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PubMed1971

Depletion of brain noradrenaline and dopamine by 6-hydroxydopamine.

1. After intracisternal administration, 6-hydroxydopamine had a greater effect on brain noradrenaline than on dopamine.2. Administration of two doses of 6-hydroxydopamine increased the depletion of noradrenaline but not of dopamine.3. Small doses of 6-hydroxydopamine decreased the concentration of noradrenaline with little or no effect on dopamine. Tyrosine hydroxylase activity was not reduced with these treatments.4. While pargyline pretreatment offered no advantage in the depletion of brain noradrenaline after 6-hydroxydopamine, depletion of brain dopamine was greatly potentiated by this treatment. The reduction of striatal tyrosine hydroxylase activity observed after 6-hydroxydopamine was also potentiated by pargyline pretreatment.5. The amounts of labelled noradrenaline and dopamine formed from (3)H-tyrosine were greatly reduced by 6-hydroxydopamine treatment. After (3)H-DOPA, formation of noradrenaline was greatly reduced while formation of labelled dopamine was only moderately reduced suggesting that decarboxylation of DOPA can occur in other than catecholamine containing neurones.6. Desmethylimipramine and imipramine inhibited depletion of noradrenaline produced by 6-hydroxydopamine but did not alter depletion of dopamine. Reserpine did not inhibit depletion of catecholamines produced by 6-hydroxydopamine.7. Administration of 6-hydroxydopamine to developing rats lowered both noradrenaline and dopamine concentrations as well as the tyrosine hydroxylase activity in the brains of these animals.

Amphetamine↗
PubMed1988

Involvement of norepinephrine neurons in the hypothermia induced by intracerebroventricular administration of 6-hydroxydopamine in mice, evidenced by antidepressants.

The intracerebroventricular (i.c.v.) administration of increasing doses of 6-hydroxydopamine (6OHDA) (12.5-50 micrograms) induces in mice a dose-dependent hypothermic effect. This hypothermic effect is not affected either by serotonin uptake inhibitors (indalpine, clomipramine, trazodone, fluoxetine) or by dopamine uptake inhibitors (GBR 12783, amineptine). On the contrary, the hypothermia is partly antagonized by norepinephrine uptake inhibitors (desipramine, nomifensine, viloxazine, maprotiline, protryptiline), as well as amfonelic acid. The antagonism elicited by desipramine is observed when the drug is administered intraperitoneally (from 5 mg/kg) or intracerebroventricularly (from 5 microgram per mouse). 6-hydroxydopamine-induced hypothermia is antagonized by imipramine after a time lag of 1 hour; this antagonism lasts 6-11 hours after intraperitoneal administration of the drug (20 mg/kg). The hypothermic effect of 6-hydroxydopamine is diminished by a previous 6-hydroxydopamine i.c.v. administration (50 micrograms, 7 days before), except in mice pretreated with desipramine at the time of the first 6-hydroxydopamine injection. The hypothermic effect is completely abolished by two previous 6-hydroxydopamine i.c.v. administrations (50 micrograms, 7 days interval). It is also decreased in mice receiving DSP4 15 days before testing (50 mg/kg, i.p.). Finally, neither haloperidol (0.5 mg/kg i.p.) nor SCH23390 (100 micrograms/kg s.c.) antagonize 6-hydroxydopamine-induced hypothermia. It is concluded that this effect is largely depending on central norepinephrine neurons.

Animals↗
PubMed1993

Uptake of 5-hydroxydopamine into non-sympathetic nerves of guinea-pig uterine artery in late pregnancy.

