Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity

Izenwasser, Sari; French, Dawn; Carroll, F. Ivy; Kunko, Paul M.

doi:10.1016/s0166-4328(98)00104-1

Cited by 36 publications

(20 citation statements)

References 26 publications

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“…The current finding that BUP, DA, and DA + NE reuptake inhibition all transiently increased locomotor activity is consistent with the idea that inhibition of the DA transporter is sufficient to cause a significant short-term increase in locomotion and even reverse the decrease in activity caused by inhibition of NE reuptake. The transient increase in locomotor activity caused by subchronic BUP infusion is identical to the effect caused by subchronic infusion of various selective DA reuptake inhibitors (Izenwasser et al, 1999). A dopaminergic mechanism for increased locomotor activity by BUP is consistent with increased striatal DA concentrations in rats following acute BUP administration (Vassout et al, 1993), the failure of BUP to increase locomotor activity in rats with selective ablation of DA neurons (Cooper et al, 1980), and a recent report by Mitchell et al (2006) demonstrating that acute BUP Figure 6 Effect of subchronic DA and NE reuptake inhibition on daily body weight and food intake.…”

Section: Discussionmentioning

confidence: 75%

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Billes

Cowley

2007

Neuropsychopharmacol

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Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA + NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA + NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA + NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA + NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA + NE reuptake (with GBR + NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.

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Section: Discussionmentioning

confidence: 75%

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Billes

Cowley

2007

Neuropsychopharmacol

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“…The potency difference found in the present study, although not as large as in other studies, is at least consistent with a DA mechanism involved in the reinforcing effect of RTI-117. In the Izenwasser et al (1999) study, there were some qualitative differences in the effects of cocaine and RTI-117. Mechanisms responsible for those differences were not clear, although both pharmacokinetics and pharmacodynamic differences may have contributed.…”

Section: Discussionmentioning

confidence: 91%

“…In vitro, RTI-117 showed approximately 13-fold higher affinity for the dopamine transporter than cocaine. Cocaine and RTI-117 have been compared behaviorally in terms of the effects of chronic administration of locomotor activity in rodents (Izenwasser et al 1999). In that study, RTI-117 was approximately sevenfold more potent than cocaine.…”

Section: Discussionmentioning

confidence: 99%

Self-administration of drug mixtures by monkeys: combining drugs with comparable mechanisms of action

et al. 2007

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Rationale-Abuse of drug mixtures is common. Drug interactions that are super-additive in terms of reinforcing effects may contribute to this phenomenon. Although quantitative methods for assessing drug interactions have been developed, they have not been widely applied to the analysis of reinforcing effects.Objectives-The present experiment was designed to study self-administration of mixtures of drugs with comparable pharmacological mechanisms of action. Our hypothesis was that the drugs would be dose-additive.Materials and methods Rhesus-monkeys prepared with i.v. catheters were allowed to selfadminister cocaine or saline under a progressive-ratio schedule in baseline sessions. When responding was stable, two mu opioid agonists, alfentanil and remifentanil, were tested alone in one group (n=5). Two dopamine (DA) uptake blockers, cocaine and RTI-117 were tested in the other group (n=6). Next, mixtures of doses of the two opioids or the two DA uptake blockers were © Springer-Verlag 2007 Correspondence to: W.L. Woolverton, wwoolverton@psychiatry.umsmed.edu. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2011 June 7.Published in final edited form as:Psychopharmacology (Berl). 2008 March ; 196(4): 575-582. doi:10.1007/s00213-007-0991-9. NIH-PA Author Manuscript NIH-PA Author ManuscriptNIH-PA Author Manuscript tested in approximate 1:1, 1:2, and 2:1 ratios of their ED 50 s. Results were analyzed using isobolographic techniques.Results-All drugs alone and drug mixtures functioned as positive reinforcers in a dose-related manner. There was no difference between experimentally determined ED 50 values and predicted additive ED 50 values for any mixture. Maximum responding maintained by mixtures, a measure of reinforcing strength, did not differ from that for single drugs.Conclusions-Mixtures of various proportions of two drugs with comparable mechanisms of action were additive, i.e., they did not interact. This result will serve as the basis for comparison to studies of mixtures of drugs with various mechanisms of action. KeywordsDrug abuse; Self-administration; Rhesus monkey; Opioid; Dopamine uptake blocker; Drug mixture; Isobologram; Additivity Abuse of drug mixtures is common. Mechanisms that have been advanced to account for polydrug abuse include interactions that enhance positive effects or diminish negative effects of one or more of the combined drugs (Ellinwood et al. 1976;Kosten et al. 1986;Kreek 1987). Several drug combinations have been studied in the laboratory in humans and non-humans under a variety of conditions, including ethanol/barbiturate (DeNoble et al. 1985;Meisch and Lemaire 1990), cocaine/marijuana (Foltin and Fischman 1990), benzodiazepine/caffeine (Rush et al. 1994), ethanol/cocaine (Ikegami et al. 2002), ethanol/marijuana (Liguori et al. 2002, and dextromethorphan/diphenhydramine (Jun et al. 2003). It is not always clear, however, whether and how results can be accounted for by these broad mechanisms. Even for the stimulant/opioid m...

