Noradrenaline Denervation Research Articles

Functional Consequences of Iron Overload in Catecholaminergic Interactions: the Youdim Factor

The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10-12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20-40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D(2) receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed "the Youdim factor", directing a DA-NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions.

Benzodiazepine binding sites in the cingulate cortex after lesion of the noradrenaline and dopamine containing afferents

The distribution of benzodiazepine binding sites was analysed in the cingulate cortex of the rat brain by quantitative radioautography of brain sections incubated with a full agonist benzodiazepine ligand, 3H-flunitrazepam (3H-FLU), or with a partial agonist with non benzodiazepinic structure, (7-3H)-4hydroxy-N(4,5-dihydroxy-2-thiazolyl)-6 methoxy-3-quinoline (3H-RU 43028), after lesion of noradrenaline (NA) and dopamine (DA) containing afferents to this structure. NA denervation was obtained by systemic administration of N-(2 chlorethyl)-N ethyl-2-bromobenzylamine (DSP4) and destruction of both NA and DA containing afferents was induced by unilateral injection of 6-hydroxydopamine (6-OHDA) in the middle forebrain bundle (MFB). A similar caudo-rostral pattern of distribution was found in the cingulate cortex after incubation with these two ligands which bound a greater number of sites in the anterior portion of the structure. In spite of a very precise anatomical sampling (200 μm intervals along the postero-anterior axis) no significant difference was observed when intact and lesioned brains were compared. It is concluded that benzodiazepine binding sites eventually localized on catecholaminergic afferents to the cingulate cortex do not represent a significant proportion of the total population of these sites in this structure.

Chronic cobalt-induced epilepsy: noradrenaline ionophoresis and adrenoceptor binding studies in the rat cerebral cortex.

Several studies indicate that brain noradrenaline (NA) depletion facilitates the occurrence of epileptogenic syndromes in various animal models. In cobalt-induced epilepsy in the rat activity is associated with a cortical NA denervation. In order to search for cortical adrenoceptor modifications, inonophoretic studies and adrenoceptor binding assays were performed. At the period of maximal seizure activity, there was a significant supersensitivity of cortical neurons to the ionophoretic application of NA. An increase in the density of beta-adrenoceptor binding sites was observed. No modification in alpha 1- and alpha 2-adrenoceptor binding sites was found. This suggests that in cobalt-induced epilepsy there is a denervation supersensitivity which rests on a selective involvement of beta-adrenoceptors.

Effects of the noradrenaline neurotoxin DSP 4 on monoamine neurons and their transmitter turnover in rat CNS.

Regional effects of DSP 4 on monoamine neurons have been analyzed by chemical assay of endogenous monoamines and their metabolites in rat CNS. The results confirmed that the neurotoxic action of DSP 4 is predominantly on noradrenaline nerve terminal projections originating from locus coeruleus, with the most marked effects on terminal fields localized most distant from the noradrenaline perikarya. DSP 4 treatment (10 days) caused no alteration of the regional DA levels, except in cingulate cortex, where a moderate increase (+40%) was observed, possibly at least partially related to a sprouting of dopamine nerve terminals following the noradrenaline denervation. 5-hydroxytryptamine levels were generally unaltered after DSP 4, except for an about 10-25% reduction in cerebral cortex and hippocampus. There was with time a certain noradrenaline recovery, most likely related to regeneration of noradrenaline nerve terminals, although this process was relatively slow (months). Analysis of catecholamine decline after tyrosine hydroxylase inhibition and metabolite/monoamine ratios, as indices for transmitter utilization rate, indicated an increased noradrenaline turnover in terminals spared by DSP 4, while dopamine turnover appeared to be reduced in many regions (i.a. cerebral cortex, striatum, accumbens, olfactory tubercle and spinal cord), most pronounced in cingulate cortex. The results indicate that noradrenaline neurons have a facilitatory action on dopamine neurons. The DSP 4 treatment did not cause any significant effect on 5-hydroxytryptamine turnover in any of the individual regions analyzed.

Modulation of 6-hydroxydopamine induced alteration of the postnatal development of central noradrenaline neurons

The effect of substance P and morphine on the 6-hydroxydopamine (6-OHDA) induced alteration of the postnatal development of central noradrenaline (NA) neurons in the rat has been investigated using neurochemical techniques. Neonatal administration of 6-OHDA systemically leads to permanent NA denervations of distant NA projections, while the projections close to the NA cell bodies are increased, leading to NA hyperinnervation. Intracisternal injection of substance P was found to counteract both the NA denervation and hyperinnervation induced by 6-OHDA. The effect of substance P disclosed a clear dose-dependent relationship. Morphine, on the other hand, was observed to potentiate the alterations induced by 6-OHDA, both the NA denervation and hyperinnervation. The effect of morphine was dose-dependent and could be blocked by the morphine antagonist naloxone. The present results give further support for the view that the 6-OHDA induced alteration of the postnatal development of central NA neurons is related to a “pruning effect.” The data furthermore imply that the end-result from a 6-OHDA induced degeneration of central NA neurons during ontogeny may be modulated by the functional state of the neurons.

Evidence for a neurotropic role of noradrenaline neurons in the postnatal development of rat cerebral cortex.

The effects of neonatal administration of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA; 1-4 doses of 100 mg/kg body weight s.c.) on the postnatal development of pyramidal neurons in several cortical regions of the rat was studied using a Golgi-Cox neuronal impregnation technique. Rats were sacrificed in the adult stage (eight weeks) and the following regions were studied: anterior frontal cortex, posterior frontal cortex (including motor cortex), anterior parietal cortex (including sensory cortex), posterior parieto-occipital cortex and cingulate cortex. Significant alterations were seen in animals which received four doses of 6-OHDA. These alterations can be summarized as follows: (1) a decreased length and branching of basolateral dendrites of pyramidal cells, with loss of dendritic spines, which were found in both the internal pyrimidal layer (layer V) and the external pyramidal layer (layer III), most abundantly in the frontal cortex and cingulate cortex; (2) an increased number of pyramidal cells of layer V with premature apical dendritic termination in layer III rather than the usual termination in layers I and II. This was most abundant in the cingulate cortex; (3) occasional disorientation of pyramidal cell apical dendrites away from the normal vertical plane by 15 or more degrees, seen in frontal, parietal and cingulate cortex; (4) an increased number of pyramidal cells with rounded somatic contours, found in frontal, anterior parietal and cingulate cortex. These phenomena were occasionally seen in normal cortex, but were significantly increased in their occurrence after four doses of 6-OHDA. Such alterations were not significant in rats treated with one or three doses of 6-OHDA. The extent and severity of morphological alterations correlate with reductions in endogenous noradrenaline (NA) in cerebral cortex, which was found to average 50% of control levels after one dose of 6-OHDA, and 80% reduction after three doses, and a 97-98% reduction after four doses, suggesting that the NA denervation must be almost complete to result in readily detectable significant morphological changes in the development of cortical pyramidal cells. No consistent changes in endogenous dopamine (DA) levels were observed, except for an increase in the cingulate cortex. The anatomical alterations in pyramidal cells described in the present study suggest that NA neurons which project into the cerebral cortex have a neurotrophic role in the postnatal development of cortex.