Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain

Garris, Paul A.; Ciolkowski, Edward L.; Pastore, Paolo; Wightman, R. Mark

doi:10.1523/jneurosci.14-10-06084.1994

Cited by 436 publications

(388 citation statements)

References 67 publications

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“…Lesion and stimulation studies have shown that DA plays an important integrative role in motor performance, exploration, and cognition (Le Moal and Simon, 1991). Spatial and temporal signaling of DA neurotransmission is controlled by the plasma membrane DAT (Amara and Kuhar, 1993;Garris et al, 1994). In the present study, we have investigated behaviors in mice that have either one or both Dat1 alleles disrupted.…”

Section: Discussionmentioning

confidence: 97%

“…Alterations in dopaminergic function have been associated with several different neurological and psychiatric conditions that include Parkinson's and Huntington's diseases, schizophrenia, Tourette's syndrome, attention deficithyperactivity disorder (ADHD), and substance abuse (Carlsson, 1987). A primary mechanism for regulating the concentrations of extracellular DA is through control of catecholamine reuptake by the DA transporter (DAT) (Amara and Kuhar, 1993;Garris et al, 1994). The distribution of the DAT within the mammalian CNS has been described and it is positively associated with the density of DA innervation (Scheffel et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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Novelty Seeking and Stereotypic Activation of Behavior in Mice with Disruption of the Dat1 Gene

Pogorelov

Rodriguiz

Insco

et al. 2005

Neuropsychopharmacol

137

116

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Disruption of the dopamine (DA) transporter (Dat1) gene in mice leads to a 50% reduction or complete elimination of Dat1 expression in striatum of respective heterozygous (HZ) and knockout (KO) mice. Compared to wild-type (WT) controls, extracellular DA is increased approximately two-and five-fold in the mutants. Although open field (OF) activity is similar for WT and HZ animals, it is enhanced for KO mice. The purpose of the present investigations was to study spontaneously emitted behaviors and to determine the behavioral and neurochemical mechanisms that may contribute to the hyperactivity of KO animals. Heterozygotes are less anxious than other genotypes and they engage in novelty-seeking behaviors that include increased time spent in the center of the OF, enhanced investigation of objects, and augmented free exploration of a novel environment. By comparison, KO mice display neophobia when initially exposed to novel conditions. Over time the anxiety-like response habituates and behaviors become activated and stereotyped; these responses are unrelated to exploration or novelty seeking. No alterations in extracellular DA levels or tissue contents from several brain regions are detected at the time of stereotypic activation of KO mice. By contrast, this behavior is accompanied by changes in serotonin metabolism in basal ganglia. This feature may contribute to the behavioral inflexibility of KO mice in different experimental contexts. Collectively, these findings suggest that disruption of the Dat1 gene in mice leads to two different phenotypes; one related to anxiety-reducing and novelty seeking, while the other has some homology to disorders with a stereotypical-perseverative spectrum.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Novelty Seeking and Stereotypic Activation of Behavior in Mice with Disruption of the Dat1 Gene

Pogorelov

Rodriguiz

Insco

et al. 2005

Neuropsychopharmacol

137

116

View full text Add to dashboard Cite

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“…The released DA can diffuse a few micrometers away from its release sites before being taken up by DA transporters (DAT) localized presynaptically outside of synaptic contacts [44]. The relatively slow dynamics of reuptake allows DA to invade the extrasynaptic space for a maximum of 12 μm [31,45] (Figure 2C), supplying a sustained, nearly homogenous, DA concentrations in the 10 nM range. This ambient concentration, which primarily acts on the D2 receptors in their high affinity state in the striatum [46], is believed to play an enabling role in movement, cognition, and motivation [47].…”

