Doctor of Philosophy / Department of Psychology / Stephen W. Kiefer / Methamphetamine is a potent psychomotor stimulant and a major drug of abuse. There is currently no effective medication available for treatment for methamphetamine addiction. The present study investigated the role of the dopamine D3 receptor on IV methamphetamine self-administration and its effect on methamphetamine induced neurochemical changes. Acute administration of the putative D3 receptor antagonists PG-01037 (10, 30 mg/kg, ip) and SB-277011A (12, 24, mg/kg, ip) significantly decreased the break-point for methamphetamine self-administration under a progressive-ratio (PR) schedule by 45 - 70%. Furthermore, both drugs dose dependently attenuated methamphetamine -triggered reinstatement of drug-seeking behavior in the reinstatement model of relapse. As with other drugs of abuse, the rewarding effects of methamphetamine are believed to be mediated by elevated levels of extracellular dopamine in the mesocorticolimbic system. The present study utilized in vivo microdialysis to examine the neurochemical mechanisms modulating the rewarding effects of methamphetamine actions evident in the various animal models of addiction. In the nucleus accumbens and ventral pallidum, acute methamphetamine (1.0 mg/kg, i.p.,) increased extracellular dopamine by 800 - 900% and decreased GABA by 60 – 65 % in the nucleus accumbens and ventral pallidum. Pretreatment with SB-277011A (12, 24 mg/kg) potentiated the methamphetamine induced dopamine increase but attenuated the methamphetamine-induced GABA decrease. Take together these data suggest that D3 selective antagonists’ pharmacotherapeutic potential in the treatment of methamphetamine addiction may involve a GABAergic mechanism.

Previous research has suggested that lobeline, a plant alkaloid derived from Lobelia inflate, has potential to be an efficacious pharmacotherapy for the treatment of methamphetamine dependence. In addition to attenuating methamphetamineinduced dopaminergic alterations in vitro, lobeline has been shown to decrease the primary rewarding effects and discriminative stimulus properties of methamphetamine in rats. It is of clinical interest to assess the utility of lobeline to decrease methamphetamine conditioned cues as these cues have been shown to significantly contribute to relapse. The current studies assessed the ability of lobeline to block the acquisition and expression of methamphetamine-induced conditioned place preference in rats. Lobeline blocked the acquisition of methamphetamine-induced conditioned place preference when a low dose of methamphetamine was used during conditioning. However, this blockade was surmounted with higher doses of methamphetamine. Furthermore, the expression of methamphetamine-induced conditioned place preference is attenuated following repeated administration, indicating that lobeline not only blocks the primary reinforcing effects of methamphetamine, but it also blocks the environmental cues that become associated with drug administration. These results provide further evidence that lobeline may be an efficacious treatment for methamphetamine dependence. The rewarding properties of psychostimulants are thought to be mediated, at least in part, by the nucleus accumbens shell. The effects of lobeline on methamphetamine-induced alterations in this dopaminergic region were assessed using microdialysis in rats. Acute lobeline did not have an effect on the methamphetamine-induced increases in dopamine, indicating that repeated lobeline administration may be more efficacious. Interestingly, lobeline potentiated the methamphetamine-induced decrease of the dopamine metabolite, DOPAC. These results suggest that acute lobeline may function to redistribute vesicular dopamine pools within the terminal bouton.

The production of methamphetamine in clandestine laboratories presents a particular hazard due to the environmental hazards it poses. In addition to the dangers associated with using caustic and reactive solvents, these clandestine laboratories also have to potential to cause a fire or explosion. This danger has caused some states to redefine arson to include fires caused by the illicit manufacture of drugs. Arson investigation can be challenging due to the destructive nature of the crime. Much of the evidence that existed prior the fire can be consumed and evidence that does survive can be difficult to identify in the rubble. Despite these difficulties, methods have been developed to determine the types of accelerants present in addition to identifying illicit substances such as methamphetamine and the precursor drug pseudoephedrine. This study was designed to determine if solid phase microextraction combined with gas chromatography/mass spectrometry could be used to analyze burned samples of wood to which pseudoephedrine had been applied. In addition, an experiment was designed to determine what concentration of pseudoephedrine must be present before a fire in a controlled laboratory setting, for a detectable amount to remain. Samples were created by adding pseudoephedrine hydrochloride, either in powder form or dissolved in methanol, to blocks of Douglas Fir and exposing the surface to a flame for two minutes. Additional samples were created by adding trace amounts, i.e. microliter quantities, of pseudoephedrine standard to blocks of wood before placing them in a fire for ten minutes. A thermal degradation product of pseudoephedrine was detected in samples containing more than 15 mg of the drug. To verify that the detected product was a result of thermal degradation, 10 mg of pseudoephedrine were heated at 200 °C for one hour. The product of the thermal degradation study and the product detected following two minutes of exposure to a flame had the same retention time and mass spectrum. Therefore, it was concluded that the detected thermal degradation product may be used to indicate the presence of pseudoephedrine in a fire.

