Chronic administration of the selective dopamine uptake inhibitor GBR 12909, but not cocaine, produces marked decreases in dopamine transporter density

Kunko, Paul M.; Loeloff, Richard; Izenwasser, Sari

doi:10.1007/pl00005091

Cited by 33 publications

(19 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The microdialysis findings with modafinil are much like our previous findings with GBR12909 and its analogspretreatment with these drugs substantially reduces DA release produced by intravenous amphetamine or METH (Baumann et al, 1994(Baumann et al, , 2002. Evidence indicates that GBR12909 and related compounds can prevent DA-releasing effects of METH by persistent occupation of DAT sites or internalization of DAT proteins (Kunko et al, 1997;Baumann et al, 2002). Arguably the most intriguing finding reported here is that modafinil pretreatment diminishes METH-induced ambulation.…”

Section: Discussionsupporting

confidence: 83%

Evidence for the Involvement of Dopamine Transporters in Behavioral Stimulant Effects of Modafinil

Żółkowska¹,

Jain²,

Rothman³

et al. 2009

J Pharmacol Exp Ther

171

183

View full text Add to dashboard Cite

Modafinil is prescribed for numerous medical conditions, but the drug's mechanism of action is unclear. Here, we examined the interaction of modafinil with receptors and transporters in vitro and compared pharmacological effects of the drug with those produced by indirect dopamine (DA) agonists 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) and (ϩ)-methamphetamine (METH). Modafinil was screened at various receptors and transporters using binding assays. Transporter-mediated uptake and release were examined in rat brain synaptosomes. Effects of modafinil on motor activity and neurochemistry were determined in rats undergoing in vivo microdialysis in nucleus accumbens. Of the receptors and transporters assayed, modafinil displayed measurable potency only at DA transporters (DAT), inhibiting [ 3 H]DA uptake, with an IC 50 value of 4.0 M. Accordingly, modafinil pretreatment (10 M) antagonized METH-induced release of the DAT substrate [3 H]1-methyl-4-phenylpyridinium. Intravenous modafinil (20 and 60 mg/kg) produced dose-dependent increases in motor activity and extracellular DA, without affecting serotonin (5-HT). Analogous results were observed for GBR12909 (1 and 3 mg/kg), whereas METH (0.3 and 1 mg/ kg) increased DA and 5-HT. Locomotor effects of all drugs were positively correlated with dialysate DA (P Ͻ 0.001). Interestingly, modafinil pretreatment reduced METH-induced ambulation and DA release. Our data show that modafinil interacts with DAT sites in rat brain, a property shared with agonist medications under investigation for treating cocaine dependence. Nondopaminergic mechanisms may also contribute to the pharmacology of modafinil. Finally, the results suggest that modafinil should be tested as an adjunct for treating METH addiction.Modafinil (2-[(diphenylmethyl) sulfinyl] acetamide) is a wake-promoting agent approved for the treatment of narcolepsy (Wise et al., 2007). Recently, modafinil has been prescribed for other psychiatric disorders such as attentiondeficit hyperactivity disorder (Swanson et al., 2006) and cocaine dependence (Dackis et al., 2005). In a clinical laboratory setting, modafinil pretreatment reduces cocaine selfadministration (Hart et al., 2008) and positive subjective effects Malcolm et al., 2006), supporting the utility of the drug as a pharmacotherapy for stimulant addiction. The off-label use of modafinil for treating cocaine dependence is noteworthy because no approved medications

show abstract

Section: Discussionsupporting

confidence: 83%

Evidence for the Involvement of Dopamine Transporters in Behavioral Stimulant Effects of Modafinil

Żółkowska¹,

Jain²,

Rothman³

et al. 2009

J Pharmacol Exp Ther

171

183

View full text Add to dashboard Cite

show abstract

“…Kunko et al (1997) observed that subchronic infusion of GBR12909 in rats (30 mg/kg/day for 7 days), which mimics the administration GBR-decanoate shown herein, dramatically reduces the B max for DAT binding in the striatum and nucleus accumbens. This effect is persistent, lasting several days after the cessation of GBR12909 infusion.…”