Perivascular nerve fibres of the uterine artery of virgin and late pregnant guinea-pigs were examined under the electron microscope following loading with 5-hydroxydopamine, a marker for catecholamine uptake, and immunohistochemistry for dopamine beta hydroxylase, neuropeptide Y, vasoactive intestinal polypeptide, substance P and calcitonin gene-related peptide. Varicosities, loaded with 5-hydroxydopamine labelled vesicles, and immunoreactive axons were counted in whole transverse sections of uterine arteries. Localization of the immunoreactivities in 5-hydroxydopamine-labelled vesicles was also studied. Colocalization of substance P and dopamine beta hydroxylase immunoreactivities was investigated at the light microscopic level. Both total and relative number of varicosities with 5-hydroxydopamine-labelled vesicles in a whole section of the artery increased in late pregnancy (61.2 +/- 10.2 versus 24.5 +/- 3.2 in virgin, representing 35% and 27% respectively, of all varicosities). Also the number of neuropeptide Y, vasoactive intestinal polypeptide, substance P and calcitonin gene-related peptide-immunoreactive axons increased, but their relative proportion remained unchanged. In virgin guinea-pigs only calcitonin gene-related peptide and neuropeptide Y immunoreactivities were associated with varicosities loaded with small dense-cored vesicles, while in late pregnancy 5-hydroxydopamine-labelled vesicles were also seen in a number of vasoactive intestinal polypeptide, substance P and calcitonin gene-related peptide-immunoreactive axons. Double immunolabelling for dopamine beta hydroxylase and substance P immunoreactivity showed that substance P immunoreactivity was not present in dopamine beta hydroxylase-immunoreactive axons of the uterine artery, of neither virgin nor late pregnant guinea-pigs. It is concluded that vascular hypertrophy of the uterine artery in late pregnancy is associated with an increase in the number of perivascular nerve fibres, that involves many, if not all of the subpopulations of neurons supplying the uterine artery. Also 5-hydroxydopamine-labelled varicosities were increased, but the results of the present study indicate that some of the nerve fibres that are able to take up 5-hydroxydopamine in late pregnancy are not sympathetic (i.e. are sensory and/or parasympathetic in origin). The relevance of these findings in pregnancy is discussed.

Animals↗
PubMed1975

Mechanisms of selective depletion of brain regional noradrenaline by systemic 6-hydroxydopamine in newborn rats.

6-Hydroxydopamine injected systemically into newborn rats caused permanent depletions of the noradrenaline content of only certain brain regions. When 6-hydroxydopamine was given i.p. on days 1 and 2 after birth only the cortex, hippocampus and spinal cord were permanently depleted. 6-Hydroxydopamine given on days 9 and 10 after birth caused a permenent depletion predominantly from the cerebellum. Other regions were unaffected or were depleted for 4 days or less. The hypothalamus showed a gradual recovery of noradrenaline levels over a period of more than 20 days after injection, suggesting that only in this region was the apparent lack of effect of 6-hydroxydopamine due to neuronal regrowth. 6-Hydroxydopamine appeared to gain access to all regions except the pons-medulla when injected up to 10 days after birth, since at least temporary effects on noradrenaline storage were observed. 3H-Noradrenaline after i.p. injection was found in similar relative amounts in all brain regions in rats up to 20 days old. Thus regional differences due to age in the ability of 6-hydroxydopamine to reach various brain regions apparently do not explain the selective susceptibility to permenent depletion. It is suggested that the selective depletion must be due to interactions between the maturity of the adrenergic neurones and other factors such as their ability to take up or retain the 6-hydroxydopamine.

Aging↗
PubMed1976

The effects of 6-hydroxydopamine on the appearance of granulated vesicles in glomus cells of the rat carotid body.

