Central Catecholamine Research Articles

Brain catecholamine alterations accompanying development of anorexia in rats bearing the walker 256 carcinoma

In the present study, the relationship between central catecholamine levels and the anorexia induced by Walker 256 carcinoma was investigated. Results indicate that the anorexia is not due to depletion of central catecholamines. Tumor bearing rats sacrificed at night, when spontaneous food intake is selectively depressed, showed increased norepinephrine levels in the hypothalamus, cortex and hippocampus and increased dopamine levels in the striatum, midbrain, and cortex. Increased nighttime hypothalamic norepinephrine levels were positively correlated with the magnitude of spontaneous food intake in tumor rats.

Central catecholamines mediate different forms of arousal

Central catecholamines mediate different forms of arousal

Pharmacological interference with the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse

The effect of pretreatment with various MAO and catecholamine uptake inhibitors on the MPTP-induced reduction of endogenous catecholamine levels and [ 3H]catecholamine uptake in mouse striatum and cerebral cortex associated with the neurotoxic action of MPTP on dopamine and noradrenaline neurons was investigated. Pargyline and deprenyl almost completely reversed the MPTP-induced reduction of these parameters in both regions while chlorgyline was without effect. Pretreatment with the dopamine uptake inhibitor amfolenic acid preferentially counteracted the depleting effect of MPTP on striatal dopamine levels. The noradrenaline uptake inhibitors desipramine, nortripityline and LY 139603 all antagonized the MPTP-induced reduction of noradrenaline levels in cerebral cortex, while none of these inhibitors affected the action of MPTP on striatal dopamine. The results suggest that MAO-B and the catecholamine uptake system may be critically involved at certain steps in the neurotoxic action of MPTP on catecholamine neurons. The interaction with the uptake mechanism most likely explains the selective neurotoxic action of MPTP on catecholamine neurons.

Chronic salt loading and central adrenergic mechanisms in the spontaneously hypertensive rat.

The effects of chronic salt loading on central adrenergic mechanisms were evaluated in spontaneously hypertensive rats maintained on tap water or 1.2% sodium chloride drinking water for 4 weeks. Basal blood pressure was increased by 10% in the high salt group. Central catecholamines were measured spectrofluorimetrically after cation exchange chromatography. Endogenous levels of noradrenaline (NA) were not influenced by salt loading but the NA turnover (disappearance of NA following synthesis inhibition by alpha-methyltyrosine) was increased in the hemisperes. Central alpha 2-adrenoceptor sensitivity was assessed as the clonidine-induced reduction in blood pressure and as the clonidine-induced deceleration of NA turnover and locus coeruleus (LC) NA cell firing rate (single unit recording). The results were slightly disparate but the unchanged sensitivity of clonidine to reduce LC NA cell firing suggests that there were no alterations in central alpha 2-adrenoceptor sensitivity following a salt load. There were also no changes in alpha 1-adrenoceptor function, which was assessed semiquantitatively as the clonidine-induced increase in flexor reflex activity in spinalized rats. In salt loaded rats there was an enhanced blood pressure and heart rate reduction following ganglionic blockade which may be interpreted as an increased basal sympathetic tone. In the periphery the pressor responses to phenylephrine were increased whereas the chronotropic response to isoprenaline was unchanged. In conclusion, in the spontaneously hypertensive rat on a high salt intake the aggravated development of hypertension was not associated with major changes in central alpha 1 and alpha 2-adrenoceptor mediated functions or in neuronal activity of brain stem NA neurons. There were indications of an increased basal sympathetic tone and increased blood pressure response to pressor substances.

The effect on the development of cerebral vasospasm in the rat of lesioning of the peripheral and central catecholamine systems

An experimental SAH was produced in the rat by the intracisternal injection of blood. The animals were examined with bilateral vertebral angiography or autoradiographic CBF- and CMRgI-studies. A biphasic vasospasm was seen with a maximal acute spasm at ten minutes and a maximal late spasm at two days post SAH. On day two post SAH, CBF studies demonstrated focal low flow areas in the cortex and caudate-putamen. The CMRgI examinations revealed focal areas with deoxyglucose accumulation corresponding to the low flow areas, suggesting an anaerobic glycolysis. Adrenal demedullation did not change the degree of spasm. Cranial sympathectomy reduced the degree of late spasm by about 50%. Lesioning of the ascending CA pathways in the mesencephalon prior to the SAH, prevented the development of both the acute and the late spasm. It also prevented the development of the focal CBF and CMRgI changes.

