Cocaine abuse is a major public health problem in the United States. In the latest national study, the number of people over the age of 12 who are current cocaine users is estimated at 1.6 million, or 0.7% of the total population. In recent years extensive research has demonstrated that cocaine addiction is associated with neuroadaptations and consequent pathology of reward learning. Chronic cocaine exposure leads to alterations in glutamatergic synapses, including changes in glutamate release, gene and protein expression, and synaptic plasticity. Further elucidating the mechanisms underlying these changes and how they lead to relapse is the goal of this grant application. More specifically, work utilizing both in vitro slice physiology and in vivo field recordings indicate tat repeated exposure to cocaine leads to a decrease in long-term depression within the nucleus accumbens (NAc). Although the exact mechanisms underlying this effect are unclear, existing evidence from the learning and memory field indicates that PKC-mediated AMPA receptor endocytosis is necessary for long-term depression. Our preliminary results show that blocking this endocytosis, utilizing a transgenic mouse lacking the PKC phosphorylation site on the AMPA receptor GluA2 subunit, leads to increased reinstatement of drug seeking behavior.
The specific aims for the mentored component of the proposed grant are designed to use this genetic mouse to probe the molecular mechanisms underlying cocaine reinstatement.
Aim 1 focuses on delineating the mechanisms responsible for reinstatement promoted by cocaine-associated cues using patch clamp electrophysiology.
Aim 2 expands this work to include stress- induced reinstatement of cocaine seeking.
Aims proposed for the independent (R00) phase of the grant will investigate further the individual components of AMPA receptor trafficking, examining the role of the novel PKC isoform, PKM?, in the ability of cues and stress to elicit reinstatement. Thus, the overall goal of the proposed experiments is to determine the role of AMPA receptor trafficking in cocaine-induced changes in synaptic plasticity and whether these changes in plasticity are required for two distinct forms of cocaine reinstatement, an animal model of relapse. My research so far in the field of cocaine addiction has given me a solid foundation in behavioral and molecular approaches. However, the specialized training proposed in electrophysiology during the K99 phase of this award will broaden my knowledge base and allow for a truly multi-disciplinary approach in my future career. Furthermore, this training and individualized research project will serve me well as I prepare for a future academic tenure-track position.
Cocaine is a major health problem in this country and worldwide. In a recent national study, the number of people over the age of 12 who are current cocaine users is estimated at 1.6 million, almost 1% of the total population. The public health costs incurred as a result of cocaine addiction is upwards of 100 billion dollars annually. The proposed research will be directed towards a mechanistic understand of cue- and stress- induced cocaine relapse, using state of the art behavioral and physiological techniques. This project will not only help us better understand what causes addicts to relapse when exposed to drug cues and stressful situations but will identify new pharmacological targets for the treatment of cocaine addiction.
|Briand, Lisa A; Lee, Bridgin G; Lelay, John et al. (2015) Serine 133 phosphorylation is not required for hippocampal CREB-mediated transcription and behavior. Learn Mem 22:109-15|
|Ortinski, Pavel I; Briand, Lisa A; Pierce, R Christopher et al. (2015) Cocaine-seeking is associated with PKC-dependent reduction of excitatory signaling in accumbens shell D2 dopamine receptor-expressing neurons. Neuropharmacology 92:80-9|
|Briand, Lisa A; Hilario, Monica; Dow, Holly C et al. (2015) Mouse model of OPRM1 (A118G) polymorphism increases sociability and dominance and confers resilience to social defeat. J Neurosci 35:3582-90|
|Briand, Lisa A; Kimmey, Blake A; Ortinski, Pavel I et al. (2014) Disruption of glutamate receptor-interacting protein in nucleus accumbens enhances vulnerability to cocaine relapse. Neuropsychopharmacology 39:759-69|
|Gundersen, Brigitta B; Briand, Lisa A; Onksen, Jennifer L et al. (2013) Increased hippocampal neurogenesis and accelerated response to antidepressants in mice with specific deletion of CREB in the hippocampus: role of cAMP response-element modulator Ï„. J Neurosci 33:13673-85|