Locomotor inhibition by the D3 ligand R-(+)-7-OH-DPAT is independent of changes in dopamine release

Svensson, Kjell; Carlsson, Arvid; Waters, Nicholas

doi:10.1007/bf01283032

Cited by 126 publications

(58 citation statements)

References 7 publications

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“…However, mice homozygous for the mutant allele were hyperactive in an open field test for exploratory behavior, with increased locomotor activity and rearing. Data derived from genetic ablation of the D3R gene in mice were therefore consistent with pharmacological studies in which 7-OH-DPAT, a dopaminergic agonist which binds preferentially to D3 receptors, inhibits locomotor activity [Svensson et al, 1994], whereas UH232, a D3-preferring antagonist, causes hyperactivity [Waters et al, 1993]. Although the selectivity of these drugs remains controversial, these studies support the conclusion that hyperactivity in D3R mutant mice is the result of ablation of D3Rs rather than the effect of compensatory changes.…”

Section: D3r Molecular Biology and Mice Lacking D3rsupporting

confidence: 72%

Dopamine Receptors and Dopamine Transporter in Brain Function and Addictive Behaviors: Insights from Targeted Mouse Mutants

et al. 1998

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Recent advances in molecular biology have resulted in a number of genetically manipulated mice with defined changes at dopamine receptor and the dopamine transporter (DAT) loci. Mice with targeted mutations at the D1 receptor (D1R) are growth-retarded and show downregulated expression of dynorphin and substance P. Behavioral assessment indicates that mutants have deficiencies in spatial learning and initiating movement, as well as in responding to novel stimuli. D1R mutants do not become locomotor activated with cocaine or show upregulated immediate early gene (IEG) expression, but D2 receptor-dependent IEG changes are intact. Acute cocaine administration increases substance P levels, suggesting that striatal expression of this neuropeptide can be modulated by D1R-independent processes. Failure of locomotor activation is also seen with repeated amphetamine treatment. Surprisingly, D1R-deficient mice retain cocaine-conditioned place preference. In contrast, D2 receptor knockout mice are bradykinetic, show increased striatal enkephalin expression and an absence of opiate rewarding effects. D3 receptor mutants are hyperactive when assessed in an exploratory assay and display reduced anxiety-associated behavior in an elevated plus maze test. The recently described D4 receptor homozygous mutants exhibit a reduction in baseline locomotor activity and were shown to be supersensitive to the locomotor activating effects of alcohol and psychostimulant drugs. As expected, DAT knockout mice are hyperactive and do not respond to cocaine or amphetamine. The observation that D2 and D4 dopamine receptor and DAT mutants show compensatory effects, together with the complicating issue of their hybrid genetic background may temper conclusions regarding the direct effects of the targeted mutation on phenotype.

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Section: D3r Molecular Biology and Mice Lacking D3rsupporting

confidence: 72%

Dopamine Receptors and Dopamine Transporter in Brain Function and Addictive Behaviors: Insights from Targeted Mouse Mutants

et al. 1998

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“…Both laboratories observed a similar hypolocomotor response to PD 128907 or 7-OH-DPAT in WT and D3 receptor mutant mice , while the locomotor inhibitory effect was absent in D2 receptor mutant mice (Boulay et al, 1999a). Although all but one of these studies (Xu et al, 1999) employed 7-OH-DPAT doses at least 10-fold higher than the 10 mg/kg dose inhibitory to rodent locomotion in other investigations (Daly and Waddington, 1993), these results were interpreted by both laboratories as suggesting that locomotor inhibitory effects of 7-OH-DPAT, previously thought to result from D3 activation (Svensson et al, 1994), are mediated through D2 autoreceptors or other receptors.…”

Section: D3 Agonist Selectivity In Vivo Is Controversialmentioning

confidence: 65%

7-OH-DPAT and PD 128907 Selectively Activate the D3 Dopamine Receptor in a Novel Environment