Postmortem central catecholamines and antemortem cognitive impairment in elderly schizophrenics and controls.

Central catecholamine concentrations were determined in autopsy brain samples from 19 elderly schizophrenic patients and controls. Data from the hypothalamus and nucleus accumbens demonstrate altered catecholamine metabolism associated with cognitive impairment in these subjects. Both loci show decrements of norepinephrine concentrations, while the nucleus accumbens samples also show increased dopamine, dihydroxyphenylacetic acid, and 3-methoxy-4-hydroxyphenylglycol concentrations associated with dementia in these subjects. The data argue for examination of catecholamine metabolism with respect to dementia in a broad range of elderly subjects.

Gastric hypersecretion by intracisteral TRH: Dissociation from hypophysiotropic activity and role of central catecholamine

Y. TACHÉ, D. LESIEGE, W. VALE and R. COLLU, Gastric hypersecretion by intracisternal TRH: dissociation from hypophysiotropic activity and role of central catecholamine, European J. Pharmacol. 107 (1985) 149–155. Intracisternal injection of the TRH analogs, MK 771 (0.01-1 μg) or A 3475 [pGlu-His-(1,3'-dicarboxymethyl)-Pro-NH 2] (0.1-1 μg), dose-dependently stimulated gastric acid secretion in pylorus-ligated rats although A 43475 was devoid of TSH-releasing activity by cultured anterior pituitary cells. Depletion of brain catecholamine by combined administration of the neurotoxic agent, 6-hydroxydopamine, and the catecholamine synthesis inhibitor, α-methyl-ptyrosine, completely abolished intracisternal TRH-induced stimulation of gastric secretion. Blockade of dopamine receptors by intracisternal haloperidol, peripheral depletion of catecholamine by chronic treatment with guanethidine combined with acute adrenalectomy or cervical cord transection at C5 level, did not modify gastric response to TRH. These results suggested that the stimulation of gastric secretion by intracisternal TRH is unrelated to its hypophysiotropic activity and required the integrity of central but not peripheral catecholaminergic system.

Amphetamine-induced enhancement of ethanol consumption: role of central catecholamines.

Rats administered continuous low levels of amphetamine increase their free choice consumption of a 10% ethanol solution. The present experiment sought to determine the roles of central catecholamines in producing this effect by comparing the changes of ethanol consumption in rats implanted with control pellets or amphetamine pellets following intracerebral injections of 2 X 250 micrograms of 6-hydroxydopamine (6-OHDA), 6-OHDA preceded by 25 mg/kg of desipramine (to protect noradrenergic neurons from damage), or vehicle. The increase of ethanol consumption associated with continuous amphetamine administration was prevented by intracerebral 6-OHDA administration, but not by intracerebral 6-OHDA preceded by desipramine. There were no significant changes of ethanol consumption in animals receiving either 6-OHDA regimen followed by control pellet implantation. These data indicate that the increased consumption of ethanol obtained with continuous amphetamine administration is mediated by central noradrenergic systems.

Electrophysiological and neurochemical correlates of the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an agent which produces a parkinsonian syndrome in man. To explore the use of MPTP in a rodent model of parkinsonism, male albino mice (NMRI) were given MPTP (50 mg/kg, s.c.) twice with a 6-8 h interval. Up to 10 weeks after injection, mice were killed and high-pressure liquid chromatography was used to assay dopamine (DA) and noradrenaline (NA) concentrations in various regions of the CNS. At 4 and 10 weeks after injection, DA levels were significantly reduced in occipital cortex (-40%), hippocampus (-30%), and striatum (-60%). NA levels were reduced by 60-80% in frontal and occipital cortex, hippocampus, and cerebellum. Neither DA nor NA concentration was reduced in spinal cord. Dopaminergic denervation was also suggested by electrophysiological data which showed that treatment with MPTP increased the spontaneous discharge rate of caudate neurons and decreased the potency of locally administered phencyclidine, an indirect DA agonist. However, denervation was evidently not complete enough to produce postsynaptic receptor supersensitivity, as MPTP treatment did not increase the potency of locally applied DA, and it did not increase 3H-spiperone binding in striatal membrane preparations. These results suggest that MPTP causes regionally selective and long-term reductions of catecholamine transmission in the CNS of the mouse.

