell prostatic carcinoma in rats. Castration produced a significant reduction in the levels of reduced (GSH) and oxidized (GSSG) glutathione and glutathione reductase activity in the prostate. Replacement of testosterone (50 mg/kg) daily for 7 days to castrated animals elevated the reduced glutathione level and the activity of glutathione reductase almost to normal limits. Squamous-cell carcinoma was implanted in castrated and intact animals. Tumor growth in normal rats produced a decrease of almost 30% in the weight of the ventral prostate at 21 days post-implantation, although the glutathione levels remained unaffected. Much greater activity of glutathione reductase was detected in the tumor in comparison to the values noted for the normal tissue. The tumor also showed significantly higher values for the GSH/GSSG ratio. No apparent difference could be found in the rate of the growth of tumors whether implanted in normal or castrated animals. The levels of reduced and oxidized glutathione and glutathione reductase activity also seemed identical in tumors obtained from both groups of animals. Administration of testosterone (50 mg/kg) or beta-estradiol (2 mg/kg) daily for 11 days to tumor-bearing castrated animals did not alter the levels of glutathione and glutathione reductase activity. A significantly higher level of blood reduced glutathione was found in tumor-bearing rats in comparison to that seen for the normal subjects. Our results demonstrate that androgen depletion and replacement therapy influence the metabolism of glutathione in rat ventral prostate. Squamous-cell carcinoma of the prostate appears to differ from the normal tissue with respect to the observed androgen effects. There is dissimilarity in the metabolism of glutathione in the two tissues since greater activity of glutathione reductase and lower values of reduced glutathione were seen in the tumor as compared to those of the ventral prostate. Treatment with beta-estradiol, an antiprostatic agent, does not seem to influence the growth or glutathione metabolism of squamous-cell carcinoma of the prostate. The observed changes in blood glutathione levels might prove to be useful as an index of rapid growth of the neoplastic tissue.

Animals↗
PubMed1983

Diazepam potentiates the effect of neuroleptics on behavioural activity as well as dopamine and norepinephrine turnover: Do benzodiazepines have antipsychotic potency?

A single injection of diazepam (10 mg/kg, s.c.), haloperidol (2 mg/kg, i.p.) or chlorpromazine (10 mg/kg, i.p.) decreased the ambulatory as well as sniffing behaviour of rats. These behavioural responses were further decreased when diazepam was administered concurrently with the neuroleptic. Acute haloperidol or chlorpromazine treatment increased striatal dopamine as well as cerebro-cortical norepinephrine turnover. In contrast, diazepam diminished the release of both of these catecholamines. When diazepam was administered together with haloperidol or chlorpromazine, a further decrease particularly in dopamine release was seen in striatum. This effect of diazepam on norepinephrine and dopamine turnover persisted even after 21 days of daily treatment, Similarly, the sedative effect of diazepam elicited in the form of depressed locomotor activity was also apparent after long-term administration of this benzodiazepine. However, chronic administration of neuroleptics enhanced the spontaneous locomotor activity and sniffing behaviour by about 25%. Furthermore, repeated neuroleptic treatment decreased the synthesis and turnover of dopamine and norepinephrine. This was reflected in decreased tyrosine hydroxylase and homovanillic acid level in striatum as well as by low concentration of 3-methoxy-4-hydroxyphenylethylene glycol in the cerebral cortex. When diazepam was administered together with haloperidol or chlorpromazine for 21 days, behavioural activity remained elevated and was comparable to groups of rats receiving neuroleptics alone. The cocomitant injection of diazepam and neuroleptics for 21 days elicited a synergistic effect on decreased synthesis and release of dopamine as well as norepinephrine. These data provide neurochemical evidence for potentiation of the neuroleptic effects by a benzodiazepine.

Animals↗
PubMed1983

Behavioural and biochemical alterations following haloperidol treatment and withdrawal: the animal model of tardive dyskinesia reexamined.

Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal gamma-aminobutyric acid content and glutamic acid decarboxylase activity by 17% and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.

Animals↗
PubMed1983

SL76002 - effect on gamma-aminobutyric acid and dopamine in animals treated chronically with haloperidol.

Daily haloperidol injection at the dose of 5 mg/kg for 34 days did not change the levels of dopamine in the corpus striatum, frontal cortex, and midbrain of rats. However, the gamma-aminobutyric acid (GABA) level was increased by 27% in the corpus striatum. Haloperidol withdrawal for 4 days after 30-day treatment increased GABA levels of the corpus striatum and the frontal cortex to 140 and 125%, respectively, of control values. GABA, by its inhibitory actions, depleted dopamine level in the corpus striatum and frontal cortex by 17 and 29%, respectively. Administration of SL76002, a new GABA agonist, for 4 days at the dose of 400 mg/kg i.p. to haloperidol-withdrawn rats increased GABA levels in striatum by 23% of control values. The dopamine levels were also decreased significantly in the frontal cortex and corpus striatum. Our data demonstrate that SL76002, by altering the GABA levels, probably influences DA functioning in the corpus striatum, a region responsible for involuntary movements.

