R.B. Rastogi

CADMIUM ALTERS BEHAVIOUR AND THE BIOSYNTHETIC CAPACITY FOR CATECHOLAMINES AND SEROTONIN IN NEONATAL RAT BRAIN

Abstract— Daily exposure to cadmium (10 μg/100g) for 30 days since birth significantly increased spontaneous locomotor activity as well as striatal tyrosine hydroxylase and mid‐brain tryptophan hydroxylase. The endogenous levels of norepinephrine, dopamine and serotonin failed to change in various brain regions of cadmium‐treated rats. In contrast, the concentration of 5‐hydroxyindoleacetic acid tended to rise but was significantly different from controls only in the mid‐brain region. The data suggest that cadmium treatment in early life increased the synthesis and physiological utilization of these putative transmitters which in turn probably altered locomotor performance.

Brain biogenic amines and altered thyroid function.

Abstract Evidence has been presented that alterations in thyroidal status produce marked changes in the metabolism of several biogenic amines in developing brain. Neonatal hypothyroidism induced either by 131I or by an anti-thyroid agent, methimazole, markedly decreased the concentrations of norepinephrine, dopamine and 5-hydroxytryptamine and the activity of their rate-limiting enzymes, tyrosine hydroxylase and tryptophan hydroxylase. However, the levels of 5-hydroxyindoleacetic acid, the chief metabolite of 5-hydroxytryptamine were elevated in several regions of the brain. Whereas thyroid deficiency in early life produced no appreciable change in whole brain monoamine oxidase activity, it was increased in mid brain and decreased in the hypothalamus. Brain acetylcholine levels were significantly elevated and the activity of acetylcholinesterase remained unchanged in rats made hypothyroid at 1 day of age. Delaying thyroidectomy for 20 days after birth produced less appreciable changes in norepinephrine and 5-hydroxytryptamine metabolism. Thyroid deficiency suppressed the ontogenesis of behavioural arousal and spontaneous locomotor activity. The administration of L-triiodothyronine to hypothyroid animals in early life restored the metabolism of various neurohumors virtually to the normal limits. However, when the replacement therapy was postponed until adulthood, L-triiodothyronine failed to produce any restorative effects, suggesting that a critical period exists in early life during which thyroid hormone must be present to permit normal developmental pattern of central amines. Data also have been obtained demonstrating that neonatal hyperthyroidism induced by daily administration of L-triiodothyronine results in an increased turnover of norepinephrine and 5-hydroxytryptamine. These amine changes were accompanied by a marked rise in the spontaneous locomotor activity in hyperthyroid rats. Finally, chronic treatment with lithium, an antimanic drug, also known to suppress thyroid hormone production, significantly decreased not only the spontaneous locomotor activity, but also changes in the turnover of 5-hydroxytryptamine and norepinephrine in neonatally hyperthyroid rats.

EVIDENCE FOR THE ROLE OF ADRENOCORTICAL HORMONES IN THE REGULATION OF NORADRENALINE AND DOPAMINE METABOLISM IN CERTAIN BRAIN AREAS

1 Bilateral adrenalectomy suppressed body growth and increased the activity of tyrosine hydroxylase in rat striatum in a time‐dependent manner. Fifteen days after adrenalectomy, the concentrations of noradrenaline were decreased significantly in hypothalamus and striatum, as were those of dopamine in brain stem and striatum. 2 Catechol‐O‐methyltransferase failed to change in response to adrenalectomy, but the activity of monoamine oxidase in cortex was significantly increased 7 days after surgery. These changes in various neurochemical parameters were even more pronounced 15 days after adrenal ablation. 3 Administration of corticosterone (10 mg/kg i.p.) to adrenalectomized rats effectively reversed the observed effects on brain amine metabolism. Corticosterone treatment for 7 days beginning from the 8th day of adrenalectomy virtually restored the concentrations of noradrenaline and dopamine as well as the activities of striatal tyrosine hydroxylase and cerebrocortical monoamine oxidase to the values seen for sham‐operated controls. 4 Our data suggest that changes seen in brain noradrenaline and dopamine of adrenalectomized rats are specific to adrenocortical steroids and that these hormones play a role in the regulation of catecholamine formation.

Evidence for the role of brain biogenic amines in depressed motor activity seen in chemically thyroidectomized rats.