The glomus cells of the rat carotid body reveal an intense fluorescence after exposure to paraformaldehyde vapor and contain catecholamines. After initial fixation in glutaraldehyde, many granulated vesicles are seen in the glomus cells. After initial fixation in osmium tetroxide, most of the vesicles are depleted of their dense interiors and granulated vesicles occur infrequently. Administration of 6-hydroxydopamine followed by initial fixation in osmium tetroxide leads to the reapperance of dense interiors in virtually all vesicles. 6-Hydroxydopamine apparently is taken up by the membrane pump of the glomus cell and is incorporated into the amine storage granules, thereby displacing the endogenous monoamines. Osmium tetroxide does not dissolve the 6-hydroxydopamine from the vesicles, as it apparently does for the normal vesicular contents. The 6-hydroxydopamine does not fluoresce, hence 6-hydroxydopamine administration results in a decreased intensity of formaldehyde induced fluorescence in the glomus cells. Administration of reserpine after 6-hydroxydopamine treatment (and subsequent initial fixation in osmium tetroxide) depletes the previously restored dense material from the vesicles of the glomus cells. 6-Hydroxydopamine acts like a monoamine in that it is taken up by the glomus cell, incorporated into the vesicles, and can be depleted from the vesicles by reserpine.

Animals↗
PubMed1993

Effects of neonatal 6-hydroxydopamine injections on glutamate decarboxylase, preproenkephalin and dopamine D2 receptor mRNAs in the adult rat striatum.

The effects of neonatal 6-hydroxydopamine injections on the levels and cellular distribution of glutamate decarboxylase (GAD67), preproenkephalin and dopamine D2 receptor messenger RNAs were studied in the striatum of adult rats. Cerebroventricular injections of 150 micrograms or 100 micrograms of 6-hydroxydopamine to 3-day-old neonate rats resulted in the total disappearance of neurons labeled with a tyrosine hydroxylase probe in sections of the substantia nigra and ventral tegmental area. In the striatum of adults, both doses of 6-hydroxydopamine induced an increase in GAD67 and preproenkephalin mRNA levels compared to controls. A smaller but consistent increase in dopamine D2 receptor mRNA levels was also found on adjacent sections of the striatum only in animals injected with 150 micrograms of 6-hydroxydopamine. Regional analysis of labeling showed that the increased GAD67, preproenkephalin or dopamine D2 receptor mRNA levels occurred in all striatal sectors examined. Emulsion radioautographs confirmed the increased GAD67, preproenkephalin and dopamine D2 receptor mRNA labeling at cellular level. The present study demonstrates that bilateral 6-hydroxydopamine lesions of dopamine neurons in neonate rats are able to induce a long-term and widespread alteration in the expression of genes encoding for GAD67, preproenkephalin and dopamine D2 receptor in the striatum. In view of previous results after 6-hydroxydopamine lesions in adults, it appears that the behavioral differences observed after adult or neonatal 6-hydroxydopamine lesions are accompanied by a similar alteration of GAD67, preproenkephalin and dopamine D2 receptor gene expression in presumed striatal projection neurons.

Animals↗
PubMed1995

Intrastriatal injection of opioid receptor agonists inhibits apomorphine-induced behavior in 6-hydroxydopamine-treated mice.

The effects of intrastriatal (i.st.) injections of mu-, delta-, and kappa-selective opioid receptor agonists on the augmentation of apomorphine-induced behaviors were determined in 6-hydroxydopamine-treated mice by using multidimensional behavioral analyses. 6-Hydroxydopamine (16 mu g/mu l, i.st.) was unilaterally injected into the striatum 30 min after pretreatment with desipramine (25 mg/kg, s.c). Mice were tested 14 days after injection of 6-hydroxydopamine. Apomorphine (0.5 mg/kg, s.c.) produced a marked increase in linear locomotion, contralateral circling and/or rearing behavior in 6-hydroxydopamine- but not vehicle-treated mice. Although the mu-selective opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) (0.1 and 0.3 ng, i.st.) or the kappa-selective opioid agonist dynorphin A-(1-13) (0.1 and 0.3 mu g, i.st.) did not produce any significant effects on behavior, these peptides had an inhibitory effect on the apomorphine (0.5 mg/kg, s.c.)-induced increase in behavioral responses such as linear locomotion, contralateral circling and/or rearing behavior in 6-hydroxydopamine-treated mice. The inhibitory effects of DAMGO (0.3 ng, i.st.) and dynorphin A-(1-13) (0.3 mu g, i.st.) were fully reversed by selective opioid receptor antagonists such as beta-funaltrexamine (5 mu g, i.c.v.) and (--)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorph an (Mr2266) (10 mg/kg, s.c.), respectively. In contrast, the delta-selective opioid receptor agonist [D-Pen2,L-Pen5]enkephalin (DPLPE) (0.03, 0.1 or 0.3 mu g, i.st.) had no marked effects on the apomorphine (0.5 mg/kg, s.c.)-induced behavior in 6-hydroxydopamine-treated mice. These results suggest that the stimulation of mu- and kappa- but not delta-opioid receptors plays an inhibitory role in the behavioral augmentation induced by the activation of postsynaptic dopamine receptors in the striatum sensitized with 6-hydroxydopamine.