Section: Spine Da Receptors Mediate Extrasynaptic Transmissionmentioning

confidence: 99%

Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

109

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Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling. The Central Dopaminergic Systems: An OverviewDopamine (DA) is a prototypical slow neurotransmitter that plays pivotal roles in a variety of cognitive, motivational, neuroendocrine, and motor functions [1][2]. Two major groups of DAcontaining neurons in the mammalian brain reside in the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA) [3]. SN neurons form the nigrostriatal pathway, which projects mainly to the dorsal part of striatum where they control postural reflexes and initiation of movements. VTA neurons give rise to two pathways: the mesolimbic pathway, which projects to the subcortical and limbic nuclei, and the mesocortical pathway, which projects mainly to the cingulate, entorhinal and medial prefrontal cortices. Dysfunction of dopaminergic transmission in these major pathways has been implicated in an array of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1][2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.The action of DA is mediated by a family of seven-transmembrane G protein-coupled receptors (GPCRs) encoded by at least five DA receptor genes (D1, D2, D3, D4, and D5) in the mammalian brain [4]. These receptors are classified into two subfamilies, the D1-class and Corresponding author: Wei-Dong Yao, Ph.D., Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough,...

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“…The action of DA in the synapse is terminated primarily by reuptake to the presynaptic membrane through the dopamine transporter (DAT) [6] . Otherwise, DA is partially removed by oxidation by monoamine oxidase orcatechol-O-methyltransferase in the synaptic cleft (Fig.…”

mentioning

confidence: 99%

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

et al. 2014

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Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the fi rst technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major fi ndings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic DA receptors. These results have corroborated the role of DA in addiction and increased the understanding of its underlying mechanisms.Keywords: dopamine; dopaminergic system; drug addiction; positron emission tomography ·Review· Brain Dopaminergic System Dopamine (DA) is a catecholamine neurotransmitter in the nervous system. It has many functions in the brain, including punishment, reward, voluntary movement, mood, attention, motivation, sleep, working memory, and learning [1] .DA is synthesized by the hydroxylation and decarboxylation of L-tyrosine in DA neurons and, before being released into the synapse in response to an action potential, it is stored within presynaptic vesicles (Fig. 1). The action of DA occurs by binding to postsynaptic DA receptors, resulting in the formation of second messengers. There are fi ve subtypes of DA receptors, which can be grouped into two classes or families: D1-like and D-2 like [1,2] . The D1-like receptor family comprises the D1 and D5 receptors, encoded by genes with no introns, acting by way of Gs-proteins and activating adenylyl cyclase, thus increasing cAMP production [3,4] .The D2-like receptor family comprises the D2, D3, and D4 receptors, encoded by genes containing introns. D2-like receptors act via Gi-proteins, inhibit adenylyl cyclase activity, and thus decrease cAMP activity [3,5] .The action of DA in the synapse is terminated primarily by reuptake to the presynaptic membrane through the dopamine transporter (DAT) [6] . Otherwise, DA is partially removed by oxidation by monoamine oxidase orcatechol-O-methyltransferase in the synaptic cleft (Fig. 1).T h e d o p a m i n e r g i c n e u r o n s , w h o s e p r i m a r y neurotransmitter is DA, interconnect many areas of the brain to form a system which originates in the substantia nigra (SN) pars compacta, ventral tegmental area (VTA), and hypothalamus. The dopaminergic system is typically divided into four major pathways: mesocortical (from the VTA to the frontal cortex), mesolimbic (from the VTA to the nucleus accumbens), nigrostriatal (from the SN to the striatum), and tuberoinfundibular (from the hypothalamus to the pituitary gland). The mesostriatal and mesocortical pathways are currently recognized to contribute most to drug addiction [7] . Neurosci Bull October 1, 2014, 30(5): 765-776 766 Drug AddictionThe term addiction is derived from the Latin verb addicere, which referred to the Roman court action of binding a person to another. From the 17th century, addiction has been used to refer to psychoactive substances (...

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Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain

Cited by 436 publications

References 67 publications

Novelty Seeking and Stereotypic Activation of Behavior in Mice with Disruption of the Dat1 Gene

Novelty Seeking and Stereotypic Activation of Behavior in Mice with Disruption of the Dat1 Gene

Dopaminergic signaling in dendritic spines

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

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