The origin of the dopamine nerve terminals in limbic and frontal cortex. Evidence for meso-cortico dopamine neurons (original) (raw)
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Brain Research, 1977
The neurotoxic specificity of injections of 6-hydroxydopamine (6-OHDA) into discrete brain regions as a means of destroying catecholamine neurons is not unequivocal. Several authors have reported only minimal non-specific histological changes after injection of 6-OHDA into the substantia nigra 8As, caudate nucleus 8,~1 or the dorsal noradrenergic bundle ~7, while others have observed large necrotic lesions after local 6-OHDA injections 4,'20. Among the factors which can influence the extent of non-specific damage are the parameters of the 6-OHDA injection such as the amount, concentration and injection rate of the 6-OHDA solution e~. The purpose of the present experiments was to determine the neurotoxic specificity of 6-OHDA lesions of the nucleus accumbens and caudate nucleus which we have used in our studies of druginduced motor behaviorsn, la I~L As indices of non-specific tissue damage we have measured the activity of choline acetyltransferase (CAT), k-glutamic acid decarboxylase (GAD) and cyclic AM P phosphodiesterase (PDE) in the injected regions. There have been only a few previous biochemical studies of the specificity of localized 6-OHDA injections into the striatum r~,e~ and in both of these studies 6-OHDA injections were investigated which differ from those which we have used in the amount, concentration and injection rate of the 6-OHDA solution. To our knowledge there have been no previous studies of the specificity of 6-OHDA injections into the nucleus accumbens.
Localization of dopamine receptors in rat brain
Recently, several lesioning techniques have been developed which selectively destroy various neuronal elements. 6-Hydroxydopamine (6-OHDA), has been demonstrated to preferentially destroy catecholamine-containing neurons 22. Injection of 6-OHDA in the lateral hypothalamic area near the substantia nigra (SN), causes degeneration of the nigrostriatal dopamine pathway (NSP). Kainic acid (KA), a neurotoxin, is believed to destroy neuronal cell bodies near the site of injection, while sparing adjacent axons or terminals 4. Both neurotoxins have been extensively employed in order to better understand the mechanisms underlying neurotransmission in the brain.
Destructive action of systemically administered 6-hydroxydopamine on the rat area postrema
Brain Research, 1976
lntracisternal or intraventricular 6-hydroxydopamine (6-OHDA)administration results in the destruction of central noradrenergic elements2,4,5,2L The absence of central noradrenergic degeneration in adult animals after systemic 6-OHDA administration has been attributed to the inability of this drug to pass the blood-brain barrier (BBB)13,15,19. This reasoning is supported by studies demonstrating 6-OHDA toxicity in central noradrenergic neurons following systemic administration to immature animals prior to the establishment of the BBB1,17. There is, however, evidence that the established BBB of the adult does not completely protect central noradrenergic neurons from the degenerative effects of 6-OH DA when administered in high systemic doses (100 mg/kg i.v.) is. Reduction of norepinephrine levels in rat cerebral cortex and spinal cord has been demonstrated is. Ultrastructural evidence of nerve terminal destruction in the intermediolateral column of the spinal cord in adult rats after systemic 6-OHDA (100 mg/kg i.v.) administration has also been reported 24. Therefore, it is possible that 6-OHDA accumulates in the cerebrospinal fluid via passage through CNS structures that are in direct contact with the ventricular system and that appear to lack a BBB. The circumventricular organs (CVO), such as the area postrema (AP), median eminence, pineal and subfornical organ, possess such qualities 1°. With the exception of the median eminence and pineal, little is known of the functional significance of the CVO. The AP is situated in the caudal portion of the medulla near the obex and has been reported to serve several functions. Originally the AP was thought to serve a secretory function or to regulate blood flow 6. However, other investigators t4 have demonstrated that lesions of the AP cured intractible vomiting in humans. Recently, physiological evidence has been presented H, indicating that the AP may be the central site of action for angiotensin. Alternatively, it has been postulated that the AP controls choroid plexus function 2°. From the variety of proposed functions, it would appear that the AP remains incompletely understood. The present study was undertaken to determine whether 6-OHDA is able to exert its toxic effect on the AP when administered systemically in high doses. In this study 12 Sprague-Dawley male albino rats (75-100 g) were used. Eight rats received 6-OHDA. HBr (100 mg/kg i.p., free base) while 4 control rats received
