Central Catecholamine Depletion Research Articles

Differential effects on body weight of central 6-hydroxydopamine lesions in obese (ob/ob) and diabetes (db/db) mice.

Obese (ob/ob) and diabetes (db/db) mice are genetic mutants that have been shown to have altered levels of central catecholamines as well as syndromes of obesity, hyperphagia, and hyperglycemia. Because of catecholamines, and particularly norepinephrine (NE), are implicated in the control of feeding, levels of central catecholamines were experimentally reduced in ob/ob and db/db mice to investigate the role of the catecholamines in these cases of spontaneously occurring obesity. Lesions produced by 6-hydroxydopamine (6-OHDA) were used to produce large depletions of NE and dopamine (DA) in both ob/ob and db/db mice and in lean control mice of the same background strains. In the db/db but not the ob/ob, central catecholamine depletion was accompanied by a significant and persistent weight loss and by a reduction in plasma glucose levels when compared with vehicle-infused controls. Treatment with the NE uptake blocker desmethylimipramine (DMI) prior to 6-OHDA infusions attenuated NE but not DA depletion. Diabetes mice that received DMI pretreatment showed a weight loss and decrease in plasma glucose proportional to the amount of NE depletion. Lean mice that received the 6-OHDA treatments showed only a transient weight loss and no significant change in blood glucose. It is concluded that abnormalities in central noradrenergic systems may account for part of the obesity syndrome observed in the diabetes mouse.

Effects of extended training on rats depleted of central and/or peripheral catecholamines

Thirty-two Wistar rats were used to investigate the effects of extended training on avoidance performance of rats depleted of Catecholamines. They were injected with 6-hydroxydopamine either (i) intracisternally, (ii) intraperitoneally, or (iii) both IP and IC, and trained on a two-way shuttlebox avoidance task. The results on peripheral noradrenaline depletion led to the conclusion that extended training ameliorates the observed behavioural deficit significantly back to the level of controls. The conclusion that is indicated by the present central catecholamine depletion are: (i) central catecholamine depletion has long term effect on behavioural deficit, (ii) central depletion is more detrimental to avoidance learning than peripheral depletion, and (iii) plasma corticosterone plays no significant mediating roles.

Central catecholamine and peripheral noradrenaline depletion: Effects of one-way trace-conditioning

The present study evaluated the differential contributions of the central and peripheral catecholaminergic systems in aversive learning using trace-conditioning procedure. Twenty-seven male Wistar rats were randomly assigned to one of the three groups: central drug and peripheral saline (C DP S) injections, central saline and peripheral drug (C SP D) injections, and central saline and peripheral saline (C SP S) injections. Results showed that: (1) the rate of acquisition and the overall avoidance responses for the drug treated groups was significantly poorer than the control group; (2) there was no significant difference in performance between the two drug treated groups; and, (3) neither central nor peripheral catecholamine depletion had a significant effect on the secretion of plasma corticosterone. The findings failed to confirm the hypotheses (1) that central CA depletion is more detrimental than peripheral NA depletion, (2) that plasma 11-OHCS plays a mediating role in the acquisition of avoidance and escape responses in rats depleted of catecholaminergic systems.

Central catecholamine and peripheral noradrenaline depletion by 6-hydroxydopamine and active avoidance learning in rats.

Three experiments are reported on the relation among catecholamine (CA) depletion, plasma corticosterone (11-OHCS) levels, and active aversive learning. A baseline study showed no significant relation beteen resting levels of 11-OHCS and central and/or peripheral CA depletion. On a two-way avoidance learning task, depletion of brain CAs produced a widespread learning deficit. When both central and peripheral CAs were depleted, only escape learning emerged. Similar effects occurred on a one-way task, but differences were not so marked. The findings are discussed in terms of a theory of CA-dependent cues.

6-Hydroxydopamine destruction of central adrenergic neurones prevents or reverses developing DOCA-salt hypertension in rats

The role of brain catecholaminergic neurones in the pathogenesis of DOCA-salt hypertension in the rat was investigated by selective depletion of central catecholamines using intraventricular or intracisternal administration of 6-hydroxydopamine (6-OHDA). Only the intraventricular injections prevented the development of hypertension. In addition, intraventricular 6-OHDA reversed the hypertension produced by two weeks but not six weeks of DOCA-salt treatment. The ability of intraventricular injections of 6-OHDA to prevent or reverse DOCA-salt hypertension while intracisternal injections do not, appears to be related to the greater depletion of brain catecholamines produced by the intraventricular injections. Only in the spinal cord and in the locus coeruleus were the norepinephrine contents depleted equally by either injection route. These findings suggest that central catecholaminergic neurones other than those originating in the locus coeruleus or descending in the spinal cord are important in the initiation, but not in the long term maintenance, of DOCA-salt hypertension. The influence of the central catecholamine neurons involved in the development of DOCA-salt hypertension might be mediated neurally via nonadrenergic pathways or hormonally via the brain-pituitary-endocrine system.

Central mechanism of vasopressin-induced changes in antidiuretic hormone release.

