Balaji Krishnan - US grants

[unreadable] DESCRIPTION (provided by applicant): Drug addiction is a significant health problem nationally and locally. Texas was named as one of 2 sites with highest rate of cocaine-related deaths from 2003 to 2004. In 2004, 34.2 million Americans (12 and over) reported lifetime use of cocaine. Thus treatment of addiction to cocaine is a national health issue. Cocaine craving and relapse to cocaine abuse is a feature of addiction that has devastating consequences even after long periods of abstinence. Factors that trigger this relapse include the presence of drug, drug paraphenalia, or environment associated with previous use of the drug. A brain area implicated in cuebased drug associative behavior is the amygdala. Since cues can trigger craving after long periods of abstinence, long-term changes in neuronal plasticity due to chronic cocaine use are likely. These changes may include the strengthening of certain synapses which may underlie the association between the drug and the context or environment in which drug-taking occurred. Such modifications can be mediated through changes in glutamatergic transmission similar to learning and memory mechanisms. Understanding the mechanisms contributing to the lasting association between the cues and cocaine administration is extremely valuable information since data will be directly applicable to treatments that will focus on targeting mechanisms underlying cocaine-craving and cocaine-associative behaviors. These studies would ultimately provide information that contributes to therapies which produce significantly higher success rates in treating cocaine addiction. Conditioned place preference (CPP) is an animal model measuring cue-induced cocaine associative behavior. We have shown that the activity of the enzyme, phospholipase D (PLD), is increased in the amygdala after cocaine-induced conditioned place preference. The overall goal of the proposed research is to determine the role of PLD in the synaptic changes that occur in cue-induced cocaine associative behavior during withdrawal from chronic cocaine. Two specific aims address this goal: specific aim 1, to characterize the role of amygdala PLD activity and mGluR-linked PLD in CPP and specific aim 2, to determine the mechanism by which the mGluR-linked PLD causes an increase in synaptic strength in the basolateral to central amygdala pathway. In this proposal, I plan to utilize behavioral, electrophysiological, and neurochemical approaches to study glutamatergic transmission in the amygdala of animals exhibiting CPP and undergoing 2 week withdrawal from chronic cocaine administration. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Relapse to cocaine can be initiated after long periods of abstinence in response to cues (visual, auditory, tactile) associated with drug-taking. Repeated use of cocaine induces long-term changes (neuroadaptations) in the key brain regions potentially by usurping the learning mechanisms normally used to reinforce natural rewards. The rewarding properties and interoceptive feelings linked to cocaine become associated with environmental cues. This association is clinically important since intense drug craving causing the addicts to remain highly susceptible to relapse can predominantly occur in response to such environmental cues. However, we still have a poor understanding of the molecular mechanisms underlying drug-dependent learned associations. In the present proposal, we will test the hypothesis that expression of a conditioned behavioral response to a previously cocaine-paired environment requires phospholipase D (PLD) signaling in the amygdala, a key brain area for the formation and expression of associative memories downstream to serotonin (5-hydroxytryptamine, 5-HT) 2C receptors (5-HT2CRs). We propose to investigate the requirement of PLD and 5-HT2CR function for the expression of cocaine induced conditioned hyperactivity behavior using pharmacological intervention and to determine the effect of modulating PLD activity specifically in the amygdala and study its effect on 5-HT2CR mediated suppression of conditioned hyperactivity. Such amygdala specific experimental investigation of cocaine-cue associated neuroadaptations in long-term memory mechanism act two-fold by advancing the basic understanding of the signaling mechanism associated with drug-environment conditioned associations and performing preliminary investigations of therapeutic potential in preclinical models directed towards reducing the risk of relapse.

PROJECT SUMMARY/ABSTRACT Despite significant research advances in the past two decades, Alzheimer?s disease (AD) remains the sixth leading cause of death that cannot be prevented, cured or even slowed. Compelling evidence indicates that early events in AD are triggered by synaptic dysfunction resulting in memory deficits associated with AD clinical manifestation. However, the mechanism leading to synapse dysfunction associated memory deficits remains elusive thus impeding successful therapeutic intervention. Bridging this critical gap in our current knowledge is the goal of this proposal. We present compelling preliminary results that support our hypothesis that phospholipase D1 (PLD1) contributes to the detrimental impact on synapses and subsequent cognitive deficits. We will test our central hypothesis by pursuing the following specific aim: testing whether synaptic PLD1 levels/signaling are elevated through epigenetic regulation in the CNS of AD patients as a function of disease severity and cognitive decline. The present project is highly significant because the proposed studies will establish PLD1 as a key player in synaptic dysfunction and associated cognitive deficits. The successful completion of the aims will provide insight into the involved molecular mechanisms and therapeutic possibilities using small molecule inhibitors for PLD1 in preventing memory deficits associated with AD clinical progression. The proposed project will improve our scientific understanding of how synaptic dysfunction is mediated by PLD1 and its associated signaling partners in contributing to synaptic vulnerability.

PROJECT SUMMARY/ABSTRACT Despite significant research advances in the past two decades, Alzheimer?s disease (AD) remains the sixth leading cause of death that cannot be prevented, cured or even slowed. Attention has shifted towards under- standing early synaptic events in AD and related dementia (ADRD), resulting in memory deficits. However, the mechanism recruited and leading to synapse dysfunction associated memory deficits remains elusive thus im- peding successful therapeutic intervention. Bridging this critical gap in our current knowledge is the goal of this proposal. We present compelling preliminary results that support our hypothesis that inducible phospholipase D (PLD1) overexpression and the resulting aberrant signaling contributes to the progressive detrimental impact on synapses and subsequent cognitive deficits. We will test our central hypothesis by pursuing the following specific aims: (I) testing how elevated synaptic PLD1 levels/signaling contributes to synaptic dysfunction and memory deficits in ADRD; (II) evaluating the functional contribution of elevated PLD1 in preclinical mouse models and studying partners contributing to ADRD-like synaptic dysfunction and memory deficits. The present project is highly significant because the proposed studies will establish elevated PLD1 and the associated signaling part- ners as key players in promoting vulnerability causing progressive synaptic dysfunction and underlying cognitive deficits. The successful completion of the aims will provide insight into the involved molecular mechanisms and therapeutic possibilities using well-tolerated small molecule PLD1 inhibitor in preventing memory deficits asso- ciated with ADRD progression. The proposed project will improve our scientific understanding of how synaptic dysfunction is mediated by elevated PLD1 and interacting signaling partners in contributing to synaptic vulnera- bility.