The neural mechanisms mediating one-trial and multi-trial behavioral sensitization during early ontogeny are poorly understood. The purpose of this thesis was to assess the importance of D2-like receptors for the induction of cocaine- and methamphetamine-induced one-trial and multi-trial behavioral sensitization during the middle and late preweanling period. In a series of four experiments, rats were injected with saline or the selective dopamine D2-like receptor antagonist raclopride 15 min prior to treatment with the indirect dopamine agonists cocaine or methamphetamine. Acute control groups received two injections of saline. The pretreatment regimens occurred on either PND 16 or PND 20 (one-trial behavioral sensitization) or PND 13-16 or PND 17-20 (multi-trial behavioral sensitization). On PND 17 or PND 21, rats were challenged with either cocaine or methamphetamine and sensitized responding was assessed. With only a single exception, both one -trial and multi-trial cocaine- and methamphetamine-induced sensitization was evident on PND 17 and PND 21. Importantly, the D2-like receptor antagonist raclopride did not prevent the induction of cocaine- or methamphetamine-induced one-trial behavioral sensitization. In regards to multi-trial behavioral sensitization, raclopride failed to inhibit cocaine -induced sensitized responding on PND 17 and PND 21. Interestingly, higher doses of raclopride (0.5 and 1 mg/kg) were able to prevent the induction of multi-trial methamphetamine-induced sensitization on PND 17. Therefore, D2-like receptor antagonism differentially affected methamphetamine -induced behavioral sensitization depending on whether a one-trial or multi-trial paradigm was employed. When considered together, these results suggest that the neural mechanisms underlying the methamphetamine -induced behavioral sensitization of preweanling rats differs depending on the type of experimental paradigm (one- vs multi-trial) being used. Other potential explanations (i.e., nonspecific antagonist effects, impact of contextual conditioning, etc.) for this interesting effect are presented in the Discussion.

Victims of childhood trauma are vulnerable to substance abuse due to their inability to develop coping skills following trauma, which can lead to criminal and violent behavior. Guided by the ecodevelopmental theory, this phenomenological study attempted to relate the perceived experiences of violent behaviors as a result of methamphetamine use in women to the types of childhood trauma the women experienced. Fourteen women were recruited using purposive sampling in collaboration with the South Brunswick Counseling Center, based on inclusion criteria that included being over the age of 18; having abstained from methamphetamine use for at least a year; having experienced a childhood trauma including physical, sexual, emotional/verbal abuse or neglect; and having perpetrated violence against others as an adult while under the influence of methamphetamine. Data were analyzed using Moustakas' qualitative analysis method and revealed 5 themes: unresolved anger over childhood trauma, 'roller coaster of emotions,' lack of coping resources, initial negative influences, and therapist influence. The participants confirmed previous research findings that unresolved anger over past childhood trauma is the main consequence associated with methamphetamine-induced violence. The study impacts social change by adding to the body of knowledge regarding the shared experiences of these women between childhood trauma and methamphetamine-induced violence. These findings could aid in the development of community-based prevention and intervention programs for victims of childhood trauma, mental health professionals establishing evidence-based interventions, and victims' parents, who are susceptible to substance abuse and resulting violence.

Lacking a healthy attachment to a caregiver and having in-utero methamphetamine exposure have been linked to a variety of cognitive delays, developmental delays, and mental health issues throughout a person's lifespan. It is unknown if there is a relationship between in-utero methamphetamine exposure and the ability to build a healthy attachment to a caregiver. The purpose of this generic qualitative study was to improve understanding of the perceptions of caregivers about attachment efforts for foster children under the age of 3, who have had in-utero methamphetamine exposure. This study was guided by attachment theory. Purposeful sampling was used to select 7 participants who had provided care to foster children with in-utero methamphetamine exposure within the last year. Data were collected through the use of semistructured interviews, which were conducted in-person, audiotaped, and then transcribed. Data was analyzed through text searches of themes, axial coding, and repetitive words. Trustworthiness was obtained through member checking and generating a rich description of the participants' experiences. The findings revealed that many of the participants feel that these children do not respond to their efforts to build a healthy attachment to them. They also felt that the foster children did not process stimuli, such as touch, in the same way as other children; that the foster children found such interactions to be aversive. The findings of this study have the potential to impact social change by assisting therapists, caseworkers, and foster parents better understand the needs of foster children and to create a foundation for interventions to better serve foster children with in-utero methamphetamine exposure.

