The current study was designed to analyze the roles of both α7 and α4β2 nicotinic receptors (nAChRs) in behavioral sensitization and its effects on Brain Derived Neurotrophic Factors (BDNF) and the mammalian target of rapamycin (mTOR) in the neonatal quinpirole model of schizophrenia. Animals were treated neonatally with either quinpirole (1 mg/kg) or saline starting on P1 and treatment persisted through P21. Starting on P33, animals were sensitized to nicotine (0.5 mg/kg free base) every other day up to P49. Following sensitization, brains were harvested at 1 h and 24 h post-drug treatment and BDNF protein and total mTOR activity were assessed in the nucleus accumbens. Results revealed that α7 antagonism failed to block nicotine sensitization regardless of neonatal quinpirole treatment, and appears to block the initial hypoactive response to nicotine in males but not females. In addition, α7 antagonism effectively blocked the enhanced BDNF response to nicotine in both saline and quinpirole treated animals but was ineffective at blocking mTOR at the 1 h time point, and resulted in decreases of mTOR at the 24 h time point. Antagonism of the α4β2 nAChR effectively blocked nicotine sensitization in both males and females but the higher dose resulted in a significant initial hypoactive response to nicotine. In addition, α4β2 nAChR antagonism blocked nicotine induced increases in BDNF. Total mTOR revealed that neonatal quinpirole produced a decrease in mTOR that was reversed by nicotine at the 1h but not the 24h time point and antagonism of nAChRs resulted in sex dependent effects. There results have implication towards the mechanisms underlying enhanced smoking in schizophrenia.

Individuals suffering from mental illness are often adversely affected by tobacco use. Historically, clinicians are reluctant and inadequately prepared to recognize and treat comorbid nicotine addiction in the chronic mentally ill (CMI) client. As evidenced by a review of the literature, healthcare providers are missing opportunities for nicotine cessation treatment. There is a lack of educational preparation amongst clinicians to treat nicotine addition and a concern that treatment of nicotine addiction can negatively impact existing psychiatric disorders. The purpose of this project was to create an educational plan for nicotine cessation for CMI clients at a community health center. The conceptual framework to guide this project is premised on Lewin's Change Theory and the Logic Model. Nine clinicians, specializing in mental health, reviewed the developing education program at three distinct times and responded to a 12-item author-developed questionnaire to determine their understanding of nicotine cessation and their willingness to initiate the nicotine cessation program. A review of the questionnaire responses indicates the clinicians agreed nicotine abuse is a problem for the CMI client, they had not received adequate training on nicotine cessation, and they would be comfortable incorporating the nicotine cessation education program in their practice. The findings were presented to key organization stakeholders at the community mental health center. Social change will result with implementation of the education program empowering clinicians, in this mental health center, to gain the knowledge to effectively diagnose and intervene when clients present with comorbid nicotine addiction and mental health conditions.

