1. Role of Aberrant Striatal Dopamine D1 Receptor/cAMP/Protein Kinase A/DARPP32 Signaling in the Paradoxical Calming Effect of Amphetamine
- Author
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Salvatore Magara, Alessandra Bonito-Oliva, Antonio Pisani, Francesco Errico, Alessandro Usiello, Robert Nisticò, Giuseppina Martella, Diego Centonze, Howard H. Gu, Manolo Carta, Nicola Biagio Mercuri, Mauro Federici, Francesco Napolitano, Napolitano, Francesco, A., Bonito Oliva, M., Federici, M., Carta, Errico, Francesco, S., Magara, G., Martella, R., Nistico, D., Centonze, A., Pisani, H. H., Gu, N. B., Mercuri, A., Usiello, Napolitano, F., BONITO OLIVA, A., Federici, M., Carta, M., Errico, F., Magara, S., Martella, G., Nisticò, R., Centonze, D., Pisani, A., Gu, H. H., Mercuri, N. B., and Usiello, Alessandro
- Subjects
Male ,ADENOSINE A(2A) RECEPTORS ,Dopamine ,Long-Term Potentiation ,Amphetamine ,pharmacology, Animals, Central Nervous System Stimulants ,pharmacology, Corpus Striatum ,drug effects/physiology, Cyclic AMP ,metabolism, Cyclic AMP-Dependent Protein Kinases ,metabolism, Discrimination (Psychology) ,drug effects/physiology, Dopamine Plasma Membrane Transport Proteins ,genetics, Dopamine and cAMP-Regulated Phosphoprotein 32 ,metabolism, Dopamine ,metabolism, Gene Knock-In Techniques, Long-Term Potentiation ,drug effects/physiology, Male, Mice, Mice ,Transgenic, Motor Activity ,drug effects/physiology, Mutation, Random Allocation, Receptors ,Dopamine D1 ,metabolism, Receptors ,Dopamine D2 ,metabolism, Signal Transduction ,Pharmacology ,Transgenic ,Mice ,Random Allocation ,Discrimination, Psychological ,SYNAPTIC PLASTICITY ,OBJECT RECOGNITION ,Receptors ,Cyclic AMP ,PKA ,GLUR1 AMPA RECEPTOR ,genetics ,Gene Knock-In Techniques ,ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ,DEFICIT HYPERACTIVITY DISORDER ,CAMP-REGULATED PHOSPHOPROTEIN ,LONG-TERM POTENTIATION ,IN-VIVO ,DISTINCT ROLES ,biology ,Chemistry ,General Neuroscience ,Dopaminergic ,Settore BIO/14 ,Articles ,Nomifensine ,Attention deficit/hyperactivity disorder (ADHD) ,medicine.drug ,Signal Transduction ,medicine.medical_specialty ,Dopamine and cAMP-Regulated Phosphoprotein 32 ,Mice, Transgenic ,Motor Activity ,Dopamine receptor D1 ,Dopamine receptor D3 ,cAMP ,Internal medicine ,medicine ,Animals ,Protein kinase A ,Dopamine transporter ,Discrimination (Psychology) ,Dopamine Plasma Membrane Transport Proteins ,Receptors, Dopamine D2 ,Receptors, Dopamine D1 ,Cyclic AMP-Dependent Protein Kinases ,Corpus Striatum ,Endocrinology ,drug effects/physiology ,nervous system ,dopamine transporter (DAT) ,Mutation ,biology.protein ,Central Nervous System Stimulants ,pharmacology ,metabolism - 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 D2 receptor (D2R) function. However, although we demonstrated that striatal D1 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 kinaseA(PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D1Rs since haloperidol, by blocking the tonic inhibition of D2R, unmasked a normal activation of striatal adenosine A2A receptor-mediated cAMP/PKA/DARPP32 cascade in mutants.Most importantly, our studies highlighted that amphetamine, nomifensine,andbupropion, 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 ofD1R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels. 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 D2 receptor (D2R) function. However, although we demonstrated that striatal D1 receptor (D 1R) 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 D1Rs since haloperidol, by blocking the tonic inhibition of D2R, unmasked a normal activation of striatal adenosine A2A receptor-mediated cAMP/PKA/DARPP32cascade 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. Copyright © 2010 the authors.
- Published
- 2010