Animals↗
PubMed1996

Investigation of 6-hydroxydopamine-induced plasma extravasation in rat skin.

Perfusion of 6-hydroxydopamine into the rat knee and trachea induces plasma extravasation, possibly by tissue-specific mechanisms involving sympathetic and sensory nerves respectively, and we aimed to identify the mediators which contribute to this response in skin. 6-Hydroxydopamine (both hydrobromide and hydrochloride salts), dose dependently increased plasma extravasation into rat dorsal skin, however, when compared to bradykinin or the tachykinin NK1 receptor agonist GR73632, high concentrations of 6-hydroxydopamine (1-10 mumol/site) were required. The response to 6-hydroxydopamine was not inhibited in chemically sympathectomised rats (6-hydroxydopamine, 300 mg/kg i.p. over 7 days) but was significantly reduced by co-administration with the histamine (H1) and the 5-HT receptor antagonists mepyramine and methysergide and in skin sites pre-injected with compound 48/80 (4 micrograms, -18 h) to degranulate dermal mast cells. The response was not inhibited by co-injection of the tachykinin NK1 receptor antagonist SRI40333 or by the cyclo-oxygenase inhibitor indomethacin (5 mg kg-1 i.p., -30 min) except at the lowest dose of 6-hydroxydopamine (1 mumol/site). We conclude that 6-hydroxydopamine is not a potent or selective mediator of increased vascular permeability in rat skin but, at high concentrations, may induce oedema formation via release of vasoactive amines from mast cells, augmented by generation of prostaglandins.

Animals↗
PubMed1995

Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine.

Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease. To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5 and 5.0 micrograms/microliters in 3.5 microliters of saline) were unilaterally injected into the striatum of rats. Animals that received 1.25 to 5.0 micrograms/microliters 6-hydroxydopamine displayed dose-dependent amphetamine and apomorphine-induced circling. 6-Hydroxydopamine also caused dose-dependent reductions in [3H]mazindol-labeled dopamine uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta (up to 93% versus contralateral binding), with smaller losses in the nucleus accumbens, olfactory tubercle and ventral tegmental area. In the substantia nigra pars compacta and the ventral tegmental area, the number of Nissl-stained neurons decreases in parallel with the reduction in [3H]mazindol binding. The reduction in [3H]mazindol binding in the striatum and the nucleus accumbens, and the reduction in [3H]mazindol binding and in the number of Nissl-stained neurons in the substantia nigra pars compacta and the ventral tegmental area is stable for up to 12 weeks after the lesion. Macroscopically, forebrain coronal sections showed normal morphology, except for rats receiving 5.0 micrograms/microliters 6-hydroxydopamine in which striatal cross-sectional area was reduced, suggesting that this high dose non-specifically damages intrinsic striatal neurons. Nissl-stained sections revealed an area of neuronal loss and intense gliosis centered around the needle track, which increased in size with the dose of neurotoxin. Striatal [3H]sulpiride binding was increased by 2.5 micrograms/microliters and 5.0 micrograms/microliters 6-hydroxydopamine, suggesting up-regulation of dopamine D2 receptors. Striatal binding of [3H]CGS 21680-labeled adenosine A2a receptors, but not of [3H]SCH 23390-labeled dopamine D1 receptors, was reduced at the highest dose, suggesting preservation of the striatal intrinsic neurons with the lower doses. This study indicates that intrastriatal injection of different doses of 6-hydroxydopamine can be used to cause increasing amounts of dopamine denervation, which could model Parkinson's disease of varying degrees of severity. Injecting 3.5 microliters of 2.5 micrograms/microliters 6-hydroxydopamine appears to be particularly useful as a general model of early Parkinson's disease, since it induces a lesion characterized by robust drug-induced rotation, changes in binding consistent with approximately 70% dopamine denervation, approximately 19% dopamine D22 receptor up-regulation, negligible intrinsic striatal damage and stability for at least 12 weeks. This study outlines a technique for inducing partial lesions of the nigrostriatal dopamine pathway in rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Pharmacological protection against the cytotoxicity induced by 6-hydroxydopamine and H2O2 in chromaffin cells.

