Altered Dopamine Release and Uptake Kinetics in Mice Lacking D<sub>2</sub>Receptors

Schmitz, Yvonne; Schmauss, Claudia; Sulzer, David

doi:10.1523/jneurosci.22-18-08002.2002

Cited by 163 publications

(185 citation statements)

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“…This is congruent with a previous report of increased striatal DAT mRNA expression and DA reuptake, but not TH-mRNA and protein expression, in D 3 −/− mice (30). In addition, D 2 −/− mice also display increased basal levels of extracellular DA and DAT up-regulation (25,26), suggesting that similar neuroadaptations occur in D 2 −/− mice. Another important finding is that D 3 R deletion attenuates the NAc DA response to cocaine.…”

Section: Discussionsupporting

confidence: 91%

“…Previous studies suggest that presynaptic D 2 Rs play a major role in regulating presynaptic DA release (25,26). Our present data demonstrate that D 3 R deletion causes a significant (twofold) increase in basal levels of extracellular NAc DA, suggesting that presynaptic D 3 Rs also play an important role in controlling presynaptic DA release, consistent with reports of significantly increased extracellular DA in the NAc or dorsal striatum in D 3 −/− mice (27)(28)(29).…”

Section: Discussionsupporting

confidence: 91%

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Increased vulnerability to cocaine in mice lacking dopamine D₃receptors

Song

Zhang

et al. 2012

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

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Neuroimaging studies using positron emission tomography suggest that reduced dopamine D 2 receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D 3 receptors (D 3 Rs) in the neurobiology of addiction remains unclear, however. Here we report that D 3 R KO (D 3 −/− ) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D 3 −/− mice. In addition, D 3 −/− mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D 3 R deletion increases vulnerability to cocaine, and that reduced D 3 R availability in the brain may constitute a risk factor for the development of cocaine addiction.O ne of the most challenging issues in drug abuse research is understanding the etiology of addiction (1-3). Identification of neurobiological factors conferring vulnerability to drug use and abuse may provide important therapeutic targets for the development of medications to treat addiction. Cumulative evidence suggests that certain vulnerability traits, such as high impulsivity, stress reactivity, novelty-seeking, negative emotionality, and abnormal structure of the frontostriatal brain system, may predispose humans to drug abuse and addiction (4-8). However, the neurobiological mechanisms by which such traits affect drug-taking and drug-seeking behavior are poorly understood. PET studies suggest that reduced dopamine (DA) D 2 receptor (D 2 R) availability in the neostriatum is associated with reduced orbitofrontal cortex functional activity, which is linked to risk for impulsivity and compulsive cocaine administration in both humans (9-12) and nonhuman primates (2, 13). Whether reduced D 2 R availability is a determinant or consequence of cocaine abuse remains unclear, however (2,(12)(13)(14).It should be noted that the reduced D 2 R availability observed in PET or micro-PET studies is based on the use of D 2 R-preferring ligands, such as [ 11 C]raclopride (∼10-to 20-fold selectivity for D 2 over D 3 ). This raises the question of whether striatal D 3 Rs are also involved in increased susceptibility to drug-taking behavior. Compared with D 2 Rs, which are expressed uniformly throughout the striatum (15), D 3 Rs are expressed preferentially in the nucleus accumbens (NAc) shell, islands of Calleja, and olfactory tubercle (16,17). A recent neuroimaging study with the D 3 R-preferring ligand [ 11 C]-PHNO (with 10-fold selectivity for D 3 over D 2 ) revealed significant reduction in D 3 R binding in the dorsal striatum of heavy methamphetamine polydrug users (18). In rodents, a significant reduction in ...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Increased vulnerability to cocaine in mice lacking dopamine D₃receptors

Song

Zhang

et al. 2012

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

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“…2). The mechanisms by which estrogen exerts its promotion of DA release may be related to direct actions on DA terminals which can down-regulate DA autoreceptors (Bazzett and Becker 1994;Schmitz et al 2002). This leads to a release from the inhibitory action of these receptors, enhanced stimulated DA release and a decrease in the affinity of the DA transporter.…”

Section: Discussionmentioning

confidence: 99%

Increased dopamine release in vivo by estradiol benzoate from the central amygdaloid nucleus of Parkinson's disease model rats

