Azetidine is a four-membered nitrogen-containing heterocyclic ring that has recently received a great deal of attention as a molecular scaffold for the design and preparation of biologically active compounds. Structure-activity studies employing functionalized azetidines have led to the development of variety of drug molecules and clinical candidates encompassing a broad spectrum of biological activities. Herein, the synthesis a novel series of 3-aryl-3-arylmethoxyazetidines is described. Selected 3-aryl-3-arylmethoxyazetidines were evaluated for their binding affinity to multiple monoaminergic transporters for the potential treatment of methamphetamine addiction. It was discovered that this scaffold exhibits high binding affinity (nM) for both the serotonin and dopamine transporters. In addition, a new method was developed for the synthesis of 3,3-diarylazetidines. This new approach provides a facile and efficient method to synthesize a variety of diaryl heterocycles including 3,3-diarylazetidines, 3,3-diarylpyrrolidines, and 4,4-diarylpiperidines in moderate to good yields.

The focus of these studies was directed towards the synthesis of novel N-heterocyclic compounds and pharmacological evaluation of these compounds for activity at monoamine transporters. A series of novel piperidine and pyrrolidine analogues were prepared from commercially available starting material with a three and four step synthetic method, respectively. A variety of substituents on the aromatic ring were incorporated to achieve a diverse library of compounds. The preliminary binding studies of piperidine molecules showed strong affinity towards serotonin transporters and moderate affinity towards dopamine transporters. The focus of further studies was directed towards utilization of iridium catalysis for the development of new synthetic methods for biologically important molecules. This research has led to the development of a new synthetic strategy for the construction of nicotine and its analogues. In addition, the iridium catalysis was also used for alkylation of amides with primary and secondary alcohols under microwave conditions.

>Magister Scientiae - MSc / Introduction The blood-testis barrier (BTB) is formed by tight junctions between adjacent Sertoli cells. The barrier formed by these tight junction helps to create a specialized environment for spermatogenesis and provide an immunological barrier to protect developing germ cells. Methamphetamine (Meth) is known as neurotoxin however, its effects on the male reproductive system, especially on Sertoli cells and, the BTB are not well established. Therefore, this study aimed to determine the effects of Meth on the TM4 mouse testis Sertoli cell line and on the integrity of the BTB permeability. Materials and Methods This study investigated the effect of selected concentrations of Meth (0.1 μM, 1 μM, 10 μM, 20 μM and 100 μM) on TM4 mouse testis Sertoli cell line for 24 until 96 hours, using two treatments: an “acute” study (24 hrs exposure) and a “chronic” study, where treatment occurred on a daily basis over 96 hrs. The following parameters were investigated: viability, cell proliferation, mitochondrial activity, monolayer permeability.

3,4-methlenedioxymethamphetamine (MDMA), the main constituent of Ecstasy, is a ring-substituted amphetamine commonly abused in recreational users. High doses of MDMA determined by allometric scaling produce serotonin (5-HT) axon deneveration. Studies suggest that this interspecies scaling does not reflect human use. An 'effects' scale comparing similar behavioral and physiological effects between species has been postulated as more accurate for translational studies. Experiment 1 examined the effects of MDMA on serotonergic forebrain innervation using immunohistochemical labeling targeting the serotonin transporter protein (SERT). Experiments 2 and 3 examined low and high doses of MDMA on spatial memory, prefrontal functioning, and serotonergic neurotoxicity using 'effects' scaling. Long Evans rats were given MDMA regimens of: chronic low dose (daily injections of 1.5 mg/kg for 10 days); binge low dose (2 days of 4 x 1.5 mg/kg spaced 2 hours apart), binge high dose (2 x 7.5 mg/kg sp aced 2 hours apart). Acquisition, retention, and spatial reversal (SR) were measured in a water maze task. A 2.0 mg/kg MDMA drug challenge was then given prior to a serial spatial reversal (SSR) task to assess performance while under the effect of the drug. Attentional set shifting and behavioral flexibility were assessed in an intradimensional extradimensionl (IED) task using odor/texture discriminations. MDMA chronic and binge low doses did not impair water maze or IED performance and produced no reductions in SERT expression. MDMA binge high dose resulted in significant reductions of SERT density in the prefrontal cortex, striatum, cortical mantle, hippocampus, amygdala, and many thalamic nuclei. Despite prominent 5-HT denervation, water maze performance was unaffected. Selective impairment in behavioral flexibility on the IED test was found. / This suggests that low doses of MDMA do not produce long-term deleterious effects. But, high doses of MDMA taken in 'binges' produces widespread loss of forebrain SERT fiber innervation and significant impairments in reversal learning, while leaving attentional set shifting and spatial navigation unscathed. / by Stephanie Brooke Linley. / Thesis (Ph.D.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