Pritchard

Logue

Hayes

et al. 2003

Neuropsychopharmacol

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The D3 dopamine receptor is expressed primarily in limbic brain areas, and appears to play an inhibitory role in rodent locomotor behavior. Evidence suggests a potential role for the D3 receptor in the pathology of neuropsychiatric disease. Progress in elucidating D3 receptor function has been hampered, however, by a lack of well-characterized, selective ligands and by conflicting information regarding the behavioral phenotype of D3 receptor knockout mice. Here, we describe studies evaluating the behavioral effects of ( 7 )-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and PD 128907, two D3 receptor agonists whose in vivo selectivity has been a topic of considerable controversy. We demonstrate that both compounds inhibit locomotion under novel environmental conditions in wild-type (WT) mice, but are without measurable behavioral effect under identical conditions in D3 receptor knockout mice. Additionally, we demonstrate that at low, D3 selective doses, these compounds are without behavioral effect in both WT and D3 receptor knockout mice that have acclimated to the testing environment. These findings suggest that D3 receptor stimulation inhibits novelty-stimulated locomotion, and establish conditions for the use of 7-OH-DPAT and PD 128907 as D3 receptor agonists in vivo. Potential implications of these observations are discussed.

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“…The observation that female D 3 KO mice exhibited reduced MDMA locomotor effects is somewhat surprising given previous data, suggesting that D3 activation reduces locomotor activity. For example, D 3 blockade via antagonists or constitutive gene deletion induces hyperactivity (Accili et al, 1996;Waters et al, 1993) and D 3 agonists reduce activity (Daly and Waddington, 1993;Svensson et al, 1994). Additionally, D 3 KO mice have been reported to exhibit a 'hyperdopaminergic' phenotype, with increased striatal DA tone (Joseph et al, 2002;Koeltzow et al, 1998) and enhanced D 1 /D 2 intracellular signaling (Mizuo et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Differential Contributions of Dopamine D1, D2, and D3 Receptors to MDMA-Induced Effects on Locomotor Behavior Patterns in Mice

Risbrough

Masten

Caldwell

et al. 2006

Neuropsychopharmacol

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MDMA or 'ecstasy' (3,4-methylenedioxymethamphetamine) is a commonly used psychoactive drug that has unusual and distinctive behavioral effects in both humans and animals. In rodents, MDMA administration produces a unique locomotor activity pattern, with high activity characterized by smooth locomotor paths and perseverative thigmotaxis. Although considerable evidence supports a major role for serotonin release in MDMA-induced locomotor activity, dopamine (DA) receptor antagonists have recently been shown to attenuate these effects. Here, we tested the hypothesis that DA D 1 , D 2 , and D 3 receptors contribute to MDMA-induced alterations in locomotor activity and motor patterns. DA D 1 , D 2 , or D 3 receptor knockout (KO) and wild-type (WT) mice received vehicle or ( + /À)-MDMA and were tested for 60 min in the behavioral pattern monitor (BPM). D 1 KO mice exhibited significant increases in MDMA-induced hyperactivity in the late testing phase as well as an overall increase in straight path movements. In contrast, D 2 KO mice exhibited reductions in MDMA-induced hyperactivity in the late testing phase, and exhibited significantly less sensitivity to MDMA-induced perseverative thigmotaxis. At baseline, D 2 KO mice also exhibited reduced activity and more circumscribed movements compared to WT mice. Female D 3 KO mice showed a slight reduction in MDMA-induced hyperactivity. These results confirm differential modulatory roles for D 1 and D 2 and perhaps D 3 receptors in MDMA-induced hyperactivity. More specifically, D 1 receptor activation appears to modify the type of activity (linear vs circumscribed), whereas D 2 receptor activation appears to contribute to the repetitive circling behavior produced by MDMA.

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Locomotor inhibition by the D3 ligand R-(+)-7-OH-DPAT is independent of changes in dopamine release

Cited by 126 publications

References 7 publications

Dopamine Receptors and Dopamine Transporter in Brain Function and Addictive Behaviors: Insights from Targeted Mouse Mutants

Dopamine Receptors and Dopamine Transporter in Brain Function and Addictive Behaviors: Insights from Targeted Mouse Mutants

7-OH-DPAT and PD 128907 Selectively Activate the D3 Dopamine Receptor in a Novel Environment

Differential Contributions of Dopamine D1, D2, and D3 Receptors to MDMA-Induced Effects on Locomotor Behavior Patterns in Mice

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