Involvement of central catecholamines in mediation of pressor responses of the rat to carotid occlusion.

Carotid occlusion evoked a pressor response in rats after transection of the spinal cord. Intraventricular pretreatment with 6-hydroxydopamine inhibited the pressor response. The pressor response to occlusion was also diminished by the intraventricular but not by the intravenous injection of guanethidine. Intravenous atropine or mecamylamine, or intraventricular captopril did not affect the pressor response. Thus, it appears that central catecholaminergic mechanisms are involved in the mediation of the pressor response to carotid occlusion.

Chronic Serotonergic Blockade with Ketanserin in the Spontaneously Hypertensive Rat

Spontaneously hypertensive rats were fed ketanserin-enriched (17 mg/100 g) or control chow for 6 weeks. After 6 weeks the blood pressure was reduced (16%). Pressor responses to phenylephrine were not different from control responses, which indicates that at this time the antihypertensive effect was not directly related to an alpha-adrenoceptor blockade. Cardiovascular responses to stress (jet air), baroreceptor sensitivity (bradycardia to phenylephrine), and central catecholamine turnover were unchanged, which supported the view that central mechanisms probably do not contribute to the antihypertensive effects of ketanserin.

Accelerated regeneration of central catecholamine fibers in cat occipital cortex: effects of substance P

Remarkably fast regeneration of central noradrenaline (NA) fibers was recently observed in the 6-hydroxydopamine (6-OHDA)-perfused occipital cortex. In the present study, we found that this reinnervation by NA fibers was further accelerated by substance P (SP) perfused into the fourth ventricle but not by SP directly perfused into the cortex. The site of SP's action is therefore most likely located in the soma-dendritic area of NA cells in the locus coeruleus (LC). The regeneration-stimulating effect of SP seems to be mediated by a process specific to SP, since the similar treatment with bethanechol in place of SP was ineffective.

MPTP alters central catecholamine neurons in addition to the nigrostriatal system

The present studies were undertaken to determine if MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treatment in mice alters catecholamine or serotonin systems of the brain in addition to reported effects on the dopaminergic nigrostriatal system. Male Swiss-Webster mice were injected with 30 mg/kg MPTP daily for three days. Treated and control animals were sacrificed 10 and 24 days after the last injection, and brains were prepared for serotonin immunocytochemistry and catecholamine histofluorescence. MPTP treatment resulted in a reduced number of neurons and a reduced intensity of the fluorescence in the remaining cell bodies of substantia nigra pars compacta. A reduced presence of catecholamine varicosities in the medullary raphe nuclei and the ventromedial reticular formation of the medulla was observed. Immunocytochemical studies revealed no alteration in the number of serotonin positive cell bodies in the dorsal and median raphe nuclei. We suggest that MPTP treatment selectively alters some non-nigrostriatal catecholamine systems of the brain stem in addition to its toxic effects on the dopaminergic nigrostriatal system, while leaving other non-nigrostriatal catecholamine systems intact.

A Role for Amine Accumulation in the Syndrome of Ingestive Deficits following Lateral Hypothalamic Lesions

Lesions of the lateral hypothalamus produce ascending catecholamine neuron degeneration which results in terminal depletion and proximal accumulation above the lesions. The occurrence of deficits in ingestive behaviour has been attributed traditionally to the loss of functional dopamine neurotransmitter in the terminal fields. However, release of functional amines may occur in the lateral hypothalamus at areas of accumulation, to produce at least some of the behavioural symptoms characterizing the lateral hypothalamic syndrome. Recovery from behavioural deficits as a result of various pharmacological treatments, after dopamine-depleting lesions, may be mediated by changes in amine release or modified sensitivity of receptors affected by released amines. We conclude that amine accumulation should be considered when interpreting experiments implicating central catecholamine systems in the control of consumatory behaviour and the regulation of body weight.

