Pharmacology and behavioral pharmacology of the mesocortical dopamine system

Tzschentke, Thomas

doi:10.1016/s0301-0082(00)00033-2

Cited by 424 publications

(262 citation statements)

References 1,155 publications

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“…[25][26][27][28] Furthermore, mPFC DA activity has been shown to attenuate mesolimbic DA release. 29,30 In the present study, we show that in adult dcc heterozygous mice there is a selective increase in basal TH levels in the mPFC, without a corresponding increase in DBH levels. The increase in TH, therefore, reflects changes in DA and not noradrenergic terminals.…”

Section: Discussionsupporting

confidence: 58%

Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine

et al. 2004

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Netrins are guidance cues that play a fundamental role in organizing the developing brain. The netrin receptor, DCC (deleted in colorectal cancer), is highly expressed by dopaminergic (DA) neurons. DCC may therefore participate in the organization of DA circuitry during development and also influence DA function in the adult. Here we show that adult dcc heterozygous mice exhibit a blunted behavioral response to the indirect DA agonist amphetamine and do not develop sensitization to its effects when treated repeatedly. These behavioral alterations are associated with profound changes in DA function. In the medial prefrontal cortex, dcc heterozygotes exhibit increased tyrosine hydroxylase (TH) protein levels and dramatic increases in basal concentrations of DA and DA metabolites. In contrast, in the nucleus accumbens, dcc heterozygotes show no changes in either TH or DA levels, but exhibit decreased concentrations of DA metabolites, suggesting reduced DA activity. In addition, dcc heterozygous mice exhibit a small, but significant reduction in total number of TH-positive neurons in midbrain DA cell body regions. These results demonstrate for the first time that alterations in dcc expression lead to selective changes in DA function and, in turn, to differences in DA-related behaviors in adulthood. These findings raise the possibility that changes in dcc function early in life are implicated in the development of DA dysregulation observed in certain psychiatric disorders, such as schizophrenia, or following chronic use of drugs of abuse. Keywords: axon guidance; DCC; prefrontal cortex; schizophrenia; drug abuse; psychostimulant drugs Repeated exposure to stimulant drugs, such as amphetamine, leads to the development of increased sensitivity to the behavioral-activating effects of these drugs. This phenomenon, known as behavioral sensitization, is long-lasting and is accompanied by enhanced stimulant-induced dopamine (DA) release in the nucleus accumbens (NAcc). 1,2 Individual differences in susceptibility to the effects of stimulants on behavior and on the release of DA have been demonstrated in both humans and adult laboratory animals. [3][4][5][6][7][8] Although the processes that lead to differences in vulnerability to stimulant drugs remain to be elucidated, evidence indicates that both genetic factors 9 and exposure to environmental insults early in life are involved. 10 Perinatal insults can result in sensitized behavioral and mesolimbic DA responses of adult rats to an acute injection of amphetamine. 11 Similarly, lesions of forebrain structures made in neonatal rats lead to enhanced behavioral responses to amphetamine in adult animals. 5,12 These findings suggest that anomalies in the development and organization of DA circuitry contribute to subsequent functional and behavioral abnormalities in the adult. However, little is known about the molecular mechanisms that regulate the development of DA systems.Netrins are a family of secreted proteins that play a fundamental role in the organization of the develop...

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Section: Discussionsupporting

confidence: 58%

Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine

et al. 2004

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“…The current data also fail to provide simple correlations with models that postulate that enhanced PFc DA levels are necessary and sufficient for cocaine reward. This hypothesis has also been supported by a substantial body of lesion and microinjection data (Goeders and Smith, 1983;Goeders et al, 1986;Bardo, 1998;Tzschentke, 2001). Cocaine increases DA ex in PFc of both wild-type and homozygous DAT-KO mice that exhibit cocaine reward and DAT/SERT double homozygous KO mice that do not display cocaine reward.…”

Section: Differential Da Responses In To Cocaine In Cpu Nac and Pfcmentioning

confidence: 76%

Regional Differences in Extracellular Dopamine and Serotonin Assessed by In Vivo Microdialysis in Mice Lacking Dopamine and/or Serotonin Transporters

Shen

Hagino

Kobayashi

et al. 2004

Neuropsychopharmacol

184

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Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DA ex ) and serotonin (5-HT ex ) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT-or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DA ex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DA ex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DA ex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DA ex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DA ex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HT ex in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DA ex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT ex can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.

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“…Another means by which the mPFC can modulate NAcc function involves a direct glutamatergic pathway projecting from the mPFC to the NAcc (Sesack et al, 2003;Tzschentke, 2001). For example, it has been demonstrated that electrical activation of cells within the mPFC produces an elevation in neuronal activity within the NAcc that cannot be easily accounted for by indirect activation via other brain structures (O'Donnell & Grace, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Pyramidal cells in mPFC, which receive DA-ergic input from the VTA, project to NAcc, where they terminate on cells receiving DA input from the VTA. Furthermore, mPFC neurons feed-back onto the very VTA cells that project to mPFC and NAcc (for reviews see Sesack et al, 2003;Tzschentke, 2001). These connections allow mPFC to modulate activity in both NAcc and VTA, thus influencing the neuronal response of these regions to reinforcing stimuli, and consequently altering the behavioral response to such stimuli (Duvachelle et al, 1998;Jackson et al, 2001;Mitchell & Gratton, 1992;Thompson & Moss, 1995).…”

Section: Introductionmentioning

confidence: 99%

Dynamic interaction between medial prefrontal cortex and nucleus accumbens as a function of both motivational state and reinforcer magnitude: A c-Fos immunocytochemistry study

2007

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This study examined the effects of simultaneous variations in motivational state (food deprivation) and reinforcer magnitude (food presentation) on c-Fos immunoreactivity in the pre-and infralimbic medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) core and shell, and dorsal striatum. In the first experiment, c-Fos was reliably increased in pre-and infralimbic mPFC of animals 12-and 36-h compared to 0-h deprived. In the second experiment, a small meal (2.5g) selectively increased c-Fos immunoreactivity in both mPFC subdivisions of 36-h deprived animals, as well as in both NAcc subdivisions of 12-h deprived animals. Correlational analyses revealed a changing relationship between mPFC subregions and the NAcc compartments to which they project. In subjects 12-h deprived and allowed a small meal, c-Fos counts in prelimbic mPFC and NAcc core were positively correlated, as were those in infralimbic mPFC and NAcc shell (r = . 83 and .76, respectively). The opposite was true of animals 36-h deprived, with prelimbic mPFC/NAcc core and infralimbic mPFC/ NAcc shell negatively correlated (r = -.85 and -.82, respectively). The third experiment examined the effects of unrestricted feeding (presentation of 20g food) after 0, 12, or 36-h deprivation. No differences between mean c-Fos counts were found, though prelimbic mPFC/NAcc core, and mPFC/ NAcc shell were positively correlated in animals 36-h deprived (r = .76 and .89, respectively). These data suggest that the activity within the mPFC and NAcc, as well as the interaction between the two, change as a complex combinatorial function of motivational state and reinforcer magnitude. Section:

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Pharmacology and behavioral pharmacology of the mesocortical dopamine system

Cited by 424 publications

References 1,155 publications

Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine

Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine

Regional Differences in Extracellular Dopamine and Serotonin Assessed by In Vivo Microdialysis in Mice Lacking Dopamine and/or Serotonin Transporters

Dynamic interaction between medial prefrontal cortex and nucleus accumbens as a function of both motivational state and reinforcer magnitude: A c-Fos immunocytochemistry study

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