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Fishberg Department of Neuroscience Mount Sinai School of Medicine |
Program Project Grant on the Molecular Neurobiology of Drug AddictionFunded by the National Institute on Drug AbuseOur Program Project Grant (PPG), housed at the Mount Sinai School of Medicine, supports highly integrated and collaborative studies on molecular and cellular actions of opiates and cocaine in discrete target brain regions. These studies have a high priority for two central reasons. First, from a clinical perspective, drug addiction continues to exact enormous human and economic costs on society, yet available treatments are inadequately effective for most people. An improved understanding of the molecular and cellular mechanisms underlying drug addiction will lead to better treatments. Second, from a basic neuroscience perspective, studies of the neurobiology of drug addiction offer a unique opportunity to establish the biological basis of a complex and clinically relevant behavioral abnormality. This is because prominent features of drug addiction can be reproduced in laboratory animals with increasing accuracy, thereby allowing detailed investigations of the relevant mechanisms involved. The Center enjoys crucial collaborations at several subcontracting institutions, Harvard, Stanford, UT Southwestern, and Yale.
Administrative Core (Eric Nestler, PPG Director, Mount Sinai) The Administrative Core is responsible for overseeing all aspects of the PPG’s functioning. It coordinates the highly interactive studies across the several Cores and Projects that carry out our program of research.
Transgenic Core (PI, Eric Nestler, Mount Sinai) (Includes Subcontract with Rachael Neve, MIT) The Transgenic Core oversees the generation and efficient use of numerous lines of mutant mice and viral vectors that are required for the PPG's Projects. The Core specializes in novel methods of overexpressing or deleting proteins within highly localized regions of adult brain.
Behavioral Core (PI, Eric Nestler, Mount Sinai) (Includes Subcontract with Bill Carlezon, Harvard University, and Jane Taylor, Yale University) The Behavioral Core provides a broad array of behavioral assays that measure distinct domains of complex actions of drugs of abuse in rats and mice. These relatively high throughput assays complement more labor-intensive, sophisticated assays which are the focus of Project 4.
Project 1: Role of CREB in Opiate and Cocaine Addiction (PI, Eric Nestler, Mount Sinai) Project 1 focuses on the role of the transcription factor CREB in the nucleus accumbens and several other key brain regions in mediating the long-term actions of opiates and cocaine on neuronal function. The goal of ongoing studies is to characterize the behavioral output of CREB activity in these brain regions and to identify target genes through which CREB produces these effects in addiction models.
Project 2: Cellular Actions of ΔFosB and CREB in Brain Reward Neurons (PI, Rob Malenka, Stanford University) The focus of Project 2 is to explore, at the cellular level, the adaptations in synaptic transmission and neuronal excitability that drugs induce in the mesolimbic dopamine system, and to relate these molecular and cellular actions to behavioral features of addiction. The Project focuses on two transcription factors, CREB and ΔFosB, and key target genes, in mediating this long-term cellular plasticity.
Project 3: Chromatin and Gene Regulation in Opiate and Cocaine Addiction (PI, Eric Nestler, Mount Sinai) (Includes Subcontract with Chris Cowan, UT Southwestern) Project 3 supports broad methods to characterize opiate and cocaine regulation of gene expression and chromatin modifications in the brain’s reward regions. This includes studies of CREB and ΔFosB action at the chromatin level. It also includes assays of drug regulation of the chromatin remodeling machinery in these brain regions.
Project 4: Neuroadaptations in Drug Self-Administration and Relapse (PIs, David Self, UT Southwestern) Project 4 continues a major PPG effort: to study the molecular basis of changes in cocaine reinforcement mechanisms produced by chronic drug exposure that could contribute to a state of addiction. The Project focuses on key drug-induced molecular adaptations in brain reward regions identified in Projects 1-3 and studies them in advanced drug self-administration and relapse models in rats and mice.
Examples of Recent Publications of PPG Research
Figure. Scheme of some common, chronic actions of drugs of abuse on the ventral tegmental area (VTA) – nucleus accumbens (NAc) circuit. The top panel (Control) shows a VTA neuron innervating an NAc neuron, and cortical glutamatergic inputs to the VTA and NAc neurons, under normal conditions. After chronic drug administration, several adaptations occur. In the VTA, drug exposure induces TH and increases AMPA glutamatergic responses (Glut), possibly via induction of GluR1 and altered trafficking of AMPA receptors. There is also evidence that VTA dopamine neurons decrease in size, an effect demonstrated thus far with chronic opiates only, but presumed for other drugs of abuse due to common associated biochemical adaptations (e.g., reduced levels of neurofilament proteins). Induction of CREB activity, and alterations in neurotrophic factor (NTF) signaling may partly mediate these various effects. In the NAc, all drugs of abuse induce the transcription factor ΔFosB, which may then mediate some of the shared aspects of addiction via regulation of numerous target genes. Several, but not all, drugs of abuse also induce CREB activity in this region, which may be mediated via upregulation of the cAMP pathway. Several additional changes have been found for stimulant exposure; it is not yet known whether they generalize to other drugs. Stimulants decrease AMPA glutamatergic responses in NAc neurons, possibly mediated via induction of GluR2 or repression of several postsynaptic density proteins (e.g., PSD95, Homer-1). These changes in postsynaptic glutamate responses are associated with complex changes in glutamatergic innervation of the NAc, including reduced glutamatergic transmission at baseline and in response to normal rewards, but enhanced transmission in response to cocaine and associated cues, effects mediated in part via upregulation of AGS3 in cortical neurons and downregulation of the cystine-glutamate transporter (system xc-) in glia. Stimulants and nicotine also induce dendritic outgrowth of NAc neurons, although opiates are reported to produce the opposite action. The net effect of this complex dysregulation in glutamate function and synaptic structure is not yet known.
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TRANSMITTER | Fishberg Department of Neuroscience | Mount Sinai School of Medicine | contact us Copyright © 2009 MSSM Department of Neuroscience |
