Cigarette smoking is a leading cause of cancer as well as cardiovascular and respiratory disease and is the leading preventable cause of death in the United States. Many factors contribute to cigarette smoking, including nicotine, other chemicals in tobacco smoke, and conditioned reinforcers. This competing continuation of an R01 proposal focuses on nicotine and nicotinic acetylcholine receptors (nAChR) as critical determinants of smoking behavior and smoking cessation pharmacotherapy.

Depression is a debilitating and recurring psychiatric disorder. Approximately half of the patients with depressive disorder fail to respond to currently available antidepressants. The long-term goal of this project is to understand the pathogenesis of depressive disorders and to develop new therapeutic approaches for this disease. This is a resubmission of the application for competitive renewal of our current funding to study the molecular and cellular mechanisms underlying the antidepressant-like effect of the adipocyte- derived hormone, leptin.

Our work demonstrates the presence of axo-glial septate junctions (AGSJs) inDrosophila nerves and establishes structural and molecular similarities betweenDrosophila and vertebrate AGSJs. Drosophila proteins: Neurexin IV (NRX IV), Contactin(CONT) and Neuroglian (NRG) form a tripartite complex that localizes to AGSJs. Theirmurine orthologs Contactin-associated protein (Caspr), Contactin (Cont) andNeurofascin (NF155) also form a complex at the paranodal AGSJs in myelinated axons.Drosophila nrx IV, cont and nrg, and mouse Caspr, Cont and NF155 mutants all fail toorganize AGSJs.

A competing renewal of R01 award MH074457 (currently in year 9) is requested. The R01 seeking renewal sustains the BrainMap Project (www.brainmap.org). The overall goal of the BrainMap Project is to provide the human brain mapping community with data sets, computational tools, and related resources that enable quantitative meta-analyses and co-activation mapping and functional decoding of neuroimaging data.

Cognitive dysfunction is a major component of depression, and may in fact underlie many of the mood symptoms. Specifically, a deficit in cognitive flexibility, associated with hypoactivity in the medial prefrontal cortex (mPFC), creates negative biases about the self, the world and the future. Chronic stress is also a major risk factor for depression, and we have shown previously that performance on an attentional set-shifting test (AST), which is a measure of prefrontal-dependent cognitive flexibility in rats, is compromised by chronic stress.

AbstractMarijuana use is a public health concern. Withdrawal that occurs in over one-half of dailymarijuana users is responsible, in part, for marijuana smoking. However, cannabinoids inmarijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). Whileprogress has been made toward establishing receptor mechanisms underlying the behavioraleffects of cannabinoids, it is not clear whether the clinically useful actions and abuse liability ofcannabinoids vary as a function of pharmacologic efficacy at cannabinoid receptors.

This project is an opportunity to identify biological mechanisms underlying binge drinking and their relationship to individual differences in the capacity to reduce drinking. We propose to characterize serotonin transporter (SERT) function using an immortalized human lymphoblastoid cell line (LCL) model among Binge and Non-Binge drinking adults recruited from R01-AA014988.

Alcohol binge drinking is associated with dangerous levels of intoxication that are costly to both the individual and society. NIAAA (2004) and others have defined a 'binge' as a drinking episode that produces a blood alcohol concentration of e .08 percent, which typically corresponds to five drinks for men and four drinks for women consumed within 2 hours. Most of what is known about binge drinking is based on studies of college students, however, most binge drinkers are older adults.

This competing continuation of K05DA17918 is submitted in response to PA-09-076 and requests 5additional years of support to provide protected time for the PI to continue a successful preclinicalresearch program on the behavioral pharmacology of opioids and other drugs and to mentor studentsand other young investigators in the area of drug abuse.

Ion channel currents are the fundamental units of electrical activity in most organisms. In our nervous system, K+ and Ca2+ channels are critical, and their regulation provides a way to directly control neuronal excitability and release of neurotransmitter (NT) at synapses. The modulations are crucial to basic nervous function and their understanding should contribute to novel modes of medical interventions for a range of disorders involving the brain, nerves and muscles.