In the USA, approximately 15% of women smoke tobacco cigarettes during pregnancy. In utero tobacco smoke exposure produces somatic growth deficits like intrauterine growth restriction and low birth we

Methamphetamine (METH) is a highly addictive substance that is highly prevalent in today’s society, with over 1 in 20 adults over 26 having taken it at least once. While it is known that METH, a common psychostimulant, acts on both the mesolimbic dopamine (DA) and nigrostriatal DA systems by affecting proteins involved in DA reuptake and vesicular packaging, the specific mechanism of what is known as METH neurotoxicity remains obscure, but has been shown to involve oxidative stress. Studies have shown that reactive oxygen species act on the same proteins that METH affects. Oxidative species have also been known to catalyze the formation of melanins in dopaminergic cells. We explore this link more fully here. In an in vitro system, oxidative species (including Fe3+, an inorganic catalyst for oxidative stress), enhance the rate of melanization of DA. Methamphetamine increased oxidative stress in an in vivo model. Additionally, METH enhanced phasic (stimulated) DA release and caused an electrically-independent efflux of DA. Lidocaine abolished phasic DA release, but did not affect METH-induced DA efflux, indicating action-potential dependent and independent mechanisms behind METH’s effects. The sigma-1 receptor antagonist BD 1063 significantly attenuated METH’s effect on DA release. Depletion of intracellular calcium (Ca2+) reserves also attenuated METH-enhancement of DA release. We investigated the role of oxidative species in METH-induced DA efflux. Reduced glutathione (the substrate for glutathione peroxidase) and 4-hydroxy-TEMPOL (a superoxide dismutase mimetic) blocked METH’s effect on DA release, suggesting that a reactive oxygen species (ROS), most likely superoxide, is necessary for METH-induced DA efflux. Finally, oxidative stress as well as acute METH impairs the vesicular monoamine transporter 2 (VMAT2) by S-glutathionylation modification of Cys-488, highlighting VMAT2 as a likely regulator of METH’s effects on electrically independent DA release. These findings help outline a model in which METH induces DA release in the NAc through a signaling cascade involving the sigma receptor and ROS signaling molecules.

Methamphetamine is the most common amphetamine used and, along with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy), is considered part of a worldwide drug epidemic. Monitoring metham-phetamine levels in the body is important for purposes of drug screening for employment, criminal investigations, and therapeutic drug monitoring. While methamphetamine is suitable for detection using immunoassay techniques, these methods tend to have significant cross reactivity with other compounds. Over the last decade, more than eighty different quantitative, confirmatory analytical methods for measuring methamphetamine in biological samples have been published in the scientific literature. Analytical instrumentation used in these methods includes gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), capillary electrophoresis (CE), among others. These assays are capable of quantifying methamphetamine concentrations in a variety of biological matrices, including blood, plasma, urine, hair, and fingernails. Some of these techniques can achieve detection as low as 0.1 ng/mL (1 ppb) concentra-tions. The strengths and limitations of these methodologies will be discussed in the context of methamphetamine analysis. Additionally, methods that can simultaneously measure methamphetamine levels as well as metabolites and other drugs of abuse will be highlighted.

Adolescence is a vulnerable developmental period in regards to drug initiation and use. The gateway hypothesis suggests that adolescent cigarette smoking may result in a heightened risk for methamphetamine use. However, little is understood about the role of nicotine on adolescent methamphetamine addiction. The aim of the present study was to determine whether early, late, or continuous adolescent nicotine exposure would alter oral methamphetamine self-administration, extinction, or reinstatement. A total of 164 male and female Sprague-Dawley rats were pretreated with saline or nicotine (0.16, or 0.64 mg/kg, sc) beginning on postnatal day (PD) 25 for 10 consecutive days. On PD 35, rats in the 0.16 and 0.64 mg/kg pretreatment groups were evenly divided and assigned to a group that either continued to receive the same nicotine dose they received as adolescents or saline. Rats that had received saline as adolescents were divided into three equal groups, where they received 0.16 or 0.64 mg/kg nicotine or continued to receive saline injections. Drug treatments starting on PD 35 continued until the end of the experiment. Thus, there were a total of 7 groups: SAL–SAL, 0.16–0.16, 0.16–SAL, SAL-0.16, 0.64–0.64, 0.64–SAL, SAL-0.64. On PD 35, all rats began nose poke training. Rats were exposed to a methamphetamine fade in, sucrose fade out procedure across 5 different methamphetamine-sucrose combinations. This procedure resulted in exposure to a 40 mg/l methamphetamine solution for 3 consecutive days on a FR2 schedule. Following the last day of methamphetamine self-administration, rats were exposed to extinction training. Once the extinction criteria were met, rats were given a priming injection of methamphetamine (1.0 mg/kg, ip). Data from the present investigation revealed two main important findings: a) acquisition of oral methamphetamine self-administration can be attained in adolescent rats; and b) adolescent nicotine exposure differentially alters oral methamphetamine self-administration. Exposure to a low dose of nicotine (0.16 mg/kg), but not a high dose of nicotine (0.64 mg/kg), attenuated consumption and responding for methamphetamine during self-administration. During the extinction and reinstatement periods, we found that nicotine (0.16 or 0.64 mg/kg) exposure did not alter consumption or responding for methamphetamine. Female rats showed augmented total active nose pokes and active nose pokes within the reinforcement period compared to male rats. Conversely, male rats showed augmented sucrose and methamphetamine solution consumption across methamphetamine acquisition sessions 1–6. These data suggest that for adolescents who already present moderate cigarette smoking behavior at the time of methamphetamine cessation treatment, total abstinence from both nicotine and methamphetamine may be a less effective form of treatment. It may be clinically beneficial to first treat the methamphetamine addiction, and subsequently treat the nicotine addiction. Regardless of the method of treatment for adolescent methamphetamine addiction, nicotine exposure should be closely monitored.