<p>This study presents a discursive journey with regard to the risk and protective factors confronting individuals who engage in methamphetamine use within the Manenberg area. Given that this journey requires a cautious and sensitive approach to the meaning making of the lived experiences of the six (6) individual users (the informant base) / the study adopted an analysis process that would allow for a guided &ldquo / tour&rdquo / of these experiences. In doing so, the study made use of the grounded theory method that allowed for this guided &ldquo / tour&rdquo / to be fully anchored in the collected data. External to this data, and once the data emerged as engageable themes, the study introduced, relevantly so, Bronfenbrenner&rsquo / s social-ecological model of human development, so to multiply and deepen the meanings embedded within the data. The merging of this external frame, provided by Bronfenbrenner&rsquo / s model, and the rich data provided by the six (6) informants, uncovered critical themes in understanding the risk and protective factors at play within Manenberg. These themes relate to the historical identity of Manenberg, given the history of Apartheid, the role of the local community and its perceived tolerance of the practice of drug use, which is further echoed in the identity of the family and its limited ability to support drug users in the face of ever-growing poverty. The themes also uncovered the bipolarity in the practice of drug trade and gangsterism as serving a subsistence function, at one level, and an exploitative function at another. Furthermore, the study solidified traditional views that the peer collective is, indeed, a critical actor on the stage of drug use and that the individual (as an actor) continues to be confronted by a script of poverty and disillusionment. This script, as will be illustrated, is also active in preconceived notions of gender stratification.</p>

Thesis (M.S.)--University of Massachusetts Amherst, 2009. / Includes bibliographical references (p. 47-59).

Over 110,000 known methamphetamine (meth) clandestine labs were reported in the U.S. from 1999 to 2008. The production of meth is regarded as a national epidemic, and can lead to substantial contamination of indoor materials. Due to its chemical and physical properties, meth residual can persist on indoor surfaces and in indoor air for prolonged periods. Unfortunately, most remediation techniques lack strong scientific support and cleanup standards are inconsistent across different states. A better understanding of the mechanistic interactions between meth and indoor environment can help improve remediation strategies and the development of regulations. In this study, equilibrium partitioning coefficients (Ke) between a meth surrogate and wall materials were estimated based on laboratory experiments. The resulting Ke values were then used in a screening model to predict meth decay rates from wall materials and indoor air. The effects of ventilation and indoor air mixing on meth off gassing were explored. / text

<p><font size="3"> <p>The blood-brain barrier (BBB) is an interface between the brain parenchyma and the circulating system. This barrier plays a vital role in protecting the CNS by restricting free paracellular diffusion of molecules from the systemic circulation. Methamphetamine (MA) is a highly addictive psychostimulant and has demonstrated neurotoxic properties as well as the ability to compromise the BBB. MA exposure is strongly linked with increased oxidative stress which can result in a decrease in the integrity of the BBB.<font size="3">The aim of this study was to investigate </font><i><font size="3" face="Times New Roman,Times New Roman"><font size="3" face="Times New Roman,Times New Roman">in vitro </font></font><font size="3">effects of pure and street MA &quot / tik&quot / on DNA proliferation and cell cycles in mouse brain endothelial (bEnd5) cells. <font size="3">Trypan blue was used to determine effects of MA (0.0001M-1mM) on cell viability and % cell growth. The Cell Titer Glo&reg / luminescent assay and nonradioactive analogue, 5-bromo-2'-deoxyuridine (BrdU) was used to detect ATP and DNA levels, respectively. Cell cycles (propidium iodide incorporation) were analysed using flow cytometry. Statistical analysis was performed using Wilcoxin Rank Sum Test in which P&lt / 0.05 was denoted as significant. <font size="3">Results of this study showed that:&nbsp / <font size="3">1. Viability of bEnd5 cells exposed to all selected concentrations of MA were unaffected when compared to controls (P&gt / 0.05). <font size="3">2. % Cell growth was suppressed by MA exposure at 96hrs in comparison to that of controls (P&le / 0.03). 3. Cells exposed to MA had significant higher ATP concentrations than control cells at 96hrs (P &le / .0.03) 4. DNA synthesis was markedly suppressed in cells exposed to pure MA and street MA sample 4 (P&le / 0.03), while was similar and higher in cells exposed to street MA sample 1 (P=0.39), and street MA sample 2 and 3 (P&le / 0.04), respectively at 96hrs. 5. bEnd5 cell were arrested between 72 and 96hrs at the G1-S phase. <font size="3">In conclusion, this study demonstrated pure and illicit samples of MA obtained from forensic police did not affect the viability of bEnd5 cells, however resulted in the significant suppression of their cell numbers. This growth inhibition may be due to MA-induced cell cycle arrest at the G1-S phase. The study also showed that compounds found in the samples of street MA produced results significantly different to that of pure MA. </font></font> <p>&nbsp / </p> </font>&nbsp / </font></font></font> <p>&nbsp / </p> </i></p> </font></p> <p>&nbsp / </p>