Animals↗
PubMed1983

Fluvoxamine influences serotonergic system in the brain: neurochemical evidence.

The effects of a relatively new antidepressant drug, fluvoxamine, were compared with those produced by chlorimipramine on the 5-hydroxytryptamine system in rat brain. Daily treatment with fluvoxamine (25 mg/kg, i.p.) and an equivalent dose of chlorimipramine (28 mg/kg, i.p.) for 7 days reduced (3H)5-hydroxytryptamine uptake by crude synaptosomes (P2 pellet) of brain to 56 and 45%, respectively, but produced no change in midbrain monoamine oxidase activity. Repeated administration of these drugs significantly decreased tryptophan hydroxylase activity as well as tryptophan level in the midbrain region. The concentration of 5-hydroxyindoleacetic acid also was lowered in several discrete areas of the brain, but no change was seen in the endogenous levels of 5-hydroxytryptamine. Our data suggest that fluvoxamine, like chlorimipramine, is a potent inhibitor of 5-hydroxytryptamine uptake. Unlike tricyclic antidepressants, fluvoxamine does not seem to produce any sedation in animals, which was evidenced by no significant change in spontaneous locomotor activity.

Animals↗
PubMed1983

Effects of subacute low level lead exposure on glucose homeostasis.

Administration of low levels of lead (0.001, 0.005 and 0.025 micrograms/g/day p.o.) to neonate rats from age three days to eight weeks failed to alter the activities of hepatic glucose-6-phosphatase, fructose-1,6-diphosphatase, pyruvate carboxylase and phosphoenolpyruvate carboxykinase, the four key gluconeogenic enzymes. Administration of lead at a higher dose (0.1 micrograms/g/day p.o.) was also observed to produce no alterations in enzyme activity at eight weeks. However, the higher dose did enhance the activities of fructose-1,6-diphosphatase and phosphoenolpyruvate carboxykinase at age six weeks. Plasma insulin and glucagon were not significantly altered by up to 0.025 micrograms/g exposure to lead until eight weeks of age, although levels of these hormones appear to be slightly dose-responsive tending towards elevated glucagon and decreased insulin levels with increasing lead dosage. At 0.1 micrograms/g/day glucagon was significantly increased at eight weeks. Blood glucose and hepatic glycogen remained unaltered. Blood, hepatic and pancreatic lead levels were unchanged by treatment with lead up to 0.025 micrograms/g/day to eight weeks of age, but there was evidence of lead accumulation in pancreatic tissue whereas levels of the metal in the liver paralleled those in the blood. Significant increases were observed with 0.1 micrograms/g/day lead at six and eight weeks in blood and pancreas. Data are presented which suggest that six week old animals are more influenced by subacute lead exposure than are the eight week old animals, as reflected in some alteration of gluconeogenic enzyme activity in younger rats.

Animals↗
PubMed1982

3',5'-cyclic-nucleotide-dependent protein kinase of squamous cell carcinoma of the prostate.

An adenosine 3'5'-cyclic-monophosphate (Cyclic AMP)-dependent protein kinase has been identified and partially purified from the rat prostate tumor induced by 20-methylcholanthrene. This enzyme is stimulated 2- to 3-fold by the nucleotide. Equilibrium studies at pH 5.0 suggest the presence of a major class of binding site for cyclic AMP with an association constant of approximately 10(8) M-1. The concentration of binding site is about 1 pmol/mg of protein of the enzyme preparation. The enzyme is stimulated by other cyclic nucleotides as well, but only by higher concentrations. In comparing the ability of different histone subfractions, casein and protamine, to serve as substrate for this particular protein kinase, maximal cyclic-AMP-dependent enzyme activity was observed with histones. The results suggest that factors contributing to the malignant growth of the prostatic tissue do not directly involve changes in the characteristics of a cyclic-AMP-dependent protein kinase.

Animals↗
PubMed1982

MIF-1: effects on norepinephrine, dopamine and serotonin metabolism in certain discrete brain regions.

