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Article ; Online: mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse.

Gaval-Cruz, Meriem / Weinshenker, David

2008 Volume 9, Issue 4, Page(s) 175–187

Abstract: The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps patients reduce alcohol intake. Recent clinical trials, initiated to investigate ... ...

Abstract	The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps patients reduce alcohol intake. Recent clinical trials, initiated to investigate whether disulfiram could be used to treat individuals who abuse both alcohol and cocaine, have indicated that disulfiram effectively decreases cocaine consumption. Yet the ability of disulfiram to curb cocaine intake cannot be explained by the disruption of ethanol metabolism. Here, we synthesize clinical and animal data that point to dopamine beta-hydroxylase inhibition as a mechanism underlying the efficacy of disulfiram in the treatment of cocaine dependence.
MeSH term(s)	Animals ; Clinical Trials as Topic ; Cocaine-Related Disorders/drug therapy ; Cocaine-Related Disorders/enzymology ; Cocaine-Related Disorders/prevention & control ; Disulfiram/therapeutic use ; Dopamine beta-Hydroxylase/antagonists & inhibitors ; Dopamine beta-Hydroxylase/genetics ; Dopamine beta-Hydroxylase/metabolism ; Enzyme Inhibitors/therapeutic use ; Humans ; Secondary Prevention
Chemical Substances	Enzyme Inhibitors ; Dopamine beta-Hydroxylase (EC 1.14.17.1) ; Disulfiram (TR3MLJ1UAI)
Language	English
Publishing date	2008-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2108819-6
ISSN	1543-2548 ; 1534-0384
ISSN (online)	1543-2548
ISSN	1534-0384
DOI	10.1124/mi.9.4.6
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Zs.A 5844: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.

Gaval-Cruz, Meriem / Liles, Larry Cameron / Iuvone, Paul Michael / Weinshenker, David

PloS one

2012 Volume 7, Issue 11, Page(s) e50583

Abstract: The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β- ... ...

Abstract	The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/-) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/-) and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.
MeSH term(s)	Animals ; Cocaine/pharmacology ; Disulfiram/pharmacology ; Dopamine beta-Hydroxylase/antagonists & inhibitors ; Female ; Imidazoles/pharmacology ; Locomotion/drug effects ; Male ; Mice ; Mice, Knockout ; Thiones/pharmacology
Chemical Substances	Imidazoles ; Thiones ; Dopamine beta-Hydroxylase (EC 1.14.17.1) ; Cocaine (I5Y540LHVR) ; Disulfiram (TR3MLJ1UAI) ; nepicastat (VPG12K4540)
Language	English
Publishing date	2012-11-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0050583
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Article ; Online: Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.

Meriem Gaval-Cruz / Larry Cameron Liles / Paul Michael Iuvone / David Weinshenker

PLoS ONE, Vol 7, Iss 11, p e

2012 Volume 50583

Abstract	The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/-) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/-) and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: Dopamine transporter, but not tyrosine hydroxylase, may be implicated in determining individual differences in behavioral sensitization to amphetamine.

Dietz, David M / Tapocik, Jenica / Gaval-Cruz, Meriem / Kabbaj, Mohamed

Physiology & behavior

2005 Volume 86, Issue 3, Page(s) 347–355

Abstract: Repeated administration of psychostimulants, such as amphetamine and cocaine, results in a long-lasting enhancement of behavioral responses elicited by a subsequent challenge injection of these drugs. This phenomenon has been termed behavioral ... ...

Abstract	Repeated administration of psychostimulants, such as amphetamine and cocaine, results in a long-lasting enhancement of behavioral responses elicited by a subsequent challenge injection of these drugs. This phenomenon has been termed behavioral sensitization. A well established model of individual differences based on the locomotor response to a novel environment has been shown to reliably predict the degree of behavioral sensitization to amphetamine. Rats that have high locomotor response in a novel environment (high responders or HR) develop greater behavioral sensitization to psychostimulants when compared to rats that show low locomotor activity in the same novel environment (low Responders or LR). Therefore, this model is ideal to study genetic factors that may underlie behavioral sensitization to psychostimulants. In this study, adult Sprague-Dawley rats were daily injected with amphetamine (1 mg/kg, i.p.) or saline for 9 days. Locomotor activity was recorded every other day. Following a one week-withdrawal a subsequent challenge of a lower dose of amphetamine (0.5 mg/kg, i.p.) was given to all rats (amphetamine pretreated and saline pretreated) and their locomotor activity was recorded. Our results show that HR rats, but not LR rats, develop behavioral sensitization to the locomotor activating effects of amphetamine. Furthermore, only HR rats pretreated with amphetamine exhibited an increase in dopamine transporter mRNA in the ventral tegmental area (VTA) and substantia nigra (SN). Tyrosine hydroxylase mRNA in the VTA and SN was upregulated in both HR and LR rats pretreated with amphetamine when compared to HR and LR rats pretreated with saline. These results demonstrate the existence of individual differences in behavioral sensitization to amphetamine and suggest that dopamine transporter, but not tyrosine hydroxylase, may be a critical factor in the development and expression of behavioral sensitization to the locomotor activating effects of amphetamine.
MeSH term(s)	Amphetamine/pharmacology ; Analysis of Variance ; Animals ; Behavior, Animal/drug effects ; Behavior, Animal/physiology ; Cell Count/methods ; Dopamine Plasma Membrane Transport Proteins/physiology ; Dopamine Uptake Inhibitors/pharmacology ; Exploratory Behavior/drug effects ; In Situ Hybridization/methods ; Individuality ; Male ; Motor Activity/drug effects ; Rats ; Rats, Sprague-Dawley ; Statistics as Topic ; Substantia Nigra/drug effects ; Substantia Nigra/metabolism ; Tyrosine 3-Monooxygenase/physiology ; Ventral Tegmental Area/drug effects ; Ventral Tegmental Area/metabolism
Chemical Substances	Dopamine Plasma Membrane Transport Proteins ; Dopamine Uptake Inhibitors ; Amphetamine (CK833KGX7E) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2)
Language	English
Publishing date	2005-10-15
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2005.08.005
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Article: Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures.