Orientador: Juliano Milanezi de Almeida / Banca: Edilson Ervolino / Banca: Estevam Augusto Bonfante / Resumo: Objetivo: avaliar a influência da nicotina e dos agentes antineoplásicos Cisplatina (CIS) e 5-fluorouracil (5-FU) sobre os tecidos peri-implantares, bem como os efeitos desses agentes antineoplásicos sobre os tecidos peri-implantares em animais previamente expostos à nicotina. Material e métodos: 180 ratos machos (Wistar) foram randomizados para dois grandes grupos (n=90), NIC e SS, em seguida, para três subgrupos (n=30) de acordo com os agentes antineoplásicos. Receberam 0,5ml de solução de cloreto de sódio 0,9% (SS) ou 3 mg/kg de hemissulfato de nicotina (NIC), de acordo com cada grupo, 30 dias antes e 30 dias após a cirurgia. No dia 0, todos os animais receberam os implantes de titânio (DSP Biomedical®, 4 mm x 2,2 mm) nas tíbias direita e esquerda. Aos 30 dias após a cirurgia, as aplicações de SS e NIC foram interrompidas por 5 dias e, aos 35 e 37 dias, foram administrados os agentes antineoplásicos CIS, 5-FU ou 0,5 ml de SS, via intraperitoneal, respeitando intervalo de 48 h entre as aplicações. Para CIS, 5 mg/kg e 2,5 mg/kg, e para 5-FU, 60 mg/kg e 40 mg/kg, respetivamente. SS-SS: receberam SS via subcutânea e intraperitoneal. SS-CIS: receberam SS via subcutânea e CIS via intraperitoneal. SS-5FU: receberam SS via subcutânea e 5-FU via intraperitoneal. NIC-SS: receberam NIC via subcutânea e SS via intraperitoneal. NIC-CIS: receberam NIC via subcutânea e CIS via intraperitoneal. NIC-5FU: receberam NIC via subcutânea e 5-FU via intraperitoneal. Dez animais por grupo/período... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objective: to evaluate the influence of nicotine and the antineoplastic agents Cisplatin (CIS) and 5-fluorouracil (5-FU) over the peri-implant tissues, as well as the effects of these agents over peri-implant tissues in animals previously exposed to nicotine. Material and Methods: 180 male rats (Wistar) were initially randomized to two groups (n=90), NIC and SS. Then, to three subgroups (n=30) according to the protocol of antineoplastic agents. Received 0.5 ml of sodium chloride 0.9% (SS) or 3 mg/kg of nicotine hemissulfate (NIC) according to each group, subcutaneously, 30 days before and after surgical procedure for implants placement. At day 0, all animals received the titanium implants (DSP Biomedical®, 4 mm x 2.2 mm) in both right and left tibiae. At 30 days after surgery SS and NIC was interrupted, and at 35 and 37 days were intraperitoneally administered the antineoplastic agents CIS, 5FU or 0.5 ml SS, with 48 h interval between applications. For CIS, 5 mg/kg and 2,5 mg/kg, and 5-FU, 60 mg/kg and 40 mg/kg, respectively. SS-SS: received SS subcutaneously and intraperitoneally. SS-CIS: received SS subcutaneously and CIS intraperitoneally. SS-5FU: received SS subcutaneously and 5-FU intraperitoneally. NIC-SS: received NIC subcutaneously and SS intraperitoneally. NIC-CIS: received NIC subcutaneously and CIS intraperitoneally. NIC-5FU: received NIC subcutaneously and 5-FU intraperitoneally. Ten animals per group and period were euthanized at 50, 65 and 95 days after implants placement. The collected specimens were fixed in buffered formaldehyde solution 4% for 48h and assigned to ground section processing for analysis of bone/implant contact (BIC), or conventional histologic processing with demineralization and paraffin embedding for histometric analysis of percentage of newly-formed bone (PNFB) (Complete abstract electronic access below) / Mestre

