Lesioning of Locus coeruleus Projections by DSP-4 Neurotoxin Treatment: Effect on Amphetamine-Induced Hyperlocomotion and Dopamine D2 Receptor Binding in Rats

Harro, Jaanus; Meriküla, Alar; Lepiku, Martin; Modiri, Ali-Reza; Rinken, Ago; Oreland, Lars

doi:10.1034/j.1600-0773.2000.d01-35.x

Cited by 36 publications

(8 citation statements)

References 36 publications

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“…We propose that under ''basal'' conditions, DbhϪ/Ϫ mice have very little DA signaling, but on those rare occasions that a burst of DA is released in the striatum, the hypersensitive DA receptors cause a hyperdopaminergic response manifesting as a dyskinetic-like movement. In support of this hypothesis, DSP4 lesions produce both DAreceptor hypersensitivity (49) and dyskinesias (this study), and the D1/D2 antagonist flupenthixole partially attenuates dyskinesias in DbhϪ/Ϫ mice. NE replacement with DOPS in DbhϪ/Ϫ mice worsened dyskinesias, probably by acutely restoring normal DA release without normalizing DA-receptor sensitivity.…”

Section: Discussionsupporting

confidence: 56%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

174

116

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Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine ␤-hydroxylase knockout (Dbh؊/؊) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh؊/؊ mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh؊/؊ mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh؊/؊ mice. Finally, striatal levels of phospho-ERK-1/2 and ⌬FosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh؊/؊ mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.dopamine ͉ Parkinson's disease ͉ dyskinesias ͉ dopamine ␤-hydroxylase P arkinson's disease (PD) affects Ϸ1% of the world's aging population (1). Despite this high prevalence and intensive research into its origins, the etiology of PD remains largely unknown. The disease is characterized by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN), and symptoms, which tend to manifest when Ϸ80% of striatal DA is lost, include bradykinesia, postural instability, rigidity, and resting tremor. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, is known to produce parkinsonism in humans and causes severe DA loss in animals (2). Because of its ability to recapitulate the neuropathology of PD, MPTP is used widely in PD research. However, MPTP has been unable to reliably reproduce the motor symptoms of PD in mice, which limits the utility of MPTP-treated mice as an animal model of the disease (3). Differences in mouse strain and experimental paradigms may at least partially account for these inconsistencies.Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4-6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may a...

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Section: Discussionsupporting

confidence: 56%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

174

116

View full text Add to dashboard Cite

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“…It has also been shown that extensive selective lesions of the locus coeruleus projections may reduce the psychostimulant effect of amphetamine in a novel environment (Harro et al, 2000). This strengthens the finding that exposure to a white background sound improves performance in children with ADHD Söderlund et al, 2010aSöderlund et al, , 2010b.…”

Section: Discussionmentioning

confidence: 73%

Abnormal brainstem auditory response in young females with ADHD

Claesdotter-Hybbinette

Safdarzadeh-Haghighi

Råstam

et al. 2015

Psychiatry Research

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“…Third, LRA in DbhϪ͞Ϫ mice is not blocked by prazosin, which would prevent receptor activation by either NE or DA. Fourth, a few studies demonstrate similar changes in DA receptor and amphetamine sensitivity in animals with lesions of the locus coeruleus that do not result in ectopic DA (17,18). However, because ectopic DA remains a possible mechanism, it will be important to examine LRA in mice that lack NE without producing ectopic DA.…”

Section: Discussionmentioning

confidence: 99%

Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals

Weinshenker

Miller

Blizinsky

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

104

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Acute pharmacological blockade of ␣1 adrenoreceptors (ARs) attenuates the locomotor response to amphetamine (LRA). We took a genetic approach to study how norepinephrine (NE) signaling modulates psychostimulant responses by testing LRA in dopamine ␤-hydroxylase knockout (Dbh؊͞؊) mice that lack NE. Surprisingly, Dbh؊͞؊ animals were hypersensitive to the behavioral effects of amphetamine. Amphetamine (2 mg͞kg) elicited greater locomotor activity in Dbh؊͞؊ mice compared to controls, whereas 5 mg͞kg caused stereotypy in Dbh؊͞؊ mice, which is only observed in control mice at higher doses. Prazosin, an ␣1AR antagonist, attenuated LRA in Dbh؉͞؊ mice but had no effect in Dbh؊͞؊ mice. Changes in the sensitivity of dopamine (DA)-signaling pathways may contribute to the altered amphetamine responses of Dbh؊͞؊ mice because they were relatively insensitive to a D1 agonist and hypersensitive to a D2 agonist. Daily amphetamine administration resulted in behavioral sensitization in both Dbh؉͞؊ and Dbh؊͞؊ mice, demonstrating that NE is not required for the development or expression of behavioral sensitization. Daily prazosin administration blunted but did not completely block locomotor sensitization in Dbh؉͞؊ mice, suggesting that ␣1AR signaling contributes to, but is not required for sensitization in Dbh؉͞؊ control animals. We conclude that in contrast to acute ␣1AR blockade, chronic NE deficiency induces changes similar to sensitization, perhaps by altering DA-signaling pathways.A mphetamine is a psychostimulant that is used both recreationally and therapeutically for diseases such as attentiondeficit͞hyperactivity disorder. The primary sites of amphetamine action are monoamine transporters, where it blocks reuptake and facilitates release of dopamine (DA), norepinephrine (NE), and serotonin. Although DA signaling is the focus of most amphetamine research, it is also clear that NE plays an important role in modulating cellular and behavioral responses to psychostimulants. Lesions of the locus coeruleus (the major central noradrenergic nucleus) or administration of prazosin, an ␣1-adrenoreceptor (␣1AR) antagonist, attenuate amphetamine-induced locomotion (1-3). Prazosin decreases burst firing of dopaminergic ventral tegmental area neurons and blocks the excitatory effect of amphetamine on these cells (4-6). Finally, inactivation of the ␣1bAR gene in mice attenuates amphetamine responses (7). These results suggest that NE signaling through ␣1ARs is important for the locomotor and cellular responses to amphetamine.Amphetamine produces behavioral sensitization, an enhancement of the locomotor response after repeated administration, which may model drug craving and psychosis. Sensitization is thought to involve long-term changes in both DA and other signaling pathways (8, 9). Because amphetamine sensitization is blunted in mice lacking ␣1bARs and rats treated with prazosin, ␣1AR signaling may inf luence the neural and behavioral changes that result from chronic psychostimulant use (7, 10).Drug addiction develops over time and is a ...

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Lesioning of Locus coeruleus Projections by DSP-4 Neurotoxin Treatment: Effect on Amphetamine-Induced Hyperlocomotion and Dopamine D2 Receptor Binding in Rats

Cited by 36 publications

References 36 publications

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Abnormal brainstem auditory response in young females with ADHD

Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals

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