Effects of dopamine β-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice

Bourdelat-Parks, Brooke; Anderson, George M.; Donaldson, Zoe R.; Weiss, Jay M.; Bonsall, Robert W.; Emery, Milburn S.; Liles, L. Cameron; Weinshenker, David

doi:10.1007/s00213-005-0139-8

Cited by 95 publications

(75 citation statements)

References 35 publications

(38 reference statements)

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“…However, the conversion of DA to NE may not be completely efficient, and DBH can become rate limiting when neuronal activity is high or when DBH is genetically compromised or pharmacologically inhibited. Under these conditions (and perhaps others) 'noradrenergic' neurons do appear to release DA (Scatton et al, 1984;Devoto et al, 2001;Weinshenker et al, 2002b;Carboni and Silvagni, 2004;Bourdelat-Parks et al, 2005;Devoto et al, 2005).…”

Section: Nontraditional Ne-da Interactionsmentioning

confidence: 65%

“…Disulfiram inhibits DBH and aldehyde dehydrogenase similarly, with IC 50 values in the low (mM) range for both enzymes (Green, 1964;Mays et al, 1998). Because the rewarding and aversive effects of cocaine are primarily mediated by NE and DA, we (along with others) have proposed that DBH inhibition is likely a key to the success of disulfiram treatment for cocaine dependence (McCance-Katz et al, 1998a, b;George et al, 2000;Petrakis et al, 2000;Bourdelat-Parks et al, 2005;Schank et al, 2006;Sofuoglu and Kosten, 2006).…”

Section: Disulfiram and Cocaine Dependencementioning

confidence: 92%

“…The effects of disulfiram and DBH mutations on catecholamine levels are additive in mice (Bourdelat-Parks et al, 2005), and individuals with low DBH activity are more susceptible to some aversive side effects of disulfiram, including psychosis (Heath et al, 1965;Ewing et al, 1977;Major et al, 1979) and sedation (Ewing et al, 1978). In a recent genotype-controlled pilot study, disulfiram effectively reduced cocaine intake only in individuals carrying at least one low-activity DBH allele (Cubells et al, 2000).…”

Section: Disulfiram and Cocaine Dependencementioning

confidence: 99%

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There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Neuropsychopharmacol

Self Cite

319

277

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Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine b-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.

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Section: Nontraditional Ne-da Interactionsmentioning

confidence: 65%

Section: Disulfiram and Cocaine Dependencementioning

confidence: 92%

Section: Disulfiram and Cocaine Dependencementioning

confidence: 99%

See 1 more Smart Citation

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Neuropsychopharmacol

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319

277

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“…38 Interestingly, disulfiram inhibits DA b-hydroxylase, and the resultant elevation of DA levels and receptor sensitivity can enhance the aversive properties of cocaine. 39 Cocaine and amphetamine boost dopaminergic transmission through the mesolimbic and mesocortical D1 and D2 receptors. [40][41][42] Cocaine primarily exerts its effects by inhibiting DA transporter function, thus blocking DA uptake and prolonging the presence of DA in the extracellular space.…”

Section: Methods and Review Criteriamentioning

confidence: 99%

Insights into pathophysiology of punding reveal possible treatment strategies

Fasano

Petrović²

2010

Mol Psychiatry

111

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Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, nongoal oriented, repetitive activity. Men tend to repetitively tinker with technical equipment such as radio sets, clocks, watches and car engines, the parts of which may be analyzed, arranged, sorted and cataloged but rarely put back together. Women, in contrast, incessantly sort through their handbags, tidy continuously, brush their hair or polish their nails. Punders are normally aware of the inapposite and obtuse nature of the behavior; however, despite the consequent self-injury, they do not stop such behavior. The most common causes of punding are dopaminergic replacement therapy in patients affected by Parkinson's disease (PD) and cocaine and amphetamine use in addicts. The vast majority of information about punding comes from PD cases. A critical review of these cases shows that almost all afflicted patients (90%) were on treatment with drugs acting mainly on dopamine receptors D1 and D2, whereas only three cases were reported in association with selective D2 and D3 agonists. Epidemiological considerations and available data from animal models suggest that punding, drug-induced stereotypies, addiction and dyskinesias all share a common pathophysiological process. Punding may be related to plastic changes in the ventral and dorsal striatal structures, including the nucleus accumbens, and linked to psychomotor stimulation and reward mechanisms. Possible management guidelines are proposed.

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“…Data from male and female mice were combined given that there were no detectable sex differences. Because of breeding technicalities, Dbhϩ/Ϫ mice were used as controls, because they have normal brain NE levels and are behaviorally identical to wild-type (Dbhϩ/ϩ) mice (57,58). Mice were maintained on a mixed C57BL/6J and 129SvEv background.…”

Section: Methodsmentioning

confidence: 99%

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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Effects of dopamine β-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice

Abstract: The data reveal potentially important and apparently additive effects of Dbh genotype and disulfiram administration on PFC catecholamine metabolism. These effects may have implications for genetic control of DBH activity in humans and for understanding therapeutic effects of disulfiram.

Cited by 95 publications

References 35 publications

There and Back Again: A Tale of Norepinephrine and Drug Addiction

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Insights into pathophysiology of punding reveal possible treatment strategies

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

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