Abstract— The effects of exposure to an antithyroid drug, methimazole, on brain tyrosine hydroxylase and tryptophan hydroxylase activity, as well as the levels of norepinephrine, dopamine, 5‐hydroxytryptamine and 5‐hydroxyindoleacetic acid have been investigated in maturing brain. Daily treatment of neonatal rats with methimazole for 30 days induced chemical thyroidectomy as evidenced by significant impairment of body and brain growth. The activities or brain tyrosine hydroxylase and tryptophan hydroxylase and the levels of norepinephrine, dopamine and 5‐hydroxytryptamine were markedly altered in a dose‐ and time‐dependent manner in methimazole‐treated rats. Conversely, the concentration of brain 5‐hydroxyindoleacetic acid was elevated (46%) by methimazole administration. Treatment with the antithyroid drug failed to exert any significant effect on the endogenous levels of brain tryptophan, as well as on the activity of the deaminating enzyme, monoamine oxidase. Administration of triiodothyronine (25 or 100 μg/100 g) to hypothyroid rats for 30 days did not produce any appreciable effect upon the neurochemical parameters related to either norepinephrine or 5‐hydroxytryptamine mctabolism. However, increasing the dose of triiodothyronine to 250 μg/100 g significantly elevated the levels of norepinephrine and 5‐hydroxytryplamine as well as the activities of the two synthesizing enzymes, tyrosine hydroxylase and tryptophan hydroxylase. Brain 5‐hydroxyindoleacetic acid levels were restored to normal values in thyroid hormone‐deficient rats treated with this higher dose of triiodothyronine. Evidencc also was obtained to show that chemical thyroidectomy suppressed the spontancous locomotor activity in neonatal rats; the changes being apparent at 15 days of age. Our data support the view that thyroid hormone in neonatal life displays an important regulatory effect on the metabolism of norepinephrine, dopamine and 5‐hydroxytryptamine. Since certain amines have been known to be implicated as the neurochemical substrates for behavioural arousal, it is conceivable that the observed hypoactivity in methimazolc‐treated rats may, at least in part, be related to impaired maturation of norepinephrine and dopamine‐synthesizing systems in brains of cretinous rats.

Effects of acute diazepam and clobazam on spontaneous locomotor activity and central amine metabolism in rats.

Abstract Following 2 h after a single injection of diazepam ( 10 mg/kg) although no effect was found on tyrosine hydroxylase in striatum (a region abundant in dopaminergic nerver endings), its activity in pons-medulla, a region known to be rich in noradrenergic cell bodies, was enhanced by 17%. Diazepman elevated the levels of norepinephrine and dopamine in several brain regions. However, it decreased the concentration of homovanillic acid and augmented that of 3,4-dihydroxyphenlacetic acid, an intraneuronal metabolite of dopamine, suggesting that this anti-anxiety agent reduced the neuronal release of dopamine and possible norepinephrine. The enhanced activity of tyrosine hydroxylase in pons-medulla appears to reflect a specific compensatory response to the postulated low levels of catecholamines in the synaptic clefts. Acute diazepam treatment decreased tryptophan hydroxylase activity and the endogenous levels of its substrate, tryptophan in mid-brain region; however, the levels of 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid were markedly increased in hypothalamus, mid-brain and pons-medulla, suggesting that diazepam decreased the synthesis as well as the neuronal release of 5-hydroxytryptamine. Clobazam ( 10 mg/kg) which is a 1,5-benzodiazepine, failed to exert any significant effect on behavioural activity and catecholamine metabolism although like diazepam, it also enhanced the levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. It is suggested that whereas diazepam may exert its behavioural suppressant effect by reducing the turnover of actecholamine, its anxiolytic action may be related to decreased turnover of brain 5-HT.

Adrenocorticoids control 5-hydroxytryptamine metabolism in rat brain.

The influence of surgical adrenalectomy was examined on the biosynthetic capacity for 5-hydroxytryptamine of rat brain. The results demonstrate that adrenalectomy decreased tryptophan hydroxylase activity and its substrate tryptophan in the brain stem. A parallel change in the concentration of 5-hydroxytryptamine was seen in brain stem and striatal region of adrenalectomized rats. In contrast, the level of 5-hydroxyindoleacetic acid was significantly elevated in both of these brain regions. Replacement therapy with corticosterone (10 mg/kg i.p.) produced time-dependent increases in tryptophan, tryptophan hydroxylase and 5-hydroxytryptamine and decreases in 5-hydroxyindoleacetic acid levels. Alterations in these neurochemical parameters were more conspicuous in adrenalectomized rats receiving corticosterone for 7 days as compared to those given only for 3 days. Our data demonstrate that adrenocortical hormones regulate brain 5-hydroxytryptamine synthesis probably by enhancing both the levels of tryptophan and the activity of rate-limiting enzyme tryptophan hydroxylase. It is postulated that emotional instability seen during altered adrenocortical function might partly be associated with abnormal metabolism of central 5-hydroxytryptamine.

