Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter

Spielewoy, Cécile; Biała, Grażyna; Roubert, Christine; Hamon, Michel; Betancur, Catalina; Giros, Bruno

doi:10.1007/s002130100901

Cited by 86 publications

(78 citation statements)

References 20 publications

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“…This increased responsiveness to amphetamine is in accord with the molecular mechanism of amphetamine action in which its DA-releasing activities are dependent on DAT (9). Indeed, we and others (22)(23)(24) have reported that the DAT heterozygous animals, or animals in which DAT expression has been reduced by 50% via siRNA treatment, demonstrate a commensurate reduction in amphetamine-induced locomotor activation. It thus seems clear that the locomotor-stimulating effects of amphetamine are absolutely dependent and directly proportional to the levels of DAT.…”

Section: Discussionsupporting

confidence: 82%

Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter

Salahpour

Ramsey

Medvedev

et al. 2008

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

172

157

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The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic signaling wherein it controls both the spatial and temporal actions of dopamine. Here we evaluated the behavioral and neurochemical consequences of increased DAT function by generating DAT transgenic mice (DAT-tg) that overexpress the transporter. These mice were generated by pronuclear injection of a bacterial artificial chromosome containing the mouse DAT locus, yielding an anatomical expression pattern of DAT-tg identical to WT. In DAT-tg mice there is a 3-fold increase in the levels of total and membrane-expressed DAT, but synaptic plasma membrane fractions of DAT-tg mice show only a 30% increase in transporter levels. Functional studies reveal that in the DAT-tg animals there is a 50% increase in the rate of dopamine (DA) uptake resulting in extracellular levels of DA that are decreased by Ϸ40%. Behaviorally, DAT-tg animals display similar locomotor stimulation when treated with DAT blockers such as GBR12909, methylphenidate, and cocaine. However, these mice demonstrate markedly increased locomotor responses to amphetamine compared with WT animals. Furthermore, compared with controls, there is a 3-fold greater increase in the amount of DA released by amphetamine in DAT-tg mice that correlates with the 3-fold increase in protein expression. Finally, DAT-tg animals show reduced operant responding for natural reward while displaying preference for amphetamine at much lower doses (0.2 and 0.5 mg/kg) than WT mice (2 mg/kg). These results suggest that overexpression of DAT leads to a marked increase in sensitivity to psychomotor and rewarding properties of amphetamine.bacterial artificial chromosome transgenic ͉ locomotion ͉ addiction ͉ ADHD D opamine (DA) is a key neurotransmitter regulating motivated behaviors such as food intake, locomotion, and reward, and its dysregulation is associated with a number of psychiatric and neurological disorders including schizophrenia, Parkinson's disease, drug addiction, attention deficit hyperactivity disorder (ADHD), and depression (1-3). A key step in the control of DA neurotransmission is the reuptake of DA into presynaptic neurons by the dopamine transporter (DAT) (4). DAT, as well as the serotonin transporter (SERT) and norepinephrine transporter (NET), belongs to the large family of Na ϩ /Cl Ϫ -dependent transporters that also includes the transporters for glycine and GABA (5, 6). These transporters comprise 12 transmembrane domains and intracellular N-and C-terminal domains. Once at the plasma membrane, DAT cotransports two Na ϩ , one Cl Ϫ , and one DA molecule from the extracellular space into the cytosolic compartment of the neuron.Much insight regarding how DAT affects DA homeostasis has been gained from the study of mice lacking the DAT (DAT knockout; DAT-KO) (4, 7). In these animals, there is a 5-fold increase in the extracellular concentration of DA (8). The crucial role of DAT in determining the duration of action of extracellular DA has also been demonstrated in these animals. Usi...

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Section: Discussionsupporting

confidence: 82%

Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter

Salahpour

Ramsey

Medvedev

et al. 2008

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

172

157

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“…DAT knockout mice have also been tested for their acute stimulant response to these three drugs. In general WT mice are stimulated by an acute injection of methylphenidate, MDMA, and amphetamine while KO mice are depressed by an acute injection of these drugs Powell et al, 2004;Spielewoy et al, 2001;Zhuang et al, 2001; but see Giros et al, 1996). Therefore, for this trait, the consequence of DAT KO had similar consequences across the three drugs.…”