Gaval-Cruz, Meriem / Schroeder, Jason P / Liles, L Cameron / Javors, Martin A / Weinshenker, David

Pharmacology, biochemistry, and behavior

2008 Volume 89, Issue 4, Page(s) 556–562

Abstract: The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine beta-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). ...

Abstract	The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine beta-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh -/- mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh -/- mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh -/- mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh -/- mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.
MeSH term(s)	Alcohol Deterrents/administration & dosage ; Alcohol Deterrents/toxicity ; Animals ; Cocaine/administration & dosage ; Cocaine/metabolism ; Cocaine/toxicity ; Disulfiram/administration & dosage ; Disulfiram/toxicity ; Dopamine beta-Hydroxylase/antagonists & inhibitors ; Dopamine beta-Hydroxylase/deficiency ; Dopamine beta-Hydroxylase/genetics ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; Female ; Imidazoles/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Seizures/chemically induced ; Seizures/enzymology ; Thiones/pharmacology
Chemical Substances	Alcohol Deterrents ; Enzyme Inhibitors ; Imidazoles ; Thiones ; Dopamine beta-Hydroxylase (EC 1.14.17.1) ; Cocaine (I5Y540LHVR) ; Disulfiram (TR3MLJ1UAI) ; nepicastat (VPG12K4540)
Language	English
Publishing date	2008-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2008.02.009
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Zs.A 1060: Show issues

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Article ; Online: PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse.

Keebaugh, Alaine C / Mitchell, Heather A / Gaval-Cruz, Meriem / Freeman, Kimberly G / Edwards, Gaylen L / Weinshenker, David / Thomas, James W

PloS one

2011 Volume 6, Issue 7, Page(s) e22381

Abstract: Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT-deficiency in the mouse does not result in the profound phenotypes such as self-injurious ... ...

Abstract	Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT-deficiency in the mouse does not result in the profound phenotypes such as self-injurious behavior observed in humans, and the genetic basis for this phenotypic disparity between HPRT-deficient humans and mice is unknown. To test the hypothesis that HPRT deficiency is modified by the presence/absence of phosphoribosyltransferase domain containing 1 (PRTFDC1), a paralog of HPRT that is a functional gene in humans but an inactivated pseudogene in mice, we created transgenic mice that express human PRTFDC1 in wild-type and HPRT-deficient backgrounds. Male mice expressing PRTFDC1 on either genetic background were viable and fertile. However, the presence of PRTFDC1 in the HPRT-deficient, but not wild-type mice, increased aggression as well as sensitivity to a specific amphetamine-induced stereotypy, both of which are reminiscent of the increased aggressive and self-injurious behavior exhibited by patients with LND. These results demonstrate that PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse and could therefore have important implications for unraveling the molecular etiology of LND.
MeSH term(s)	Aggression/drug effects ; Amphetamine/pharmacology ; Animals ; Brain/drug effects ; Brain/metabolism ; Dopamine/metabolism ; Fertility ; Genes, Modifier ; Humans ; Hypoxanthine Phosphoribosyltransferase/deficiency ; Hypoxanthine Phosphoribosyltransferase/genetics ; Hypoxanthine Phosphoribosyltransferase/metabolism ; Lesch-Nyhan Syndrome/metabolism ; Male ; Mice ; Mice, Transgenic ; Neurotransmitter Agents/metabolism ; Organ Specificity/drug effects ; Stereotyped Behavior/drug effects ; Survival Analysis
Chemical Substances	Neurotransmitter Agents ; Amphetamine (CK833KGX7E) ; Hypoxanthine Phosphoribosyltransferase (EC 2.4.2.8) ; PRTFDC1 protein, human (EC 2.4.2.8) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2011-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0022381
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Article ; Online: Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.

Gaval-Cruz, Meriem / Goertz, Richard B / Puttick, Daniel J / Bowles, Dawn E / Meyer, Rebecca C / Hall, Randy A / Ko, Daijin / Paladini, Carlos A / Weinshenker, David

Addiction biology

2014 Volume 21, Issue 1, Page(s) 35–48

Abstract: Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. ...