The adverse interaction between smoking and chronic pain has been known for decades. A variety of chronic pain conditions – ranging from headache to low back pain to fibromyalgia – markedly exacerbate smoking prevalence and intensity in packs per day among multiple patient populations. In patients seeking pain treatment, the prevalence of smoking approaches 50%, compared to less than 20% in the general population. Perhaps not surprisingly, the relationship is bidirectional: not only does persistent pain increase rates and intensity of smoking, but smoking also appears to exacerbate both the intensity and associated impairment of chronic pain. In fact, smoking appears to place individuals at risk for developing a chronic pain condition and may also facilitate the transition from acute to chronic pain. The growing body of literature documenting these associations has led to the proposition of a positive feedback loop: individuals smoke in part to cope with their pain, but smoking actually worsens the pain. Despite the strong evidence for the existence of this adverse interaction, the mechanisms responsible for it remain poorly understood. A number of preclinical and clinical studies have documented that nicotinic acetylcholine receptor (nAChR) agonists, e.g., nicotine, have analgesic efficacy in the acute pain setting, such as that produced experimentally in the research laboratory or experienced by patients postoperatively. In contrast, the role of nAChR activation in modulating chronic pain is less well characterized. The experiments described in this thesis determine whether persistent pain diminishes the antinociceptive (analgesic) efficacy of an α4β2 nAChR agonist in the rostral ventromedial medulla (RVM), a key brainstem pain modulatory nucleus, and subsequently begin to elucidate the mechanisms by which persistent pain elicits this plasticity. The complete Freund’s adjuvant (CFA) model of chronic pain was employed to test the hypothesis that persistent inflammatory injury diminishes the antinociceptive efficacy of the selective and potent α4β2 nAChR agonist epibatidine in key brainstem pain modulatory nuclei. Paw withdrawal latency to a noxious heat stimulus was used to evaluate the anti-hyperalgesic and antinociceptive effects of epibatidine microinjected in the RVM or periaqueductal gray (PAG) of male rats. The effects of epibatidine were assessed both in uninjured animals and in animals at different times after intraplantar CFA injection. Interestingly, pretreatment with an α4β2-selective antagonist demonstrated that the antinociceptive effects of epibatidine in naïve rats were mediated by α4β2 nAChRs in the RVM but not in the PAG. While the antinociceptive effects of epibatidine in the RVM were abolished after two weeks of inflammatory pain, the anti-hyperalgesic effects remained unchanged. Surprisingly, epibatidine no longer appeared to be acting primarily at α4β2 nAChRs as early as four hours after injury. Persistent inflammation did not alter the anti-hyperalgesic or antinociceptive effects of epibatidine in the PAG. Radioligand binding studies were conducted to test the most parsimonious hypothesis that a global reduction in α4β2 nAChR number or binding affinity during persistent injury was in part responsible for the decreased efficacy of epibatidine in the RVM after intraplantar CFA. Saturation binding using [3H]-epibatidine in membrane homogenates prepared from RVM and PAG tissue revealed no differences in receptors between saline- and CFA-treated rats at any time after injury, suggesting that a whole-nucleus reduction in nAChRs could not explain the observed behavioral phenomena. To query functional changes with greater resolution, whole-cell patch clamp electrophysiology was employed to begin assessing the consequences of nAChR activation by nicotine at the level of the neuron. Initial studies performed in the locus coeruleus demonstrated that all neurons responded to nicotine with an inward current that desensitized with continued exposure to the drug. Neurons in the RVM exhibited significantly more heterogeneity in their response to nicotine: desensitizing inward currents were seen in some; sustained outward currents in others; inward currents followed by outward currents in a third population; and still others had no response to nicotine exposure. The sustained outward currents persisted in the presence of the sodium channel blocker tetrodotoxin, were not blocked by an α4β2 nAChR-selective antagonist, and appeared to be mediated by G protein-coupled receptors and potassium channels. Taken together, the present results demonstrate that persistent inflammatory injury produces adaptive changes in nicotinic signaling in the RVM such that the antinociceptive effects of epibatidine activation are abolished in a time-dependent manner. These changes cannot be attributed to a whole-nucleus reduction in α4β2 nAChRs. However, nicotinic signaling in the RVM is complex, and small alterations in the pre- or postsynaptic actions of nicotine may have significant ramifications for the overall nociceptive sensitivity of an animal. The data presented here suggest that plasticity in nicotinic signaling within the bulbospinal pain modulatory pathways may in part explain the adverse interaction between smoking and chronic pain observed in humans.

Nicotine, 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.

The enzyme CYP2D6 can metabolize many centrally acting drugs and endogenous neural compounds (e.g. catecholamines); it can also inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and β-carbolines that have been associated with Parkinson’s disease (PD). CYP2D6 is ideally situated in the brain to inactivate these neurotoxins. The CYP2D6 gene is also highly polymorphic, which leads to large variation in substrate metabolism. Furthermore, CYP2D6 genetically poor metabolizers are known to be at higher risk for developing PD, a risk that increases with exposure to pesticides. Conversely, smokers have a reduced risk for PD and smokers are suggested to have higher brain CYP2D6 levels. Our studies furthered the characterization and involvement of CYP2D6 in neuroprotection against PD. METHODS: We investigated the effects of CYP2D6 inhibition on MPP+-induced cell death in SH-SHY5Y human neuroblastoma cells. We compared levels of brain CYP2D6, measured by western blotting, between human smokers and non-smokers, between African Green monkeys treated with saline or nicotine, and between PD cases and controls. In addition, we assessed changes in human brain CYP2D6 expression with age. RESULTS: Blocking CYP2D6 activity in SH-SY5Y cells with four diverse inhibitors significantly increased MPP+-induced neurotoxicity. Smokers have higher brain CYP2D6 compared to non-smokers. In monkeys, basal expression of CYP2D6 varied across brain regions and was increased by chronic nicotine treatment in select regions (notably the basal ganglia) and specific cell types. Expression of human brain CYP2D6 increased from fetal to 80 years of age in the frontal cortex; the influence of age on CYP2D6 expression was brain region specific. Compared to age-matched controls, PD cases had ~40% lower CYP2D6 levels in the frontal cortex, cerebellum and hippocampus consistent with lower CYP2D6 increasing the risk for PD. In the caudate and substantia nigra, CYP2D6 levels were similar between PD case and controls using Western blotting. This is likely due to the increase in CYP2D6-expressing astrocytes and much higher cellular CYP2D6 in PD affected areas as observed with immunocytochemical staining. CONCLUSIONS: Brain CYP2D6 can meaningfully inactivate neurotoxins, and it can be increased by nicotine in brain regions of interest to PD. These findings support the contention that higher brain CYP2D6 is protective and lower levels may contribute to increased risk for PD.

