Browsing by Author "Muldoon, Pretal P."
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Item Effects of methoxsalen, a CYP2A5/6 inhibitor, on nicotine dependence behaviors in mice(Pergamon-Elsevier, 2014-10) Zhu, Andy Z.X; Muldoon, Pretal P.; Tyndale, Rachel F.; Damaj, Mohamad Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Birimi.; 15062425700Metabolism of nicotine to inactive cotinine by hepatic enzyme CYP2A6 is the principal pathway by which active nicotine is removed from circulation. We therefore hypothesized that inhibition of mouse CYP2A5, the ortolog of human CYP2A6, by methoxsalen (8-methoxypsoralen) alter dependence-related behaviors of nicotine in the mouse. Conditioned place preference (CPP) test was used to assess the appetitive reward-like properties and precipitated nicotine withdrawal to assess physical (somatic and hyperalgesia) and affective (anxiety-related behaviors) measures. The nicotine plasma levels were also measured with or without methoxsalen pretreatment. Methoxsalen (15 and 30 mg/kg, intraperitoneally) pretreatment enhanced nicotine-induced preference in mice (p < 0.05). However, there was a lack of enhancement of nicotine in the CPP test after the highest dose of the CYP-2A5 inhibitor. Similarly to the CPP results, repeated administration of methoxsalen increased the intensity of mecamylamine-precipitated withdrawal signs. The potentiation of nicotine preference and withdrawal intensity by methoxsalen was accompanied by significant increase in nicotine plasma levels in mice (p < 0.05). Finally, methoxsalen enhanced the ability of a very low dose of nicotine (0.05 mg/kg) to reverse withdrawal signs in mice undergoing spontaneous withdrawal after chronic nicotine infusion (p < 0.05). In conclusion, inhibition of nicotine metabolism by methoxsalen alters the behavioral effects of nicotine in the mouse. Combining CYP2A6 inhibitors with low dose nicotine replacement therapies may have a beneficial role in smoking cessation because it will decrease the drug elimination rate and maintain plasma and brain nicotine levels.Item Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice(Elsevier, 2016-03) Muldoon, Pretal P.; AiSharari, Shakir; Carroll, F. Ivy; Negus, S. Stevens; Damaj, M. Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32-1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid induced stretching. Ketoprofen and morphine also blocked the acid-induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics.Item In vivo interactions between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-alpha: Implication for nicotine dependence(Elsevier, 2017-03-04) Jackson, Asti; Muldoon, Pretal P.; Lichtman, Aron H.; Carroll, F. Ivy; Greenwald, Mark; Miles, Michael F.; Damaj, M. Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric alpha 7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-alpha (PPAR alpha) has been implicated as a downstream signaling target of the alpha 7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPAR alpha as a possible mediator of the effect of alpha 7 nAChR activation in nicotine dependence. Our results demonstrate the PPAR alpha antagonist GW6471 blocks actions of the alpha 7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that alpha 7 nAChR activation attenuates nicotine CPP in a PPAR alpha-dependent manner. To evaluate PPAR alpha activation in nicotine dependence we used the selective and potent PPAR alpha agonist, WY-14643 and the clinically used PPAR alpha activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPAR alpha in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPAR alpha plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of alpha 7 nAChRs in nicotine dependence.