Quantification of presynaptic α2-adrenoceptors in rat brain after short-term DSP-4 lesioning

Heal, David J.; Butler, Sarah A.; Prow, M. R.; Buckett, W. R.

doi:10.1016/0014-2999(93)90659-6

Cited by 76 publications

(39 citation statements)

References 14 publications

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“…In the latter study, a reduced effect of the a 2 -adrenoceptor antagonist, atipamezole, was found, suggesting a desensitization of a 2 -adrenoceptors. In line with this, three days after the DSP4 injection there was a decrease in the density of cortical presynaptic a 2 -adrenoceptors which was progressively masked by the development of postsynaptic a 2 -adrenoceptor supersensitivity (Heal et al 1993). In another study, a decrease in the affinity of neocortical a 2 -adrenoceptors was also found on the 10th day after DSP4 treatment (Dooley et al 1983a).…”

Section: Discussionsupporting

confidence: 52%

“…Three days after DSP4 treatment, presynaptic markers, e.g. NA uptake sites and a 2 -adrenoceptor densities, were also reduced (Lee et al 1982;Tejani-Butt 1992;Heal et al 1993;Cheetman et al 1996). Evidence of the degeneration of locus coeruleus noradrenergic terminals induced by DSP4 was supported by dopamine-b-hydroxylase immunohistochemical studies Fritschy et al 1990).…”

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confidence: 97%

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Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α₂‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

Prieto

2001

Pharmacology & Toxicology

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N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) induces a degeneration of noradrenergic axons originating in the locus coeruleus. The sensitivity of a 2 -adrenoceptors which regulate the synthesis and release of noradrenaline was investigated in three brain regions which receive an unequal innervation from locus coeruleus, 21 days after DSP4 (50 mg/kg) administration. After giving treated rats a dopa decarboxylase inhibitor, the in vivo tyrosine hydroxylase activity and the tissue concentrations of noradrenaline were also evaluated. Relevant reductions of noradrenaline levels were found in hippocampus and parietal cortex (91% and 77.5%, respectively; PϽ0.001) together with a less pronounced reduction in hypothalamus (32%, PϽ0.01). The administration of the neurotoxin led to decreases of the basal tyrosine hydroxylase activity, determined as the accumulation of 3,4-dihydroxyphenylalanine, in hippocampus and parietal cortex (75% and 50.5%, respectively; PϽ0.001), but not in hypothalamus. The inhibitory effect of clonidine on tyrosine hydroxylase activity was markedly reduced in hippocampus of rats treated with DSP4 (10∫5% vs 57∫3% in the control group, PϽ0.001) but was not changed in parietal cortex and hypothalamus. Moreover, in hippocampus, a lack of functionality of the a 2 -adrenoceptors which regulate K π -evoked [ 3 H]noradrenaline release was determined. However, in cortical synaptosomes the concentration-effect curve for the oxymetazoline shifted to the right. The administration of the neurotoxin did not modify the inhibitory effects of the agonist in hypothalamus. These results support the previously described selectivity of DSP4 for noradrenergic terminals arising from locus coeruleus and suggest a more severe lesioning of the hippocampus than the parietal cortex.

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Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 97%

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α₂‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

Prieto

2001

Pharmacology & Toxicology

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“…The areal density of immunoreactivity at morphologically identifiable synapses is low presynaptically but higher postsynaptically, where it reaches 50%. This observation confirms a previous conclusion that only a minor fraction of α 2 -adrenergic receptors are presynaptic [191]. Moreover, there is a robust expression of α 2 -adrenergic receptors prior to synaptogenesis [192].…”