Section: Discussionmentioning

confidence: 99%

“…In multiple studies examining the acute locomotor response to amphetamine of DAT KO and WT mice, the markedly elevated baseline locomotion of the KO mice likely impacted their ability to exhibit a locomotor stimulant response. In fact, WT mice exhibited the typical activation, whereas KO mice showed locomotor depression , Giros et al, 1996, Spielewoy et al, 2001, Zhuang et al, 2001. The ability of stimulants to reduce the hyperactivity of DAT KO mice has suggested to some that these mice may serve as a model of attention deficit hyperactivity disorder (ADHD).…”

Section: Dopamine-related Genes: Amphetamine and Methamphetaminementioning

confidence: 99%

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Phillips

Kamens

Wheeler

2008

Neuroscience & Biobehavioral Reviews

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Amphetamines, including methamphetamine, pose a significant cost to society due to significant numbers of amphetamine-abusing individuals who suffer major health-related consequences. In addition, methamphetamine use is associated with heightened rates of violent and property-related crimes. The current paper reviews the existing literature addressing genetic differences in mice that impact behavioral responses thought to be relevant to the abuse of amphetamine and amphetaminelike drugs. Summarized are studies that used inbred strains, selected lines, single gene knockouts and transgenics, and quantitative trait locus (QTL) mapping populations. Acute sensitivity, neuroadaptive responses, rewarding and conditioned effects are among those reviewed. Some gene mapping work has been accomplished, and although no amphetamine-related complex trait genes have been definitively identified, translational work leading from results in the mouse to studies performed in humans is beginning to emerge. The majority of genetic investigations has utilized single-gene knockout mice and has concentrated on dopamine-and glutamate-related genes. Genes that code for cell support and signaling molecules are also well-represented. There is a large behavioral genetic literature on responsiveness to amphetamines, but a considerably smaller literature focused on genes that influence the development and acceleration of amphetamine use, withdrawal, relapse, and behavioral toxicity. Also missing are genetic investigations into the effects of amphetamines on social behaviors. This information might help to identify at-risk individuals and in the future to develop treatments that take advantage of individualized genetic information.

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“…Known strain differences in several other neurochemical systems and in a variety of second messenger proteins (Kosten and Ambrosio 2002) undoubtedly influence these behaviors, as well, but the importance of DATs for AMPH responses in both rodents (e.g., Spielewoy et al 2001) and humans (e.g., Lott et al 2005) has been clearly demonstrated. Indeed, Lott and colleagues (2005) recently identified polymorphisms that affect DAT gene expression as a genetic determinant of differential subjective responsiveness among individuals to AMPH.…”

Section: Discussionmentioning

confidence: 99%

Inbred Lewis and Fischer 344 rat strains differ not only in novelty- and amphetamine-induced behaviors, but also in dopamine transporter activity in vivo

2007

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Inbred Lewis (LEW) and Fischer 344 (F344) rats are differentially sensitive to drugs of abuse, making them useful for studying addiction-related neural mechanisms. Here, we investigated whether strain differences in dopamine transporters (DATs) in dorsal striatum (dSTR) and/or nucleus accumbens (NAc) may help to explain their behavioral differences. The behavior of male LEW and F344 rats was assessed in an open-field arena during habituation to novelty and after an i.v. infusion of saline and/or 0.5 mg/kg d-amphetamine (AMPH). In vitro measures of DAT binding, protein and cellsurface expression, as well as in vitro and in vivo measures of function, were used to compare DATs in dSTR and NAc of these two strains. We found that LEW rats exhibited higher novelty-and AMPHinduced locomotion, but F344 rats exhibited greater AMPH-induced rearing and stereotypy. An initial habituation session with i.v. saline minimized the strain differences in AMPH-induced behaviors except that the more frequent AMPH-induced rearing in F344 rats persisted. Strain differences in DAT total protein and basal activity were also observed, with LEW rats having less protein and slower in vivo clearance of locally-applied DA in dSTR and NAc. AMPH inhibited in vivo DA clearance in dSTR and NAc of both strains, but to a greater extent in F344 rats. Taken together, the lower basal DAT function in LEW rats is consistent with their greater novelty-induced locomotor activation, whereas the greater inhibition of DA clearance by AMPH in F344 rats is consistent with their marked AMPH-induced rearing behavior.

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Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter

Cited by 86 publications

References 20 publications

Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter

Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter

Behavioral genetic contributions to the study of addiction-related amphetamine effects

Inbred Lewis and Fischer 344 rat strains differ not only in novelty- and amphetamine-induced behaviors, but also in dopamine transporter activity in vivo

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