We present in this report the characteristics of the damage induced by 6-hydroxydopamine and H2O2 on bovine chromaffin cells in primary culture. Cytotoxicity was quantified using catecholamine cell contents, lactate dehydrogenase (LDH) release, trypan blue exclusion and morphological appearance. An excellent correlation between these four parameters was found. The cytotoxic effects of 6-hydroxydopamine were Ca(2+)-independent. In spite of this, the Ca2+ channel antagonists R56865 (N-[1-(4-(fluorophenoxy)butyl)]-4-piperidinyl-N-methyl-2-benzo-thiazo lamine) lidoflazine exhibited marked cytoprotective effects against both 6-hydroxydopamine and H2O2. The selective dopamine uptake blocker, bupropion, increased the viability of 6-hydroxydopamine and H2O2-treated cells from 20% to around 80%. Catalase drastically protected against the cytotoxic effects of 6-hydroxydopamine and H2O2. In contrast, desferrioxamine gave better protection against H2O2 cytotoxicity; glutathione and N-acetylcysteine only afforded substantial protection against 6-hydroxydopamine. Three main conclusions emerge from this study. (1st) 6-Hydroxydopamine causes chromaffin cell damage via a mechanism probably related to the production of free radicals, but unrelated to Ca2+ ions. Cytoprotection afforded by R56865 and lidoflazine must be unrelated to their Ca2+ antagonist properties. This suggests a novel component in the cytoprotective mechanism of action of these drugs. (2nd) The strong cytoprotective effects of bupropion seem to be unrelated to its ability to block the plasmalemmal dopamine carrier. (3rd) Bovine adrenal chromaffin cells in primary cultures are a suitable model for adult neurons to study the basic mechanism of cell damage, and to screen new drugs with putative neuroprotective properties.

Acetylcysteine↗
PubMed1998

Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice.

6-Hydroxydopamine is a neurotoxin that produces degeneration of the nigrostriatal dopaminergic pathway in rodents. Its toxicity is thought to involve the generation of superoxide anion secondary to its autoxidation. To examine the effects of the overexpression of Cu,Zn-superoxide dismutase activity on 6-hydroxydopamine-induced dopaminergic neuronal damage, we have measured the effects of 6-hydroxydopamine on striatal and nigral dopamine transporters and nigral tyrosine hydroxylase-immunoreactive neurons in Cu,Zn-superoxide dismutase transgenic mice. Intracerebroventricular injection of 6-hydroxydopamine (50 microg) in non-transgenic mice produced reductions in the size of striatal area and an enlargement of the cerebral ventricle on both sides of the brains of mice killed two weeks after the injection. In addition, 6-hydroxydopamine caused marked decreases in striatal and nigral [125I]RTI-121-labelled dopamine transporters not only on the injected side but also on the non-injected side of non-transgenic mice; this was associated with decreased cell number and size of tyrosine hydroxylase-immunoreactive dopamine neurons in the substantia nigra pars compacta on both sides in these mice. In contrast, superoxide dismutase transgenic mice were protected against these neurotoxic effects of 6-hydroxydopamine, with the homozygous transgenic mice showing almost complete protection. These results provide further support for a role of superoxide anion in the toxic effects of 6-hydroxydopamine. They also provide further evidence that reactive oxygen species may be the main determining factors in the neurodegenerative effects of catecholamines.