Sensation seeking: A comparative approach to a human trait

AbstractA comparative method of studying the biological bases of personality compares human trait dimensions with likely animal models in terms of genetic determination and common biological correlates. The approach is applied to the trait of sensation seeking, which is defined on the human level by a questionnaire, reports of experience, and observations of behavior, and on the animal level by general activity, behavior in novel situations, and certain types of naturalistic behavior in animal colonies. Moderately high genetic determination has been found for human sensation seeking, and marked strain differences in rodents have been found in open-field behavior that may be related to basic differences in brain neurochemistry. Agonistic and sociable behaviors in both animals and humans and the trait measure of sensation seeking in humans have been related to certain common biological correlates such as gonadal hormones, monoamine oxidase (MAO), and augmenting of the cortical evoked potential.The monoamine systems in the rodent brain are involved in general activity, exploratory behavior, emotionality, socialization, dominance, sexual and consummately behaviors, and intracranial self-stimulation. Preliminary studies have related norepinephrine and enzymes involved in its production and degradation to human sensation seeking. A model is suggested that relates mood, behavioral activity, sociability, and clinical states to activity of the central catecholamine neurotransmitters and to neuroregulators and other transmitters that act in opposite ways on behavior or stabilize activity in the arousal systems. Stimulation and behavioral activity act on the catecholamine systems in a brain–behavior feedback loop. At optimal levels of catecholamine systems activity (CSA) mood is positive and activity and sociability are adaptive. At very low or very high levels of CSA mood is dysphoric, activity is restricted or stereotyped, and the organism is unsocial or aggressively antisocial. Novelty, in the absence of threat, may be rewarding through activation of noradrenergic neurons.

Catecholamine synapses and contents in the paraventricular hypothalamic nucleus and nucleus tractus solitarius of DOCA-salt hypertensive rats.

Central catecholamine (CA) neurons in the nucleus tractus solitarius (NTS) and paraventricular hypothalamic nucleus (PVN) were studied in Wistar rats that had been unilaterally nephrectomized. The experimental animals were then treated with deoxycorticosterone acetate (DOCA) and salt water. The control animals were treated with the vehicle and tap water. Blood pressure of animals 4 weeks after DOCA/salt treatment was significantly elevated when compared to control rats. Morphologically, CA terminals showed no noticeable changes in the DOCA/salt hypertensive rats. Furthermore, the density of CA terminals either in the NTS or in the PVN of the DOCA/salt hypertensive rats was not statistically different from that of normotensive controls, suggesting that salt does not cause lesions or destruction of CA terminals. However, an extensive electron-microscopic morphometric analysis indicated that there was an enhancement of CA synaptogenesis (expressed by increased synaptic frequency among all CA boutons labeled with 5-hydroxydopamine) in the PVN, but not in the NTS of DOCA/salt hypertensive rats. In addition, the high-performance liquid chromatography revealed decreased CA contents in the PVN, but not in the NTS, of DOCA/salt hypertensive animals. Since synapses are primary sites for neurotransmitter release, the above results collectively suggest that more CA synapses formed in the PVN may reflect a net CA release from CA terminals resulting in the decreased CA content in the axonal terminals. Such an increased CA release and enhanced CA synaptogenesis may consequently enhance CA function in the PVN of hypertensive rats 4 weeks after DOCA/salt treatment, and relate to the development and/or maintenance of hypertension in the DOCA/salt rats.

Increase of corticotropin-releasing factor staining in rat paraventricular nucleus neurones by depletion of hypothalamic adrenaline.

In response to stress, adrenocorticotropic hormone (ACTH) is released by corticotrophs in the anterior pituitary under the control of several central and peripheral factors including corticotropin-releasing factor (CRF), which was recently isolated from the brain and sequenced. Immunocytochemical studies have shown that most of the CRF-containing cell bodies that project to the median eminence are present in the hypothalamic paraventricular nucleus (PVN). A dense PNMT(phenylethanolamine-N-methyltransferase)-containing fibre network was also observed in the same region--PNMT is the final enzyme in the biosynthesis of adrenaline and has been demonstrated in the brain. In the present study we found an association of adrenergic nerve fibres and CRF neurones by immunohistochemistry using antisera to PNMT and CRF. To examine the functional significance of the adrenergic projection to the PVN, we blocked the synthesis of adrenaline using a specific inhibitor of PNMT. The depletion of adrenaline resulted in an increase in CRF immunoreactivity. The present results suggest that, as well as catecholamines which regulate ACTH release at the anterior pituitary level via a beta 2-adrenergic receptor mechanism, central catecholamines (mainly adrenaline) also affect ACTH release through their action on CRF cells. Peripheral catecholamines seem to have a direct stimulatory effect on the pituitary corticotroph cells, whereas the present findings suggest that central adrenaline-containing neurones have an inhibitory role in the physiological response to stress.

