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Role of Aberrant Striatal Dopamine D-1 Receptor/cAMP/Protein Kinase A/DARPP32 Signaling in the Paradoxical Calming Effect of Amphetamine

Napolitano, Francesco; Bonito-Oliva, Alessandra; Federici, Mauro; Carta, Manolo LU ; Errico, Francesco; Magara, Salvatore; Martella, Giuseppina; Nistico, Robert; Centonze, Diego and Pisani, Antonio, et al. (2010) In Journal of Neuroscience 30(33). p.11043-11056
Abstract
Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal... (More)
Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32kDa (DARPP32) at Thr75 residue, but preserved D-2 receptor (D2R) function. However, although we demonstrated that striatal D-1 receptor (D1R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D2R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D1R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels. (Less)
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Journal of Neuroscience
volume
30
issue
33
pages
11043 - 11056
publisher
Society for Neuroscience
external identifiers
  • wos:000281197900010
  • scopus:77955916197
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1682-10.2010
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English
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2010-09-23 12:32:58
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@article{f53b888f-c579-4c1f-b446-dd1be1a12899,
  abstract     = {Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32kDa (DARPP32) at Thr75 residue, but preserved D-2 receptor (D2R) function. However, although we demonstrated that striatal D-1 receptor (D1R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D2R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D1R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.},
  author       = {Napolitano, Francesco and Bonito-Oliva, Alessandra and Federici, Mauro and Carta, Manolo and Errico, Francesco and Magara, Salvatore and Martella, Giuseppina and Nistico, Robert and Centonze, Diego and Pisani, Antonio and Gu, Howard H. and Mercuri, Nicola B. and Usiello, Alessandro},
  issn         = {1529-2401},
  language     = {eng},
  number       = {33},
  pages        = {11043--11056},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Role of Aberrant Striatal Dopamine D-1 Receptor/cAMP/Protein Kinase A/DARPP32 Signaling in the Paradoxical Calming Effect of Amphetamine},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.1682-10.2010},
  volume       = {30},
  year         = {2010},
}