Section: Discussionsupporting

confidence: 57%

“…ૺ, P Ͻ 0.05 with respect to preinjection control levels. jpet.aspetjournals.org (Rothman et al, 1991;Rothman and Glowa, 1995;Tella et al, 1996;Kunko et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

Baumann¹,

Ayestas²,

Sharpe³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Methamphetamine abuse is a serious global health problem, and no effective treatments for methamphetamine dependence have been developed. In animals, the addictive properties of methamphetamine are mediated via release of dopamine (DA) from nerve terminals in mesolimbic reward circuits. At the molecular level, methamphetamine promotes DA release by a nonexocytotic diffusion-exchange process involving DA transporter (DAT) proteins. We have shown that blocking DAT activity with high-affinity DA uptake inhibitors, such as 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine (GBR12909), can substantially reduce amphetamine-induced DA release in vivo. In the present study, we examined the ability of a long-acting depot formulation of GBR12909 decanoate (GBRdecanoate) to influence neurochemical actions of methamphetamine in the nucleus accumbens of rats. Rats received single injections of GBR-decanoate (480 mg/kg i.m.) and were subjected to in vivo microdialysis testing 1 and 2 weeks later. Pretreatment with GBR-decanoate produced modest elevations in basal extracellular levels of DA, but not 5-hydroxytryptamine (5-HT), at both time points. GBR-decanoate nearly eliminated the DA-releasing ability of methamphetamine (0.3 and 1.0 mg/kg i.v.) for 2 weeks, whereas methamphetamine-induced 5-HT release was unaffected. Autoradiographic analysis revealed that GBR-decanoate caused long-term decreases in DAT binding in the brain. Our data suggest that GBR-decanoate, or similar agents, may be useful adjuncts in treating methamphetamine dependence. This therapeutic strategy would be especially useful for noncompliant patient populations.

show abstract

“…3 H]dopamine uptake in rat caudate putamen and nucleus accumbens, without changing basal transporter function (Izenwasser and Cox, 1992) or the density of DAT binding sites (Kunko et al, 1997b). Similarly, RTI-117 had no effect on DAT density after a week of continuous infusion.…”

Section: Role Of Dopamine Uptakementioning

confidence: 97%

The role of the dopamine transporter in cocaine abuse

Izenwasser

2004

neurotox res

View full text Add to dashboard Cite

There have been many studies aimed at understanding the role that the dopamine transporter plays in cocaine abuse. Most studies suggest that inhibition of dopamine uptake by cocaine is the primary mechanism by which its behavioral effects are produced. Because of the strong relationship between binding to the dopamine transporter and the behavioral effects of cocaine, the dopamine transporter has on occasion been referred to as the cocaine binding site. Chronic studies using cocaine or selective inhibitors of dopamine, norepinephrine, or serotonin uptake suggest that while a selective dopamine uptake inhibitor can produce sensitization to cocaine, the long-lasting sensitized response to a cocaine challenge observed in cocaine-pretreated rats is due to cocaine's action on a system other than, or in addition to, dopamine. Thus, while dopamine appears to be important for the behavioral effects of cocaine, it appears that neurochemical systems other than dopamine likely play a role in the behavioral effects of chronic cocaine.

show abstract

Chronic administration of the selective dopamine uptake inhibitor GBR 12909, but not cocaine, produces marked decreases in dopamine transporter density

Cited by 33 publications

References 41 publications

Evidence for the Involvement of Dopamine Transporters in Behavioral Stimulant Effects of Modafinil

Evidence for the Involvement of Dopamine Transporters in Behavioral Stimulant Effects of Modafinil

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

The role of the dopamine transporter in cocaine abuse

Contact Info

Product

Resources

About