A single injection of melanocyte-stimulating hormone inhibitory factor (MIF-1) in a dose of 3 mg/kg IP produced no significant effect on dopamine turnover. However, a dose of 5 mg/kg increased striatal tyrosine hydroxylase activity by 25% and homovanillic acid level by 27% when compared to control values. No change in either parameter was detected in olfactory tubercles. Dopamine levels also were elevated in striatum, pons-medulla and cerebral cortex in rats receiving 5 mg/kg dose of MIF-1. In olfactory tubercles, dopamine levels were however, reduced to 71% of control values taken as 100%. The concentration of norepinephrine tended to increase in several brain areas examined but, the change was statistically significant only in olfactory tubercles and cerebral cortex. The level of norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylene glycol, was lowered to 63% in whole brain of animals given MIF-1 at the dose of 5 mg/kg. These data suggest that MIF-1 enhances the turnover of dopamine and norepinephrine in the brain. However, MIF-1 treatment seemed to produce no consistent change in brain serotonin turnover. In striatum and cortex, this neuropeptide increased serotonin but elevated the level of its metabolite, 5-hydroxyindoleacetic acid indicating that the release of this brain amine was decreased in these two brain regions. The levels of 5-hydroxyindoleacetic acid were enhanced in hypothalamus and pons-medulla regardless of the dose of MIF-1 administered.

Animals↗
PubMed1982

Comparative effects of short- and long-term treatment with neuroleptics on behavioural activity as well as dopamine turnover in striatum.

1. Single injection of haloperidol (2 mg/kg, i.p.) or chlorpromazine (10 mg/kg, i.p.) produced an activation of dopamine synthesis and turnover as evidenced by increased activity of tyrosine hydroxylase and higher levels of homovanillic acid in the striatum of rats. 2. The endogenous concentration of dopamine remained unchanged in striatum and other brain regions examined, except in hippocampus where it was slightly (20%), but significantly decreased by acute haloperidol treatment. 3. In contrast, long-term treatment with neuroleptics over a period of 21 days decreased the synthesis and turnover of dopamine in the striatum. Whereas short-term treatment with chlorpromazine and haloperidol produced marked sedation, chronic treatment enhanced spontaneous locomotor activity by 20 and 26% and sniffing frequency by 19 and 24%, respectively. 4. Our data demonstrate that tolerance develops to the stimulating effect of haloperidol and chlorpromazine on striatal dopamine turnover. This adaptive change might be responsible for the emergence of clinical effects. 5. It is suggested that after repeated treatment, "chemical denervation" occurs as a result of chronic blockade of dopaminergic transmission in the striatum and that the proliferation of dopamine receptors (i.e. supersensitivity) is probably responsible for hyperactivity and overt sniffing behaviour.

Animals↗
PubMed1982

Bromocriptine-induced changes in dopamine and gamma aminobutyric acid in haloperidol withdrawn rats.

1. Daily administration of haloperidol (2 mg/kg, i.p.) for 35 days significantly decreased tyrosine hydroxylase activity as well as homovanillic acid in the corpus striatum of rats. 2. Long-term treatment with haloperidol significantly elevated (17%) glutamic acid decarboxylase activity as well as gamma-aminobutyric acid level in the corpus striatum. 3. Withdrawal of rats for 3 and 5 days after 32 and 30 days of haloperidol treatment increased the locomotor activity to 279% and to 211%, respectively, of control values. While haloperidol withdrawal decreased tyrosine hydroxylase activity, it produced no further change in glutamic acid decarboxylase activity and gamma-aminobutyric acid. 4. Daily injection of bromocriptine (2 mg/kg, i.p.) for 5 days in haloperidol-withdrawn rats decreased locomotor activity and dopamine release as evidenced by increased endogenous levels of dopamine and decreased homovanillic acid in striatum of rats. No further increase in striatal glutamic acid decarboxylase activity and GABA levels were reported after bromocriptine treatment. 5. Our data suggest that bromocriptine may elicit its beneficial effect in tardive dyskinesia patients by modifying dopamine turnover in the striatum.

Animals↗
PubMed1982

Time-dependent changes in plasma prolactin level and stress controllability in rats.

1. Numerous studies have shown the importance of controllability factors in the neurochemical, hormonal and behavioural changes associated with presentation of stress stimuli. 2. Previous work from our laboratory revealed that animals exposed to escapable shock had significantly higher prolactin levels than those treated with inescapable shock. 3. The present experiment examined the time-course of plasma prolactin change as a function of shock controllability. 4. Rats were exposed to intermittent escapable, inescapable or no shock for 5, 10, 30 or 60 min and sacrificed for plasma prolactin determination. Additional groups received 60 min shock condition followed by 30 or 60 min rest period prior to sacrifice. 5. Results showed that subjects exposed to 5, 10 or 30 min of escapable shock exhibited higher prolactin levels than inescapable shock or no-shock treated animals. These findings show that the prolactin response to stress is sensitive to controllability factors and is time-dependent.

Animals↗