Animals↗
PubMed1972

Eating caused by 6-hydroxydopamine-induced release of noradrenaline in the diencephalon of the rat.

1. Although it is well established that exogenous noradrenaline injected into the diencephalon causes the satiated rat to eat, it is not known whether eating may be induced by release of endogenous diencephalic noradrenaline. In the present experiment 6-hydroxydopamine was injected into the diencephalon of the rat to release catecholamines and produce degeneration of catecholamine-containing neurones.2. Injection into the preoptic area of 0.01-16.0 mug of 6-hydroxydopamine caused satiated rats to eat.3. All doses of 6-hydroxydopamine above 0.01 mug produced long-lasting partial depletion of noradrenaline and dopamine in the region of the brain composed of septum, preoptic area and hypothalamus.4. Repeated injections of 8 mug 6-hydroxydopamine at intervals of several days caused progressively less eating.5. Eating in response to 6-hydroxydopamine was inhibited by pre-treatment with desmethylimipramine, or by pre-treatment with the adrenergic blocking agents phentolamine or MJ-1999.6. Water intake after 6-hydroxydopamine was reduced by pre-treatment with desmethylimipramine or MJ-1999 but was enhanced after pre-treatment with phentolamine.7. It is concluded that release of diencephalic catecholamines by injection of 6-hydroxydopamine causes eating in rats and that the catecholamine responsible for eliciting eating is noradrenaline.

Adrenergic beta-Antagonists↗
PubMed1989

6-Hydroxydopamine releases iron from ferritin and promotes ferritin-dependent lipid peroxidation.

Iron was released from ferritin by the catecholamine analog, 6-hydroxydopamine. Iron release was more efficient under nitrogen than in air, suggesting that the hydroquinone has the major role in the process. Superoxide dismutase, alone or in combination with catalase, strongly inhibited 6-hydroxydopamine oxidation and greatly enhanced the amount of ferritin iron release. Catalase alone had a similar, but lesser effect. Iron released from ferritin accelerated the autoxidation of 6-hydroxydopamine. This occurred by a mechanism that was inhibited by a combination of catalase and a chelator, and to a lesser extent by superoxide dismutase. 6-Hydroxydopamine was a good promoter of metal-catalysed lipid peroxidation, and ferritin-iron participated in the process. Superoxide dismutase, and to a lesser extent catalase, stimulated peroxidation catalysed by adventitious levels of iron, but in the presence of ferritin, each enzyme was inhibitory. It appears that the greatly enhanced iron release seen under these conditions accelerated the autoxidation of 6-hydroxydopamine so that less was available to participate in peroxidative reactions. However, when 6-hydroxydopamine autoxidation was prevented by a combination of superoxide dismutase and catalase, lipid peroxidation was also inhibited, suggesting that some intermediate of autoxidation is a further requirement for the process.

Catalase↗
PubMed1978

Nuclear magnetic resonance studies of 6-hydroxydopamine and its interactions with SH-containing model compounds. Evaluation of possible mechanism for neurocytotoxicity.

6-Hydroxydopamine (I) is a well-known neurocytotoxic agent which has become an important tool in many neurochemical studies in recent years. Biochemical investigations of the mechanism of action of 6-hydroxydopamine indicated that this amine binds covalently and irreversibly to proteins. In the present work, molecular properties of 6-hydroxydopamine in aqueous solution such as self-association, ionization, intramolecular conformations, and possible cyclization were investigated using 1H nuclear magnetic resonance spectroscopy. A model study for the interaction of 6-hydroxydopamine with proteins was undertaken by using SH-containing molecules: cysteine, glutathione, and bovine serum albumin. The binding of these compounds to 6-hydroxydopamine was found to cause labilization of the hydrogen attached to C2 of the amine aromatic ring. This effect was interpreted in terms of nucleophilic attack of RS- on C1 of 6-hydroxydopamine. A proposed model for neurocytotoxicity is discussed.

