Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors despite significant physical, mental and social harm to the individuals involved. Progress has been made in elucidating the underlying neuroadaptions that occur in addiction. These involve, in part, a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning. One of the ways cells respond to external stimuli, including pathological stimuli such as abused psychostimulants, is by altering their pattern of gene expression and one mechanism for this is via epigenetic changes leading to altered patterns of gene transcription. Induction ?FosB is a well characterized neuroplastic event associated with chronic administration of these drugs. Exposure to abused psycostimulants, for example cocaine, leads to histone acetylation of gene promoters, and consequent transcriptional activation, of early response genes, including FosB. Increase in FosB promoter acetylation has been shown to be dependant on CBP (CREB binding protein) dependant histone acetyl transferase (HAT) activity. Thus exposure to drugs of abuse such cocaine and amphetamines have been shown to lead to increase FosB protein expression in cells of the nucleus accumbens. On chronic treatment, a longer lived truncated splice variant of FosB, ?FosB, is expressed and this accumulates in neurons as the transition to an addicted state occurs. ?FosB is present for an extended period of time after drug is withdrawn and it has thus been implicated as a causative agent in the formation of longer term addictive behaviors and hence propensity for relapse. The key biological hypothesis to be tested by the proposed research is that attenuation of CBP activity by a small molecule inhibitor will reduce acetylation of the FosB gene promoter, which in turn will lower FosB and ?FosB protein expression. High throughput screens of chemical libraries at Mount Sinai have identified two series of hit molecules in a binding assay to CBP bromodomain. Further, these hits have been shown to inhibit CBP mediated HAT activity in cell based reporter assays. These chemical lead series are amenable to exploration and elaboration by parallel synthesis techniques to create libraries of CBP inhibitors. The broad theme of this proposal is to optimize these hits via targeted library synthesis and medicinal chemistry to provide small molecules which will inhibit ?FosB induction via attenuation of CBP HAT activity. These small molecules will function as pharmacological tools to investigate the underlying neuronal adaptations in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction.

Public Health Relevance

Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors. Neuronal changes involved in addiction are partly epigenetic and result in a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning mechanisms in the brain. The theme of this proposal is to identify and optimize small molecules that modulate and attenuate the epigenetic processes associated with addiction;these small molecules will function as pharmacological tools to investigate the underlying neuronal processes in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33DA029963-05
Application #
8660675
Study Section
Special Emphasis Panel (NSS)
Program Officer
Singh, Hari
Project Start
2010-08-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$421,926
Indirect Cost
$173,002
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Smith, Steven G; Sanchez, Roberto; Zhou, Ming-Ming (2014) Privileged diazepine compounds and their emergence as bromodomain inhibitors. Chem Biol 21:573-83