Abstract	Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts DA to NE, increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh -/-) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh -/- animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh -/- MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh -/- MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G-protein coupling in NAc MSNs.
MeSH term(s)	Animals ; Arrestins/drug effects ; Arrestins/metabolism ; Behavior, Animal/drug effects ; Benzenesulfonates/pharmacology ; Chromogranins ; Cocaine/pharmacology ; Dopamine Agonists/pharmacology ; Dopamine Uptake Inhibitors/pharmacology ; Dopamine beta-Hydroxylase/antagonists & inhibitors ; Dopamine beta-Hydroxylase/genetics ; GTP-Binding Protein alpha Subunits, Gs/antagonists & inhibitors ; Locomotion/drug effects ; Mice ; Mice, Knockout ; Neurons/drug effects ; Neurons/metabolism ; Norepinephrine/metabolism ; Nucleus Accumbens/drug effects ; Nucleus Accumbens/metabolism ; Quinpirole/pharmacology ; Receptors, Dopamine D2/agonists ; Receptors, Dopamine D2/metabolism ; Receptors, Dopamine D3/agonists ; beta-Arrestins
Chemical Substances	4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate) ; Arrestins ; Benzenesulfonates ; Chromogranins ; Dopamine Agonists ; Dopamine Uptake Inhibitors ; Receptors, Dopamine D2 ; Receptors, Dopamine D3 ; beta-Arrestins ; Quinpirole (20OP60125T) ; Dopamine beta-Hydroxylase (EC 1.14.17.1) ; Gnas protein, mouse (EC 3.6.1.-) ; GTP-Binding Protein alpha Subunits, Gs (EC 3.6.5.1) ; Cocaine (I5Y540LHVR) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2014-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1324314-7
ISSN	1369-1600 ; 1355-6215
ISSN (online)	1369-1600
ISSN	1355-6215
DOI	10.1111/adb.12174
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Article ; Online: PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse.

Alaine C Keebaugh / Heather A Mitchell / Meriem Gaval-Cruz / Kimberly G Freeman / Gaylen L Edwards / David Weinshenker / James W Thomas

PLoS ONE, Vol 6, Iss 7, p e

2011 Volume 22381

Abstract	Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT-deficiency in the mouse does not result in the profound phenotypes such as self-injurious behavior observed in humans, and the genetic basis for this phenotypic disparity between HPRT-deficient humans and mice is unknown. To test the hypothesis that HPRT deficiency is modified by the presence/absence of phosphoribosyltransferase domain containing 1 (PRTFDC1), a paralog of HPRT that is a functional gene in humans but an inactivated pseudogene in mice, we created transgenic mice that express human PRTFDC1 in wild-type and HPRT-deficient backgrounds. Male mice expressing PRTFDC1 on either genetic background were viable and fertile. However, the presence of PRTFDC1 in the HPRT-deficient, but not wild-type mice, increased aggression as well as sensitivity to a specific amphetamine-induced stereotypy, both of which are reminiscent of the increased aggressive and self-injurious behavior exhibited by patients with LND. These results demonstrate that PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse and could therefore have important implications for unraveling the molecular etiology of LND.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase.

Schroeder, Jason P / Cooper, Debra A / Schank, Jesse R / Lyle, Megan A / Gaval-Cruz, Meriem / Ogbonmwan, Yvonne E / Pozdeyev, Nikita / Freeman, Kimberly G / Iuvone, P Michael / Edwards, Gaylen L / Holmes, Philip V / Weinshenker, David

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2010 Volume 35, Issue 12, Page(s) 2440–2449

Abstract: The antialcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive 'Antabuse reaction' that deters alcohol consumption. Disulfiram ...

Abstract	The antialcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive 'Antabuse reaction' that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram's inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug's ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ∼40%, did not alter the response for food or cocaine on a fixed ratio 1 schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram's efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.
MeSH term(s)	Alcohol Deterrents/pharmacology ; Animals ; Brain/drug effects ; Brain/metabolism ; Cocaine/administration & dosage ; Cocaine/antagonists & inhibitors ; Cocaine/pharmacology ; Conditioning, Operant/drug effects ; Disulfiram/pharmacology ; Dopamine/metabolism ; Dopamine beta-Hydroxylase/antagonists & inhibitors ; Drug Interactions ; Extinction, Psychological/drug effects ; Food ; Imidazoles/pharmacology ; Male ; Norepinephrine/metabolism ; Rats ; Rats, Sprague-Dawley ; Self Administration ; Thiones/pharmacology
Chemical Substances	Alcohol Deterrents ; Imidazoles ; Thiones ; Dopamine beta-Hydroxylase (EC 1.14.17.1) ; Cocaine (I5Y540LHVR) ; Disulfiram (TR3MLJ1UAI) ; nepicastat (VPG12K4540) ; Dopamine (VTD58H1Z2X) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2010-08-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/npp.2010.127
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