Cysteine↗
PubMed1973

Rapid recovery of vascular adrenergic nerves in the rat after chemical sympathectomy with 6-hydroxydopamine.

1. Twenty-four hours after the last of 4 intravenous doses of 6-hydroxydopamine (2x50 mg/kg on day 1 and 2x100 mg/kg on day 7) a complete impairment of adrenergic nerve function was observed in various organs of the rat.2. A complete recovery of adrenergic nerve function in vascular smooth muscle was observed 7 days after the last dose of 6-hydroxydopamine whilst in non-vascular smooth muscle recovery took between 14 and 21 days.3. On day 8, noradrenaline depletion produced by 6-hydroxydopamine was not as great in vascular tissues, such as the mesentery and renal artery, as in other tissues, such as the heart and salivary glands. Noradrenaline concentrations recovered much more rapidly in vascular than in other tissues.4. Electron microscope studies of small mesenteric arteries showed a complete destruction of adrenergic nerve terminals 24 h after 6-hydroxydopamine (2x100 mg/kg). However, there was a reappearance of growing terminals within 7 days and after 28 days the regrowth of adrenergic nerve terminals seemed complete.5. From the morphological and functional data it is concluded that 6-hydroxydopamine does produce complete destruction of vascular adrenergic nerve terminals. However, these terminals regenerate more rapidly than those in other tissues. This could explain the failure of intravenously administered 6-hydroxydopamine to prevent the development of experimental hypertension in the rat.

Animals↗
PubMed1991

Cholinergic stimulation of substantia nigra: abolition of carbachol-induced eating by unilateral 6-hydroxydopamine lesion of nigrostriatal dopamine neurones.

Microinjection of cholinergic agonists into the substantia nigra is known to elicit increases in eating, drinking and sexual behaviour under appropriate circumstances. It has been suggested that these effects are dependent on stimulation of nigrostriatal dopamine-containing neurones in the substantia nigra pars compacta, but no direct evidence has confirmed this. The present experiment was therefore undertaken to determine whether unilateral lesions of nigrostriatal dopamine neurones made by 6-hydroxydopamine would attenuate or abolish eating in satiated rats elicited by intranigral microinjection of the muscarinic agonist carbachol. Two groups of rats were tested: a 6-hydroxydopamine- and a sham-lesion group. Before lesions were made intranigral microinjection of 0.5 microgram/0.5 microliter carbachol stimulated significantly more eating than control microinjections in both groups. After 6-hydroxydopamine lesions, microinjection of carbachol elicited no more eating than vehicle alone. Rats given sham lesions (ascorbate-saline vehicle only) showed increased feeding to intra-nigral carbachol before and after sham-lesioning. Post-mortem analysis by HPLC was used to determine the concentration of dopamine, DOPAC, HVA, serotonin and 5-HIAA in the lesioned and non-lesioned hemispheres of both 6-hydroxydopamine- and sham-lesioned rats. In caudate-putamen there were significant reductions in the concentration of DA (to 50.03% of the level in control sides), DOPAC (to 49.34%) and HVA (to 63.98%) in the 6-hydroxydopamine-lesioned but not sham-lesioned rats. The concentration of dopamine, DOPAC and HVA were not affected in the nucleus accumbens. The turnover of dopamine (assessed by calculating the ratio of dopamine to DOPAC) in the caudate-putamen but not nucleus accumbens was also altered by the 6-hydroxydopamine lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Foetal nigral cell suspension grafts influence dopamine release in the non-grafted side in the 6-hydroxydopamine rat model of Parkinson's disease: in vivo voltammetric data.