Tolerance following the repeated administration of high doses of phencyclidine: No relation to central catecholamine depletion

The tolerance which develops following the repeated administration of phencyclidine has been attributed to both pharmacological and behavioral adaptations. In the present study, the possibility that neurochemical alterations induced by the repeated administration of phencyclidine might account for some portion of the observed tolerance was examined. Specifically, it was postulated that the repeated administration of high doses of phencyclidine might result in long lasting depletion of central catecholamine stores and that this neurochemical perturbation might result in tolerance to the drug's effects. It was observed that phencyclidine disrupted the performance of rats on a fixed-interval schedule maintained by water presentation. The repeated administration of high doses of phencyclidine (but not of a comparable volume of saline) during a period when subjects were not engaged in the fixed-interval task resulted in the development of a long lasting tolerance, but this tolerance could not be accounted for in terms of a depletion of central catecholamine stores.

Interference of clonidine and alpha-methyl-p-tyrosine with stress and central histaminergic stimulation of the corticosterone response in rats.

In conscious rats clonidine given intracerebroventricularly 1 h prior to a mild stress of immobilization intensified the stress-induced increase of pituitary-adrenocortical response, measured indirectly through corticosterone concentration in blood serum. The corticosterone response to clonidine was abolished by i.c.v. pretreatment of rats with yohimbine, an alpha 2-adrenergic antagonist, and was antagonized by pretreatment with phenoxybenzamine, an alpha 1-adrenergic antagonist. Clonidine intensified also the corticosterone response induced in stressed rats by i.c.v. injected histamine, 2-pyridylethylamine (PEA), a H1-receptor agonist, and dimaprit, a H2-receptor agonist. The depletion of brain catecholamines by alpha-methyl-p-tyrosine (alpha-MT) considerably increased the corticosterone response to stress but did not substantially change the response to histamine, PEA and dimaprit in stressed rats. These results suggest that clonidine increases the corticosterone secretion induced by a mild stress and histamine and histamine H1 and H2 agonists mainly through the activation of central alpha 2-adrenoceptors. The increase by alpha-MT of the stress-induced corticosterone response may indicate the inhibitory role of central catecholamines in the pituitary-adrenocortical response to stress in rats.

Age-related alterations in dopamine and norepinephrine activity within microdissected brain regions of ovariectomized long evans rats

The ability of several stimuli which augment central catecholamine (CA) neuronal activity to reinitiate estrous cycles in old constant estrous (CE) rats suggests CA neuronal function is impaired with advanced age. We examined the effects of age on dopamine (DA) and norepinephrine (NE) levels and turnover rates within microdissected brain regions of previously normally cycling young (3–4 months old) and middle-aged (10 months old) and CE old (20–22 months old) Long Evans 2 weeks after ovariectomy. Steady-state DA concentrations were significantly decreased in old compared to young rats in the nucleus accumbens (34%), anterior hypothalamic nucleus (54%, NHA), neurointermediate pituitary lobe (51%, NIL) and median eminence (74%, ME). The rate constant of DA loss, an estimate of neuronal activity, decreased in old versus young rats only in the preoptic area suprachiasmatica (60%, POAs) and NHA (60%) and was unchanged or augmented in the 7 other regions. In contrast, a decline in DA turnover rate of 29–67% was observed in 6 of 9 regions in middle-aged rats and 45–81% in 5 of 9 regions in old rats. Steady-state NE concentrations similarly were significantly decreased in old versus young rats in the POAs (54%), medial forebrain bundle (44%), nucleus suprachiasmatica (49%) and ME (59%). The rate constant of NE loss progressively decreased with increasing age only in the POAs and was unchanged or augmented in other regions. Turnover rate of NE was decreased from 21 to 98% in 4 of 8 regions from old animals. A strong positive correlation was noted between the rate constant of NE (but not DA) loss measured in young rats and the magnitude of the age-related depletion in NE concentrations within specific brain regions. Collectively these data indicate that with increasing age: (i) CA neuronal function is differentially altered in nuclei located along the preoptico-tuberal pathway; (ii) substantial declines in both DA and NE concentrations are the primary contributor to the reduced amine turnover noted in several of these regions; and (iii) the observed age-related alterations in CA turnover may contribute to impaired LH response and the persistent hyperprolactinemia in old CE rats.