Liu

Xie

2004

Journal of Neurochemistry

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In addition to the dopaminergic neurons in the nigrostriatal system, the properties of dopaminergic neurons in the mesolimbic system, such as the amygdala, are also of interest and importance because of their specific neuromodulatory effects in the pathophysiology of Parkinson's disease (PD). Using the fast cyclic voltammetry (FCV) technique, we present evidence to indicate that electrically-evoked dopamine (DA) release from the amygdala, especially the central amygdaloid nucleus (CAN), of ovariectomized (OVX) female rats was significantly enhanced with increasing doses of estradiol benzoate (EB; 30, 50 and 100 lg/kg). Impaired DA release from the amygdala of an OVX rat PD model can also be increased by EB treatment (50 lg/kg) to a level similar to that of controls. The well established neuroprotective effects of estrogen may be beneficial for reducing the dysfunction of dopaminergic neurons in mesolimbic structures of rat PD models and PD patients.

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“…Present knowledge, however, posits that the D2R-mediated control of DA synthesis and release is essentially cell-autonomous; in agreement, knock-out of D2Rs completely abolishes D2 autoreceptor functions (L'Hirondel et al, 1998;BenoitMarand et al, 2001;Rouge-Pont et al, 2002;Schmitz et al, 2002). Nevertheless, in D2R-null mice, both D2 autoreceptors and heteroreceptors were simultaneously ablated; lack of selective pharmacological, chemical, or genetic approaches to isolate D2R-mediated responses at these two sites induced us to generate mice with specific deletions of D2Rs either in DA neurons (D2 autoreceptor KO) or in striatal medium spiny neurons (MSNs; D2 heteroreceptor KO), using the CRE-loxP system (Branda and Dymecki, 2004).…”

Section: Introductionmentioning

confidence: 93%

Dual Control of Dopamine Synthesis and Release by Presynaptic and Postsynaptic Dopamine D2 Receptors

Anzalone

Lizardi-Ortiz²,

Ramos³

et al. 2012

Journal of Neuroscience

172

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Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine (DA) levels are causally linked to Parkinson's disease, schizophrenia, and addiction. Major sites of DA synthesis are the mesencephalic neurons originating in the substantia nigra and ventral tegmental area; these structures send major projections to the dorsal striatum (DSt) and nucleus accumbens (NAcc), respectively. DA finely tunes its own synthesis and release by activating DA D2 receptors (D2R). To date, this critical D2R-dependent function was thought to be solely due to activation of D2Rs on dopaminergic neurons (D2 autoreceptors); instead, using site-specific D2R knock-out mice, we uncover that D2 heteroreceptors located on non-DAergic medium spiny neurons participate in the control of DA levels. This D2 heteroreceptor-mediated mechanism is more efficient in the DSt than in NAcc, indicating that D2R signaling differentially regulates mesolimbic-versus nigrostriatal-mediated functions. This study reveals previously unappreciated control of DA signaling, shedding new light on region-specific regulation of DA-mediated effects.

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Altered Dopamine Release and Uptake Kinetics in Mice Lacking D₂Receptors

Cited by 163 publications

References 43 publications

Increased vulnerability to cocaine in mice lacking dopamine D₃receptors

Increased vulnerability to cocaine in mice lacking dopamine D₃receptors

Increased dopamine release in vivo by estradiol benzoate from the central amygdaloid nucleus of Parkinson's disease model rats

Dual Control of Dopamine Synthesis and Release by Presynaptic and Postsynaptic Dopamine D2 Receptors

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Altered Dopamine Release and Uptake Kinetics in Mice Lacking D2Receptors

Cited by 163 publications

References 43 publications

Increased vulnerability to cocaine in mice lacking dopamine D3receptors

Increased vulnerability to cocaine in mice lacking dopamine D3receptors

Increased dopamine release in vivo by estradiol benzoate from the central amygdaloid nucleus of Parkinson's disease model rats

Dual Control of Dopamine Synthesis and Release by Presynaptic and Postsynaptic Dopamine D2 Receptors

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Altered Dopamine Release and Uptake Kinetics in Mice Lacking D₂Receptors

Increased vulnerability to cocaine in mice lacking dopamine D₃receptors

Increased vulnerability to cocaine in mice lacking dopamine D₃receptors