The present study employed differential-pulse voltammetry to assess the influence of foetal ventral mesencephalic grafts on dopamine overflow in the contralateral caudate putamen of the 6-hydroxydopamine rat model of Parkinson's disease. The experimental design involved measurements of dopamine overflow in the grafted and contralateral striatum. Control measurements of dopamine overflow were performed in 6-hydroxydopamine-lesioned rats only and the caudate putamen of normal control rats. Cell suspensions of foetal rat ventral mesencephalic tissue were grafted into the dopamine-depleted caudate putamen of unilaterally 6-hydroxydopamine-lesioned rats. At 6 weeks, animals with functional, mature grafts (as assessed by amphetamine-amplified behavioural asymmetry), were pretreated with pargyline (75 mg/kg i.p.), and both striatal sides were monitored for dopamine overflow for 90 min following amphetamine sulphate administration (5 mg/kg i.p.). The time course of dopamine overflow inside the graft was similar to that in the contralateral caudate putamen of the same animal, the normal control animal and the contralateral caudate putamen of 6-hydroxydopamine-lesioned animals. However, in grafted animals the mean dopamine overflow detected in the contralateral caudate putamen was approximately 34% lower than the concentration of dopamine detected in the contralateral caudate putamen of 6-hydroxydopamine-lesioned control animals and approximately 39% lower than the concentration of dopamine detected in the caudate putamen of the normal control animal. There was no statistical difference in the concentration of amphetamine-induced dopamine overflow between the caudate putamen contralateral to the 6-hydroxydopamine lesion and the caudate putamen of the normal control animal. These data suggest that intrastriatal foetal ventral mesencephalic suspension grafts reduce amphetamine-induced dopamine release in the contralateral non-grafted caudate putamen.

Amphetamine↗
PubMed1996

Sustained increase in rat myocardial alpha 1A-adrenoceptors induced by 6-hydroxydopamine treatment involves a decelerated receptor turnover.

The biochemical mechanisms involved in the alpha 1-adrenoceptor up-regulation and possible changes in subtypes of adrenoceptors in the rat heart after chemical denervation were investigated. The effects of acute 6-hydroxydopamine treatment (two increasing doses 24 h apart) on the pseudo-steady state densities and turnover rates of alpha 1-adrenoceptors were studied in ventricular myocardium of the rat. We have assessed the repopulation kinetics of [3H]prazosin binding sites after irreversible inactivation of alpha 1-adrenoceptors induced by a single dose of phenoxybenzamine (1 mg/kg i.p.) in rats acutely treated either with 6-hydroxy-dopamine or with vehicle (control animals). Seven days after the last administration of 6-hydroxydopamine an enhanced density of [3H]prazosin binding sites (Bmax 58.7 +/- 3.6 fmol/mg protein vehicle-treated rats versus 82.6 +/- 5.3 fmol/mg protein 6-hydroxydopamine-treated rats) was observed. This was not accompanied by changes in the dissociation constant value. Furthermore, the proportion of high affinity sites for WB-4101 was altered (21 +/- 2% versus 72 +/- 3% for animals treated with vehicle and 6-hydroxydopamine, respectively). In rat myocardium, alpha 1-adrenoceptor turnover, evaluated during the 6-hydroxydopamine-induced up-regulation (7-19 days after the completion of treatment with 6-hydroxydopamine) revealed an increase in the half-life of the alpha 1-adrenoceptor (t1/2 of 67.2 h versus 38.7 h in control animals). The present study confirms an increase in alpha 1-adrenoceptors in rat myocardium after chemical denervation and reveals that the effect is almost completely confined to the alpha 1A-adrenoceptor subtype. Furthermore, the up-regulation of alpha 1A-adrenoceptors is the result of a decrease in the cellular processes that control the rate of receptor degradation.

Adrenergic Agents↗