1. Intracerebroventricularly (i.c.v.) administered vasopressin (0.001-1.0 u) in dogs anaesthetized with chloralose produced adose-dependent increase in urine flow with a concomitant decrease in the levels of antidiuretic hormone (ADH) in jugular vein blood. 2. Higher doses of vasopressin (1.5-2.0 u, i.c.v) on the other hand had an antidiuretic effect and produced an increase in blood ADH level. 3. Pretreatment (i.c.v.) with a beta-adrenoceptor antagonist completely blocked the diuretic response of low doses of vasopressin (i.c.v.) but did not influence the antidiuretic response obtained with high doses. 4. Repeated administration of vasopressin (1.0 u, i.c.v.) induced tachyphylaxis; central catecholamine depletion with tetrabenazine significantly inhibited the vasopressin-induced diuretic response. 5. It is concluded that intracerebroventricular vasopressin-induced changes in ADH secretion are mediated through the release of catecholamines in the central nervous system.

Prevention of hypertension in the SH rat: effects of differential central catecholamine depletion.

Six-hydroxydopamine (6-OHDA) was administered intraventricularly to 6-week-old male spontaneously hypertensive (SH) rats of the Okomoto strain and to normotensive rats of the Kyoto-Wistar strain. In addition, bilateral lateral tegmental lesions were placed in 35-40-day-old SH rats to interrupt ascending noradrenergic pathways. SH rats treated with 6-OHDA did not develop hypertension and had lower heart rates than control rats. Blood pressure and heart rate of Kyoto-Wistar animals were unaffected by the drug treatment. 6-OHDA produced widespread depletion of norepinephrine throughout the CNS of both SH and Kyoto-Wistar rats. Bilateral lateral tegmental lesions interrupted the dorsal noradrenergic bundle and depleted forebrain norepinephrine. These lesions did not prevent the development of hypertension and led to an increased heart rate. It is concluded that 6-OHDA does not produce its effect through a nonspecific lowering of blood pressure, but rather, that it interferes with the expression of the hypertensive syndrome. The lack of effect seen following depletion of forebrain norepinephrine as the result of interruption of the dorsal noradrenergic bundle indicates that the fibers destroyed by this lesion are not essential for the development of genetically determined hypertension.

Effects of 6-hydroxydopamine and alpha-methyl-para-tyrosine on the acoustic startle response in rats

The acoustic startle response was measured in rats after depletion of central catecholamines either chronically (through intraventricular injection of 6-hydroxydopamine) or acutely (through intraperitoneal injections of alpha-methyl-para-tyrosine). Chronic depletion resulted in an augmented startle response which could not be attributed to a failure of habituation or enhanced sensitization, while acute depletion depreseed startle amplitude. The results were interpreted as evidence that catecholamines normally exert a facilitatory influence on the startle response and that the enhanced response seen in the chronically lesioned animal reflects the potentiation of the role of catecholamine-containing neurons through the development of denervation supersensitivity. This interpretation is consistent with other observations which suggest that catecholamines play a general role in modulating thresholds to aversive events.

Differential effects of reserpine and alpha-methyl-P-tyrosine on norepinephrine and dopamine induced behavioral activity.

The locomotor activity of rats was monitored during the intraventricular infusion of either dopamine or norepinephrine after intraperitoneal pretreatment with saline, reserpine (5.0 mg/kg), or acute and chronic alpha-methyl-p-tyrosine (125 mg/kg-1 or 8 days). While the hyperactivity produced by norepinephrine was potentiated 24 h after reserpine, the response to dopamine was reduced by reserpine. Chronic, but not acute, alpha-methyl-p-tyrosine enhanced the effect of norepinephrine without altering the dopamine-induced activity. These results indicate: 1. dopamine-induced hyperactivity is due to its conversion to norepinephrine, and 2. prolonged depletion of central catecholamines may result in post-synaptic receptor supersensitivity.

Analysis of the action of m-tyrosine on blood pressure in the conscious rat: evidence for a central hypotensive effect.

Abstract Mean arterial blood pressure was recorded through indwelling arterial catheters in conscious normotensive rats. dl-m-Tyrosine, 400 mg/kg, was given intraperitoneally alone and after pretreatment with two inhibitors of dopa decarboxylase [dl-α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485) or N1-(dl-seryl)-N2-(2,3,4-trihydroxybenzyl)hydrazine (Ro 4–4602)]. dl-m-Tyrosine alone produced a hypertensive response, but after MK 485 it caused a significant lowering of blood pressure after 5–7 min and after Ro 4–4602 (400 + 200 mg/kg) it had no significant influence on blood pressure. The hypotensive response to dl-m-tyrosine was not influenced by the central dopamine receptor blocking agent spiroperidol (0·1 mg/kg) or by pretreatment with the tyrosine hydroxylase inhibitor H 44/68 (250 mg/kg). However, the depressor action could be completely inhibited after depletion of central catecholamines by α-methyl-m-tyrosine, 400 + 400 + 200 mg/kg, in combination with H 44/68, 250 mg/kg. Further, the depressor action was abolished by the dopamine β-hydroxylase inhibitor bis (4-methyl-1-homo-piperazinyl-thiocarbonyl) disulphide (FLA-63) 40 mg/kg. In correlative biochemical experiments the concentrations of the decarboxylation products of m-tyrosine were measured in brain and heart. dl-m-Tyrosine alone produced an accumulation of m-tyramine and m-octopamine in these tissues. MK 485 + m-tyrosine substantially reduced the levels of m-tyramine and m-octopamine in the heart, but their accumulation in brain was largely unaltered. The results suggest that when decarboxylation of dl-m-tyrosine occurs in both the central and peripheral nervous system, there is a pressor action. When decarboxylation occurs mainly in the central nervous system there is a hypotensive response which is associated with accumulation of decarboxylation products of m-tyrosine.