Section: Intact Cnssupporting

confidence: 91%

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Hertz¹,

Chen²,

Gibbs³

et al. 2004

CDTCNSND

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Considerable attention has recently been paid to astrocyte functions, which are briefly summarized. A large amount of data is available about adrenoceptor expression and function in astrocytes, some of it dating back to the 1970's and some of it very recent. This material is reviewed in the present paper. The brain is innervated by noradrenergic fibers extending from locus coeruleus in the brain stem, which in turn is connected to a network of adrenergic and noradrenergic nuclei in the medulla and pons, contributing to the control of (nor)adrenergic, serotonergic, dopaminergic and cholinergic function, both in the central nervous system (CNS) and in the periphery. In the CNS astrocytes constitute a major target for noradrenergic innervation, which regulates morphological plasticity, energy metabolism, membrane transport, gap junction permeability and immunological responses in these cells. Noradrenergic effects on astrocytes are essential during consolidation of episodal, long-term memory, which is reinforced by β-adrenergic activation. Glycogenolysis and synthesis of glutamate and glutamine from glucose, both of which are metabolic processes restricted to astrocytes, occurs at several time-specific stages during the consolidation. Astrocytic abnormalities are almost certainly important in the pathogenesis of multiple sclerosis and in all probability contribute essentially to inflammation and malfunction in Alzheimer's disease and to mood disturbances in affective disorders. Noradrenergic function in astrocytes is severely disturbed by chronic exposure to cocaine, which also changes astrocyte morphology. Development of drugs modifying noradrenergic receptor activity and/or down-stream signaling is advocated for treatment of several neurological/psychiatric disorders and for neuroprotection. Astrocytic preparations are suggested for study of mechanism(s) of action of antidepressant drugs and pathophysiology of mood disorders.

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“…Shortly after the loss of terminals, a reduction in noradrenergic cell bodies is observed in the LC (Fritschy and Grzanna, 1991). However, with time the remaining noradrenergic neurons in the LC demonstrate sprouting (Fritschy et al, 1990;Fritschy and Grzanna, 1992), and this sprouting may account for the normal levels of α 2 -AR binding sites in the cortex and hippocampus seen in DSP-4 treated rats (Dooley et al, 1983;Hume et al, 1992;Heal et al, 1993;Wolfman et al, 1994). The similarity in noradrenergic sprouting following DSP-4 treatment in rats and the sprouting of noradrenergic neurons in AD and DLB subjects suggests the terminals of noradrenergic neurons in dementia may be destroyed first and then the cell bodies die later.…”

Section: Discussionmentioning

confidence: 99%

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: Evidence of compensatory changes

et al. 2007

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In Alzheimer's disease (AD) there is a significant loss of locus coeruleus (LC) noradrenergic neurons. However, recent work has shown the surviving noradrenergic neurons to display many compensatory changes, including axonal sprouting to the hippocampus. The prefrontal cortex (PFC) is a forebrain region that is affected in dementia, and receives innervation from the LC noradrenergic neurons. Reduced PFC function can reduce cognition and disrupt behavior. Because the PFC is an important area in AD, we determined if noradrenergic innervation from the LC noradrenergic neurons is maintained and if adrenoreceptors are altered postsynaptically. Presynaptic PFC α 2 -adrenoreceptor (AR) binding site density, as determined by 3 H-RX821002, suggests that axons from surviving noradrenergic neurons in the LC are sprouting to the PFC of subjects with dementia. Changes in postsynaptic α 1 -AR in the PFC of subjects with dementia indicate normal to elevated levels of binding sites. Expression of α 1 -AR subtypes (α 1A -and α 1D -AR) and α 2C -AR subtype mRNA in the PFC of subjects with dementia is similar to what was observed in the hippocampus with one exception, the expression of α 1A -AR mRNA. The expression of the α 1A -AR mRNA subtype is significantly reduced in specific layers of the PFC in subjects with dementia. The loss of α 1A -, α 1D -and α 2C -AR mRNA subtype expression in the PFC may be attributed to neuronal loss observed in dementia. These changes in postsynaptic AR would suggest a reduced function of the PFC. Consequence of this reduced function of the PFC in dementia is still unknown but it may affect memory and behavior.

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Quantification of presynaptic α2-adrenoceptors in rat brain after short-term DSP-4 lesioning

Cited by 76 publications

References 14 publications

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α₂‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α₂‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: Evidence of compensatory changes

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Quantification of presynaptic α2-adrenoceptors in rat brain after short-term DSP-4 lesioning

Cited by 76 publications

References 14 publications

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α2‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α2‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: Evidence of compensatory changes

Contact Info

Product

Resources

About

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α₂‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α₂‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain