2009 — 2010 |
Nazarian, Arbi |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
The Effects of Acetaminophen On the Rewarding Properties of Hydrocodone in Rats @ Western University of Health Sciences
DESCRIPTION (provided by applicant): The illicit abuse of prescription opioid analgesics has been on the rise in recent years. This illicit use has been associated to the rewarding/reinforcing properties of opioid agonists. However, many prescription opioid analgesics contain a combination of two compounds: an opioid agonist, such as hydrocodone, plus a non-narcotic analgesic, such as acetaminophen. Although the combination analgesic formulations have been effective in treating pain, it is yet unknown whether the combined formulations possess greater rewarding properties, as compared to the opioid agonist alone, which may lead to greater use and abuse. Acetaminophen is not known to contain rewarding effects;however, it could possibly potentiate the rewarding properties of opioid agonists, such as hydrocodone, when combined. Interestingly, recent findings suggest that the analgesic actions of acetaminophen occur through its active metabolites. In particular, acetaminophen is metabolized into AM404, known to be a transporter blocker of the endocannabinoid anandamide, as well as an agonist for transient receptor potential vanilloid type 1 (TRPV1) receptors. We, therefore, hypothesize that acetaminophen will enhance/potentiate the rewarding properties of hydrocodone in rats through this novel mechanism. Therefore, in a series of experiments, we propose to address whether acetaminophen is able to enhance the rewarding properties of hydrocodone using the conditioned place preference paradigm. We will also address whether the enhancing effects of acetaminophen on hydrocodone reward can be blocked by prevention of AM404 formation. Lastly, we will address if the actions of acetaminophen on hydrocodone reward can be blocked by antagonism of CB1 or TRPV1 receptors. Funds provided by this funding opportunity can facilitate and supplement our current start-up research funds that have been provided by the College of Pharmacy at Western University of Health Sciences. PUBLIC HEALTH RELEVANCE: There has been a significant increase in the non-medical (illicit) use of prescription opioid analgesics in the United State over the past decade. Our project is set to determine whether prescription opioid analgesics that contain a combination of the two compounds, hydrocodone and acetaminophen (commercially known as Vicodin(R)), possess a greater rewarding effect than the individual drugs. The findings from this project will shed light on the abuse liability of drugs, such as Vicodin, and will advance our understanding as to why there has been an increase in the illicit use and abuse of prescription opioid analgesic drugs.
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0.948 |
2015 — 2016 |
Nazarian, Arbi |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Insulin Mechanisms of Diabetes-Evoked Enhancement of Nicotine Reward @ Western University of Health Sciences
? DESCRIPTION (provided by applicant): People who smoke and are diabetic are twice as likely to experience mortality and various negative health outcomes versus non-smokers. The health care costs of smokers that are diabetic are 300% higher than non- smoking diabetics, due to higher rates of vascular complications. Several lines of clinical evidence suggest that diabetic patients may be more susceptible to tobacco abuse. First, people who smoke and have diabetes are less likely to quit smoking and are more concerned about weight gain if they quit as compared to non- diabetic smokers. Second, tobacco cessation rates are lowest among diabetic smokers who also display high rates of depression and anxiety during abstinence. Lastly, the rates of smoking among individuals with diabetes have remained stable since 1994 despite a significant decrease in smoking rates in the general population. We have previously demonstrated that the rewarding effects of nicotine are magnified in streptozotocin- and high-fat diet-induced diabetic rats. Moreover, diabetic rats exhibit suppressed dopaminergic system by having blunted basal and nicotine-evoked dopamine release in the nucleus accumbens, along with a reduction in dopamine D1 receptors. These findings have led to our hypothesis that disrupted insulin signaling, produced by diabetes, alters the mesolimbic system to magnify the rewarding effects of nicotine. Therefore, the goal of this application is to determine whether insulin modulates mesolimbic reward processing in favor of promoting the rewarding effects of nicotine. To that end, we will examine the rewarding effects of nicotine upon normalizing the diabetic state by supplementing insulin in rodent models of Type 1 and Type 2 diabetes. We will also examine the reward effects of nicotine in diabetic animals whose insulin signaling has been compensated within the mesolimbic reward circuitry. The mesolimbic reward circuitry will be examined in our experiments by measurement of nucleus accumbens dopamine release and measurement of receptors and key signaling molecules (e.g. DARPP-32 and AKT) involved in reward processing. Our results will provide important information regarding the role of insulin in modulating the rewarding effects of nicotine produced by metabolic disorders, such as diabetes. Our findings will also speak to the efficacy of insulin therapy used to treat diabetes and whether these therapies can reduce the risk of tobacco use.
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0.948 |