Browsing by Subject "nicotine"
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Item Effects of Chronic Nicotine Exposure and Lack of High Affinity Nicotinic Receptors on Cortico-Hippocampal Areas in the Aging Mouse Brain(2012-07-16) Huang, Pei-SanNicotine, the major psychoactive ingredient of tobacco smoke, underlies numerous effects by activating neuronal nicotinic acetylcholine receptors. Both in vitro and in vivo studies suggest that nicotine is neuroprotective and improves cognitive performance. Epidemiology studies show that smoking is negatively correlated with the incidence of Parkinson's disease and Alzheimer's disease. Postmortem research and neuroimaging studies show that loss of nicotinic binding sites in the brain is the major feature of neurodegenerative diseases related to dementia and cognitive impairment. Caloric restriction, a regimen that extends the lifespan in all mammalian species studied so far including rodents and primates, is a highly regulated response to food deprivation. It is believed that the longevity effect of caloric restriction is mediated by SIRT1, a NAD-dependent deacetylase, and its related genes. Nicotine's effect on body weight could also lead to weight loss by decreasing caloric absorption consumption. The goal of this study was to find the possible correlation between nicotine's effects and the activation of SIRT1 and its related genes. Using beta2-/- mice that lack high affinity beta2 nicotinic acetylcholine receptors (nAChRs), we first demonstrated that beta2* nAChRs do not directly regulate expression of survival genes. However, we found that loss of beta2* nAChRs could result in augmented cellular stress, which indirectly increased expression of SIRT1, Nampt, and Ku70, possibly as an adaptive response to provide protection against neurodegeneration. We also found that loss of endogenous activation of beta2* nAChRs had less effect on synaptic connections but strongly impaired survival of hippocampal GABAergic neurons. To activate beta2* nAChRs in normal mice, we administered nicotine through drinking water. In a short-term exposure study, we determined the dose of nicotine to be used in young adult mice, and found that chronic nicotine treatment was anxiolytic, decreased caloric consumption, increased nAChR binding sites, and most importantly, increased expression of SIRT1 and its related genes. Finally, we compared long-term nicotine treatment with caloric restriction in middle-aged mice to examine their effects to brain aging, and our results indicated that in mice long term caloric restriction and nicotine treatment both tend to improve memory in aging mice, but appear to act through different mechanisms.Item Impact of Ghrelin Receptor Antagonism on Nicotine and Cocaine Drug Reactivity in Rats(2013-05-01) Clifford, Patrick ShaneGhrelin is a 28 amino acid peptide that interacts with ghrelin receptors (GHS-Rs) to modulate brain reinforcement circuits. Systemic ghrelin infusions augment cocaine (COC) stimulated locomotion and conditioned place preference (CPP) in rats, whereas genetic or pharmacological ablation of GHS-Rs has been shown to attenuate the acute locomotor-enhancing effects of nicotine (NIC) and COC, and to blunt the CPP induced by food, alcohol, amphetamine and COC in mice. The stimulant NIC can induce CPP and like COC, repeated administration of NIC induces locomotor sensitization in rats. In experiment 1, we examined the effects of GHS-R antagonism with JMV 2959 on COC-induced locomotion and found that JMV 2959 suppresses COC-induced locomotor sensitization. In experiment 2, we examined the effects of GHS-R antagonism with JMV 2959 on NIC-induced locomotion and found that JMV 2959 suppresses NIC-induced locomotor sensitization. In experiment 3, we examined the effects of GHS-R knockout on COC-induced locomotion and found that animals sustaining GHS-R knockout display a suppression of COC-induced locomotor sensitization. In experiment 4, we examined the effects of GHS-R knockout on COC-induced locomotion and found that animals sustaining GHS-R knockout display a suppression of COC-induced locomotor sensitization. In experiment 5, we examined the effects of JMV 2959 on NIC-enhanced intracranial self-stimulation (ICSS) responding and found that JMV 2959 alone had no effect, but when combined with NIC,JMV 2959 pretreatment reversed the enhancement of responding produced by NIC. In experiment 6, we examined the effects of GHS-R knockout on ICSS responding and found that animals sustaining GHS-R knockout were unable to acquire ICSS at current intensity levels that would support responding by WT animals. It was not until the intensity was ramped up four fold that these knockout rats were able to acquire responding. These results show that antagonism of GHS-Rs diminishes the reinforcing effects of NIC and COC. This provides evidence that antagonists of GHS-Rs could be useful in the treatment of drug addiction, particularly that involving nicotine.