Human immunodeficiency (HIV) infection can result in neurocognitive deficits in about one-half of infected individuals. Despite excellent systemic effectiveness, restricted antiretroviral penetration across the blood-brain barrier (BBB) is a major limitation in fighting HIV infection within the central nervous system (CNS). Drug abuse exacerbates cognitive impairment and pathologic CNS changes in HIV-infected individuals. This work investigates the effects of the HIV-1 protein, Tat, and drugs of abuse on factors affecting drug penetration into the brain. Firstly, an in vitro model of the blood-brain barrier was built to study effects of HIV-1 Tat and methamphetamine (Meth) on integrity and function of the BBB, in turn how HIV-1 Tat and meth will affect antiretroviral penetration into the brain. We found that co-exposure HIV-1 Tat and Meth results in inhibition or impairment of P-glycoprotein activity at the BBB. Also, simultaneous inhibition of P-glycoprotein (P-gp) and Multidrug Resistant Protein -1 (MRP-1), by verapamil and MK-571 causes an increase in accumulation of atazanavir inside the primary human brain endothelial cells. Secondly, we developed and validated the method for simultaneous determination of tenofovir, emtricitabine, and dolutegravir in cell extracts of CNS cells. This method was used to study how HIV-1 Tat and/or morphine affects antiretroviral penetration in CNS cells like human brain microvascular endothelial cells, human astrocytes, human microglia, and human pericytes. We found that in untreated cells, accumulation of antiretroviral drugs was higher in hCMEC/D3 cells compared to other CNS cell types. Also, HIV-1 Tat and/or morphine had no significant effect on antiretroviral penetration amongst these cell types. Overall, the rank order of intracellular accumulation observed in treated and untreated cells was dolutegravir > emtricitabine > tenofovir.

This thesis, presented as a collection of articles, journalistic in its tone, is titled "Menace or Moral Panic? Methamphetamine and the New Zealand Press". Within the collection, evidence and background information is presented that supports a claim that a moral panic fitting Stanley Cohen's classic model occurred between 1999 and 2004.This moral panic was also identified using Stuart Hall's definition of a moral panic outlined in his mugging study published in 1978 as well as the more contemporary model of Goode and Ben-Yehuda (1994). Jock Young's theory of The Deviance Amplification Spiral is also addressed and can be applied to this collection when considering the close 'symbiotic' relationship that our press here in New Zealand have with our police force. In looking at this particular subject it is vital that we look at how drugs and drug use play a role in the media. Also as part of the backgrounding for this collection it was of critical importance to find whether a moral panic happened anywhere else in the world in relation to methamphetamine. Two previous moral panics about methamphetamine are featured in this collection as part of a case study presented in "Ancient Anecdotes meet Modernity: Drugs and the Rise of Methamphetamine" in which between the years of 1989 and 1996 America passed through two moral panics brought on to a considerable extent by a mixture of media hype and political opportunism. By including a foreign case study we can begin to see how the New Zealand methamphetamine situation had similarities to the American example, making identification of New Zealand's moral panic more definitive. Giving verification to the claims, a lengthy analysis of twenty-five samples from the New Zealand press is also featured in this collection. By looking at the way the stories from the samples developed identification of the various stages of the moral panic become more visible. The last article in this collection investigates, using expert interviews, if there is enough evidence to support the claim that methamphetamine may be a menace to New Zealand society, but that the extent of that menace may be exaggerated by a moral panic brought on by our media and fuelled by our police force.