Brain Research, 1977
Slices obtained from the deeper layers of the rat dorsal frontal, parietal and occipital brain cortex were incubated in vitro with 6.25 × 10 -7 M [3H]dopamine (DA), and subsequently superfused and electrically stimulated, while held on quick transfer electrodes, and changes in the efflux of 3H and of the individual amines measured. The separation of the amines, with quantitative recoveries, was performed by chromatography on cation-exchange resins eluted sequentially with water, 1 N HC1 and 6 M urea in 1 N HC1. When no drugs were used, the prestimulation efflux was entirely formed by deaminated metabolites, while following stimulation there was an increase in the efflux of deaminated metabolites, and considerable amounts of [3H]noradrenaline (NA) now appeared. No DA was present in the pre-or poststimulation medium. Similar results were obtained in all the regions studied. When the slices were incubated with 10 -5 M desmethylimipramine (DMI), 10 -~ M nialamide and 10 -4 M tropolone, before and during incubation with [~H]DA, it was observed that, prior to stimulation, the efflux was composed of deaminated metabolites, DA and 3-methoxytyramine (MTA), and following the electrical stimulus there was an increased release of DA, NA and deaminated compounds (in order of decreasing release), while no change in that of MTA was evident. The stimulus-induced release of DA was greatest from frontal slices, intermediate from parietal, and lowest from occipital ones. DMI-resistant uptake of [3H]DA also diminished when passing from frontal to occipital. These findings are interpreted as due to the presence of dopaminergic axon terminals in all the regions studied, but with a density that diminishes in a rostrocaudal direction.
Brain Research, 1999
To investigate within one study regenerative capacities of dopaminergic axons and cell bodies, short and long term recovery of Ž . behavioral and biochemical impairments following a bilateral 6-hydroxydopamine 6-OHDA lesion of the ventral tegmental area Ž . Ž . VTA -nucleus accumbens NAc pathway was investigated in rats. Novelty-induced motility, presynaptic functions and the levels of Ž . dopamine DA and its metabolites were reduced when cell bodies in the VTA or axons in the NAc were lesioned. Spontaneous recovery of the behavioral deficit was observed 4 weeks after a lesion of the NAc. Subsequently presynaptic functions recovered as shown by the Ž .
Journal of Neurochemistry, 1973
Intravenous injection of a large dose of 6-hydroxydopamine (100 mg/kg) to adult rats caused a significant and long-lasting reduction (about 30 per cent) of the in oirro uptake of [3H]NA in the cerebral cortex and spinal cord, while no changes were seen in the hypothalamus. The endogenous NA in whole brain was similarly reduced (about 20 per cent). Fluorescence histochemistry revealed catecholamine accumulations which are degenerative signs, induced by 6-hydroxydopamine, in axons of the dorsal NA bundle innervating the cerebral cortex. It is concluded that the blood-brain barrier in adult rats is not completely protective with respect to the neurotoxic action of systemically injected 6-hydroxydopamine, which can produce degeneration of a significant number of NA nerve terminals in the cerebral cortex and spinal cord. Previous studies have shown that 6-hydroxydopamine caused a permanent and selective degeneration of a large number of central NA nerve terminals when injected systemically up to 1 week after birth, due to an incompletely developed blood-brain barrier. This barrier for 6-hydroxydopamine deveIops between the 7th and 9th day after birth (SACHS, 1973). In the present study 6-hydroxydopamine was found to cause a small transient reduction in I3H]NA uptake in cerebral cortex of rats between 9 and 28 days of age, while in older rats the damage produced by 6-hydroxydopamine was long-lasting. Thus, the NA nerves ascending to the cerebral cortex seem to possess a regenerative capacity to a 6-hydroxydopamine-induced degeneration up to about 28 days postnatally, but which later disappears or is markedly retarded.