Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors

Baik, Ja Hyun; Picetti, Roberto; Saiardi, Adolfo; Thiriet, G.; Dierich, Andrée; Depaulis, Antoine; Meur, Marianne Le; Borrelli, Emiliana

doi:10.1038/377424a0

Cited by 600 publications

(443 citation statements)

References 27 publications

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“…The generation of mice lacking D2 receptors has been reported previously (Baik et al 1995). The intrinsic and synaptic membrane properties of neurons recorded in vitro from D2 lacking striatal slices were similar to those recorded from wild-type mice and control rats, as previously reported (Calabresi et al 1997).…”

Section: Methodssupporting

confidence: 78%

“…In some cases, 6-OHDAlesioned rats were anaesthetized with diethyl ether and brain dissection confirmed that the nigrostriatal pathway was lesioned. This was monitored by using a monoclonal antibody for tyrosine-hydroxylase.The generation of mice lacking D2 receptors has been reported previously (Baik et al 1995). The intrinsic and synaptic membrane properties of neurons recorded in vitro from D2 lacking striatal slices were similar to those recorded from wild-type mice and control rats, as previously reported (Calabresi et al 1997).…”

supporting

confidence: 78%

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Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors

Centonze

Picconi

Baunez

et al. 2002

Neuropsychopharmacology

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The striatum is a brain area implicated in the pharmacological action of drugs of abuse. To test the possible involvement of both cocaine and amphetamine in the modulation of synaptic transmission in this nucleus, we coupled whole-cell patch clamp recordings from striatal spiny neurons to the focal stimulation of glutamatergic or GABAergic nerve terminals. We found that neither cocaine (1-600 M) nor amphetamine (0.3-300 M) significantly affected the glutamate-mediated EPSCs recorded from these cells. Conversely, both pharmacological agents depressed GABA-mediated IPSCs in a dose-dependent manner. This effect was mediated by the stimulation of dopamine (DA) D2 receptors since it was prevented by 3 M L-sulpiride (a DA D2-like receptor antagonist), mimicked by the DA D2-like receptor agonist quinpirole (0.3-30 M), and absent in mice lacking DA D2 receptors. A presynaptic mechanism was likely involved in this action since both cocaine and amphetamine depress GABAergic transmission by increasing paired-pulse facilitation. Cocaine and amphetamine failed to affect GABAergic IPSCs after 6-OHDA-induced nigral lesion, indicating that both drugsFollowing psychostimulant administration, markers of brain activity are altered in many areas (Stein and Fuller 1993;Lyons et al. 1996;Breiter et al. 1997), suggesting that the diverse cognitive, emotional, and motor effects of these drugs are caused by the interaction with multiple neuronal systems in the central nervous system. Increasing evidence indicates that not only cortical but also subcortical areas play a role in the cocaine-and amphetamine-mediated effects. In particular, the increased locomotor activity and stereotypy caused by psychostimulants seem to involve specifically the nucleus striatum (Kelly et al. 1975;Amalric and Koob 1993;Berke and Hyman 2000), a structure that receives virtually all the cortical information directed to the basal ganglia (Penney and Young 1983;Albin et al. 1989;McGeorge and Faull 1989;Calabresi et al. 1996 Kaneko et al. 2000). The nucleus striatum also receives profuse dopaminergic innervation from the substantia nigra and has a very high density of D1 and D2 dopamine (DA) receptors but also of D3, D4 and D5 receptors (Mansour and Watson 1995;Surmeier et al. 1996;Bordet et al. 1997;LaHoste et al. 2000). Amphetamine and cocaine cause in the striatum rapid induction of c-fos, a commonly used molecular marker for neuronal activity. Interestingly, this effect is sensitive to dopamine (DA) receptor blockade (Graybiel et al. 1990;Moratalla et al. 1993), suggesting that increased release of DA in the striatum is responsible, at least in part, for the action of these drugs. In this regard, while the full diversity of drug effects is mediated by multiple neurotransmitters acting in multiple brain regions, most drugs abused by humans share the common property of increasing DA release in this brain area (Di Chiara and Imperato 1988; Kuczenshi et al. 1991;Yamamoto and Spanos 1988;Koob et al. 1998;Ito et al. 2000). Cocaine increases DA availability in th...

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Section: Methodssupporting

confidence: 78%

supporting

confidence: 78%

Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors

Centonze

Picconi

Baunez

et al. 2002

Neuropsychopharmacology

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“…We and others have observed that D 2 KO mice exhibit significantly less locomotor activity than WT controls (Figures 2b and e) (Baik et al, 1995;Kelly et al, 1998;Phillips et al, 1998). D 2 KO mice also had a tendency to exhibit more circumscribed movements (increased spatial d; Figure 3).…”

Section: Discussionmentioning

confidence: 64%

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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“…Most experiments were performed with D2R À / À mice (B6;129S2-Drd2tmllow) obtained from the Induced Mutant Resource at the Jackson Laboratory (Bar Harbor, ME), as described previously [18][19][20] . The D2R À / À mice and WT littermates used in the initial phase of the study originated from the breeding of D2R þ /-heterozygotes, as described previously 14 . Mice were maintained in a specific pathogen-free barrier facility under constant conditions of temperature and humidity, and on a 12-h light, 12-h dark schedule.…”

Section: Methodsmentioning

confidence: 99%

“…Dopamine receptors are members of the G protein-coupled receptor family and are classified into D1-like receptors (D1 and D5) and D2-like receptors (D2, D3 and D4). The dopamine D2 receptor (D2R) is highly expressed in the central nervous system and has an important role in the regulation of diverse neural functions by dopamine [14][15][16][17][18][19][20] . It has been shown to act as an autoreceptor in presynaptic regions of the substantia nigra and ventral tegmental area in the midbrain 21 , suggesting that it may have an important role in the central regulation of homeostasis of dopaminergic neurotransmission 18,19,21 by acting at both the postsynaptic and presynaptic levels.…”

mentioning

confidence: 99%

Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours

et al. 2013

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Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction.

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Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors

Cited by 600 publications

References 27 publications

Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors

Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors

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

Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours

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