The enzyme CYP2D6 can metabolize many centrally acting drugs and endogenous neural compounds (e.g. catecholamines); it can also inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and β-carbolines that have been associated with Parkinson’s disease (PD). CYP2D6 is ideally situated in the brain to inactivate these neurotoxins. The CYP2D6 gene is also highly polymorphic, which leads to large variation in substrate metabolism. Furthermore, CYP2D6 genetically poor metabolizers are known to be at higher risk for developing PD, a risk that increases with exposure to pesticides. Conversely, smokers have a reduced risk for PD and smokers are suggested to have higher brain CYP2D6 levels. Our studies furthered the characterization and involvement of CYP2D6 in neuroprotection against PD. METHODS: We investigated the effects of CYP2D6 inhibition on MPP+-induced cell death in SH-SHY5Y human neuroblastoma cells. We compared levels of brain CYP2D6, measured by western blotting, between human smokers and non-smokers, between African Green monkeys treated with saline or nicotine, and between PD cases and controls. In addition, we assessed changes in human brain CYP2D6 expression with age. RESULTS: Blocking CYP2D6 activity in SH-SY5Y cells with four diverse inhibitors significantly increased MPP+-induced neurotoxicity. Smokers have higher brain CYP2D6 compared to non-smokers. In monkeys, basal expression of CYP2D6 varied across brain regions and was increased by chronic nicotine treatment in select regions (notably the basal ganglia) and specific cell types. Expression of human brain CYP2D6 increased from fetal to 80 years of age in the frontal cortex; the influence of age on CYP2D6 expression was brain region specific. Compared to age-matched controls, PD cases had ~40% lower CYP2D6 levels in the frontal cortex, cerebellum and hippocampus consistent with lower CYP2D6 increasing the risk for PD. In the caudate and substantia nigra, CYP2D6 levels were similar between PD case and controls using Western blotting. This is likely due to the increase in CYP2D6-expressing astrocytes and much higher cellular CYP2D6 in PD affected areas as observed with immunocytochemical staining. CONCLUSIONS: Brain CYP2D6 can meaningfully inactivate neurotoxins, and it can be increased by nicotine in brain regions of interest to PD. These findings support the contention that higher brain CYP2D6 is protective and lower levels may contribute to increased risk for PD.

As some references suggested that tobacco smoking behavior increases the risk of persistent pain and poorer recovery, but some demonstrated that nicotine decreased pain sensitivity. Both contrary conclusions make clinicians confused on how to manage the patients with tobacco smoking habit. This study conducted a retrospective way to evaluate the relationship between acute postoperative pain management and tobacco smoking behavior. This study included 511 Patients underwent general surgery were assigned to smokers or non-smokers. Site of surgery, type and duration of anesthesia were extracted from the anesthetic record. Information regarded each patient's gender, age, preoperative weight, past medical history, postoperative course, all non-opiate sedatives and opiate analgesics used in the first 72 hours were collected and recorded. Morphine administered via a patient-controlled analgesia (PCA) device was the preferred method of analgesia for these patients. Anesthesia was standardized. Exclusion criteria included the patients underwent major thoracic cardiovascular surgery, the patients with significant lung lesion, the patients with conscious disturbance, and the patients with allergic history to morphine. The results showed that of the sense of pain, the smoking group in the second day the pain scores significantly higher than non-smoking group (p<0.001), indicated that smoking patients were had more pain than non-smoking patients after surgery. And of the analgesic drug effects, the smoking group in the second and third day analgesic doses and the total analgesic doses were significantly higher than non-smoking group (p<0.023), showed that smoking patients significantly used more analgesic than non-smoking group after surgery. Smoking was associated with pain indeed existence.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 151-180). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.