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“…We chose to investigate DAT knockdown, because the behavioral effects of pharmacological or genetic inhibition of this protein have been well characterized, particularly hyperactivity (34,35). Infusion of an in vitro validated siRNA into the dorsal third ventricle led to a significant down-regulation of DAT mRNA in the ventral midbrain neurons.…”

Section: Discussionmentioning

confidence: 99%

“…30, by using [ 35 S]-labeled antisense riboprobes for detecting EGFP, GABA type A (GABA A ) receptor subunit ␣2 (GABA A␣2 ), DAT, or tyrosine hydroxylase (TH) mRNA. Hybridizing adjacent brain sections with the corresponding 35 S-labeled sense riboprobes did not reveal any mRNA signal and served as a control for each probe. The DNA templates for riboprobe synthesis were generated from cDNA fragments of EGFP (GenBank accession no.…”

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confidence: 99%

Neurochemical and behavioral consequences of widespread gene knockdown in the adult mouse brain by using nonviral RNA interference

Thakker

Natt²,

Hüsken³

et al. 2004

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

198

164

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Gene expression analysis implicates an increasing number of novel genes in the brain as potential targets for the treatment of neurological and psychiatric disorders. Frequently, these genes are ubiquitously expressed in the brain and, thus, may contribute to a pathophysiological state through actions in several brain nuclei. Current strategies employing genetically modified animals for in vivo validation of such targets are time-consuming and often limited by developmental adaptations. Somatic gene manipulation using viral-mediated RNA interference (RNAi) has emerged recently, although restricting the target validation to specific brain nuclei. We investigated whether nonviral infusion of short interfering RNA (siRNA) into the ventricular system would enable a sequence-specific gene knockdown. The temporality and extent of siRNA-induced down-regulation were analyzed by targeting a transgene, EGFP, in mice overexpressing EGFP. Extensive knockdown of EGFP was observed, especially in regions adjacent or dorsoventrally and mediolaterally distant to the infusion site (dorsal third ventricle), with lesser knockdown in more distal regions. We challenged our RNAi approach to generate a specific knockdown of an endogenous gene, encoding the dopamine transporter (DAT) in regions (ventral midbrain) far distal to the infusion site. DAT-siRNA infusion in adult mice produced a significant down-regulation of DAT mRNA and protein in the brain and also elicited a temporal hyperlocomotor response similar to that (but delayed) obtained upon infusion of GBR-12909, a pharmacologically selective DAT inhibitor. Application of this nonviral RNAi approach may accelerate target validation for neuropsychiatric disorders that involve a complex interplay of gene(s) from various brain regions.T he burgeoning use of microarray analyses to detect potential target genes relevant to neuropsychiatric disorders necessitates the validation of such targets in vivo (1-3). The approach of genetically modifying animals (knockouts or transgenics) for target validation often is limited by developmental adaptations and genetic compensation that may mask the establishment of a clear phenotype. Further, such methodology is laborious and timeconsuming and not applicable for high-throughput in vivo validation of the large number of hits generated from modern microarray and proteomic target-identification strategies. Additional approaches using ribozymes and antisense oligodeoxynucleotides for somatic gene manipulation also suffer from drawbacks of eliciting nonspecific actions. RNA interference (RNAi) recently has emerged as a potentially superior alternative to the traditional approaches for assessing gene function in adult animals (4).RNAi is a cellular surveillance mechanism that responds to double-stranded RNA (dsRNA) by destroying cytoplasmic mRNAs containing sequences homologous to the dsRNA trigger (5). dsRNAs longer than 30 nt introduced in mammalian cells can induce an undesirable IFN response to produce cell death (6, 7). Conversely, short interfer...

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Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity

Cited by 36 publications

References 26 publications

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Self-administration of drug mixtures by monkeys: combining drugs with comparable mechanisms of action

Neurochemical and behavioral consequences of widespread gene knockdown in the adult mouse brain by using nonviral RNA interference

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