Enhancement of Locomotor Activity and Catecholamine and 5-Hydroxytryptamine Metabolism by Thyrotropin Releasing Hormone

I.p. administration of thyrotropin releasing hormone (TRH) twice daily for 10 days produced a dose- and time-dependent rise in spontaneous locomotor activity of young rats. A significant increase in t

Effects of MK-771, a novel TRH analog, on brain dopaminergic and serotonergic systems

Abstract The effect of acute treatment with MK-771, a thyrotropin-releasing hormone analog, has been investigated on the synthesis and release of dopamine and 5-hydroxytryptamine in rat brain. Single injection of MK-771 in doses of 10 and 15 mg/kg produced a rise in tyrosine hydroxylase activity as well as homovanillic acid level in striatum (a site of nigrostriatal dopamine system) and olfactory tubercles (a site of mesolimbic dopamine system). The dopamine levels remained unchanged (olfactory tubercles, hippocampus) or decreased (striatum, hypothalamus, pons-medulla) after MK-771 treatment. Acute MK-771 injection at the dose of 15 mg/kg increased mid-brain tryptophan hydroxylase activity and tryptophan levels by 26% and 55%, respectively. A consistent increase in the levels of 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid was reported in several brain areas. These data suggest that MK-771 elicits a marked increase in the synthesis and turnover of brain dopamine and 5-hydroxytryptamine.

Alterations in brain norepinephrine and tyrosine hydroxylase activity during experimental hypothyroidism in rats

Abstract The regulatory influence of thyroid hormone on norepinephrine and its synthesizing enzyme, tyrosine hydroxylase, has been investigated in developing rat brain. Ontogenic studies demonstrated that the appearance of brain tyrosine hydroxylase was preceded by that of norepinephrine, since tyrosine hydroxylase activity attained 75% of adult values already at 7 days after birth when the concentration of norepinephrine was only about 40%. Experimental cretinism induced by a single intraperitoneal injection of 200 μCi of131I on the day of birth, led to an impairment of body and brain growth and interfered with the normal developmental increases in both the activity of tyrosine hydroxylase and brain norepinephrine levels. Whereas 50 μCi of131I exerted only little effect, 200 μCi of the radioisotope inhibited the ontogenic increases in tyrosine hydroxylase activity by 31% and norepinephrine levels by 34%. When the process of radiothyroidectomy was delayed for 20 days after birth, significantly smaller decreases were observed in brain norepinephrine and tyrosine hydroxylase. Treatment with L -triiodothyronine of neonatally thyroidectomized rats initiated early in life restored the observed neurochemical changes in norepinephrine metabolism in both time- and dose-dependent manner. However, when the initiation of L -triiodothyronine treatment was delayed until the hypothyroid rats had reached adulthood, this hormone failed to produce any appreciable change in both the brain norepinephrine levels and tyrosine hydroxylase activity. Our findings are consistent with the view that a critical period exists in early postnatal life during which thyroid hormone must be present in order to permit the normal development pattern of brain norepinephrine metabolism. The possibility has also been raised that the depressed behavior seen in hypothyroid rats may be related to reduced levels of norepinephrine at the postsynaptic regions.

Evidence for the role of brain norepinephrine and dopamine in “rebound” phenomenon seen during withdrawal after repeated exposure to benzodiazepines

Abstract The influence of repeated exposure to and subsequent withdrawal from diazepam and bromazepam treatment was studied on precursor tyrosine as well as the levels of norepinephrine, dopamine and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid in rat brain. Administration of diazepam and bromazepam for 22 days suppressed spontaneous locomotor activity to 39% and 51% respectively, but produced no change in body weights and striatal tyrosine levels. Chronic therapy with either of the two anxiolytic agents significantly enhanced the concentration of norepinephrine and dopamine in several regions of the brain examined. In contrast, treatment with these benzodiazephines decreased the levels of striatal homovanillic acid when compared with the control values. Data suggest that these minor tranquilizers may manifest their taming effect by decreasing the physiological release and subsequent lowering of catecholamines in the vicinity of corresponding receptors. Forty-eight hour withdrawal in rats subjected to chronic diazepam and bromazepam treatment elevated the spontaneous locomotor activity by 228% and 153% respectively, the values being significantly greater than even those seen for normal control rats. Furthermore, the levels of norepinephrine and dopamine were significantly decreased in cerebral cortex, hypothalamus, pons-medulla, mid-brain and striatum presumably due to massive release of these neurohumors. Withdrawal from these psychotropic drugs also enhanced the levels of striatal homovanillic acid which is formed as a result of extraneuronal (functional) metabolism of dopamine. The present results may constitute a neurochemical basis for the role of dopamine and possibly norepinephrine in “rebound” phenomenon seen clinically as well as in laboratory animals during the “withdrawal” phase from benzodiazepine therapy.