DOPAMINE RECEPTOR-MEDIATED NEUROPLASTICITY
Laboratory of Neuoplasticity, McLean Hospital
Christine Konradi, Ph.D.
The dopaminergic system plays a major role in neuro-psychiatric disorders. A hyperactive dopaminergic system is involved in schizophrenia, as inhibition of D2 receptors can ameliorate many of the symptoms. Addictive behaviors due to drug abuse involve the excess activation of dopamine receptors. And Parkinson's disease, a movement disorder, is caused by the loss of dopaminergic neurons and the lack of dopamine release.
Modulation of dopamine levels and of dopamine receptor activity alters gene expression and physiological properties of neurons. The molecular adaptation of neurons to altered dopaminergic tone is evident in signal transduction pathways and in the expression of new behaviors. The interests of the laboratory are focused on how the various dopamine receptors affect signal transduction pathways and gene expression, and how these alterations might translate into altered behaviors. We study the activation of kinases, the phosphorylation of receptors and of signaling molecules and the expression of genes, after modulation of dopamine receptor activity. We use primary neuronal cultures and animal models for these studies. Projects are focused on models of drug addiction, schizophrenia, and Parkinson's disease.
Key Words: Dopamine receptors, signal transduction pathway, transcription factors, gene expression, CREB phosphorylation, glutamate receptors, addiction, schizophrenia, Parkinson's disease
Grant Support: NIDA RO1 DADA07134, PSYCHOSTIMULANT REGULATION OF NEURAL GENE EXPRESSION
Project Site: Laboratory of Neuroplasticity, McLean Hospital, Belmont, MA 02478
Project Director: Christine Konradi, Director, Laboratory of Neuroplasticity, MRC 215, McLean Hospital, 115 Mill Street, Belmont, MA 02478
Contact Person: Christine Konradi; konradi@mclean.harvard.edu
Training Opportunities: Post-doctoral positions are currently available
Representative Publications:
Leveque J-C, MacÌas W, Rajadhyaksha A, Carlson R, Barczak A, Kang S, Li X-M, Coyle JT, Huganir RL, Heckers S, Konradi C. Intracellular modulation of NMDA receptor function by antipsychotic drugs. J. Neurosci 2000; 20(11):4011-4020.
MacÌas W, Carlson R, Rajadhyaksha A, Barczak A, Konradi C. Potassium chloride-depolarization mediates CREB phosphorylation in striatal neurons in an NMDA receptor-dependent manner. Brain Res 2001; 890: 222-232.
Konradi C, Heckers S. Antipsychotic drugs and neuroplasticity: Insights into the treatment and neurobiology of schizophrenia; Biol Psych. 2001; 50:729-742.
Pliakas A, Carlson RR, Neve RL, Konradi C, Nestler EJ and Carlezon WA Jr. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated CREB expression in nucleus accumbens; J Neurosci. 2001; 21:7397-7403.
Andersson M, Konradi C, Cenci MA. The cyclic AMP response element binding protein is required for dopamine-dependent gene expression in intact but not dopamine-denervated striatal neurons. J Neurosci, in press
Konradi C, Cepeda C, Levine MS. Dopamine-Glutamate Interactions. In DiChiara G. (Ed.) Handbook of Experimental Pharmacology: Dopamine in the CNS, Springer Verlag, Heidelberg, in press