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- Creators: Neisewander, Janet
- Creators: Barrett, The Honors College
- Resource Type: Text
Description
Globally, addiction to stimulants such as methamphetamine (METH) remains a significant public health problem. Despite decades of research, no approved anti-relapse medications for METH or any illicit stimulant exist, and current treatment approaches suffer from high relapse rates. Recently, synthetic cathinones have also emerged as popular abused stimulants, leading to numerous incidences of toxicity and death. However, contrary to traditional illicit stimulants, very little is known about their addiction potential. Given the high relapse rates and lack of approved medications for METH addiction, chapters 2 and 3 of this dissertation assessed three different glutamate receptor ligands as potential anti-relapse medications following METH intravenous self-administration (IVSA) in rats. In chapters 4 through 7, using both IVSA and intracranial self-stimulation (ICSS) procedures, experiments assessed abuse liability of the popular synthetic cathinones 3,4-Methylenedioxypyrovalerone (MDPV) , methylone, α-pyrrolidinovalerophenone (α-PVP) and 4-methylethylcathinone (4-MEC). Results from these seminal studies suggest that these drugs possess similar abuse potential to traditional illicit stimulants such as METH, cocaine, and 3,4-methylenedioxymethamphetamine (MDMA). Finally, studies outlined in chapter 8 assessed the potential neurotoxic or adverse cognitive effects of METH and MDPV following IVSA procedures for the purpose of identifying potential novel pharmacotherapeutic targets. However, results of these final studies did not reveal neurotoxic or adverse cognitive effects when using similar IVSA procedural parameters that were sufficient for establishing addiction potential, suggesting that these parameters do not allow for sufficient drug intake to produce similar neurotoxicity or cognitive deficits reported in humans. Thus, these models may be inadequate for fully modeling the adverse neural and psychological consequences of stimulant addiction. Together, these studies support the notion for continued research into the abuse liability and toxicity of METH and synthetic cathinones and suggest that refinements to traditional IVSA models are needed for both more effective assessment of potential cognitive and neural deficits induced by these drugs and screening of potentially clinically efficacious pharmacotherapeutics.
ContributorsWatterson, Lucas (Author) / Olive, Michael F (Thesis advisor) / Czyzyk, Traci (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2014
Description
Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement paradigm. Here, we used a nicotine self-administration and contingent cue-induced reinstatement model to examine rapid, transient synaptic plasticity (t-SP) induced by nicotine cue-triggered motivation. Although preliminary, treatment with the NMDA GluN2B subunit antagonist, ifenprodil, reduced reinstated nicotine seeking, and increased the percentage of spines with smaller head diameters. Thus, future studies are needed to fully parse out the role of NAcore GluN2B receptors in cued nicotine seeking and t-SP.
ContributorsMccallum, Joseph John (Author) / Gipson-Reichardt, Cassandra (Thesis director) / Neisewander, Janet (Committee member) / Olive, Michael Foster (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Polysubstance abuse is far more common than single substance abuse. One of the most widely abused, yet greatly understudied combination of drugs is the simultaneous use of methamphetamine (meth) and alcohol. Because little research has been conducted on the co-abuse of meth and alcohol, it is important to study the behavioral and neural mechanisms underlying the use of both to combat addiction and come closer to finding an effective treatment of this form of drug abuse. This study uses a rodent model to attempt to identify the mechanisms underlying this co-abuse through the stimulation of the medial forebrain bundle (MFB) and thus the activation of the mesocorticolimbic pathway, the brain's pleasure circuit. First, self-stimulation thresholds (the lowest electrical current the rats are willing to respond for) were determined using a process called Discrete Trials Training. This threshold was later used as a baseline measure to reference when the rats were administered the drugs of abuse: meth and alcohol, both alone and in combination. Our overall results did not show any significant effects of combining alcohol and meth relative to the effects of either drug alone, although subject attrition may have resulted in sample sizes that were statistically underpowered. The results of this and future studies will help provide a clearer understanding of the neural mechanisms underlying the polyabuse of meth and alcohol and can potentially lead to more successfully combating and treating this addiction.
ContributorsDrafton, Kaitlyn Marie (Author) / Olive, Foster (Thesis director) / Glenberg, Arthur (Committee member) / Sanford School of Social and Family Dynamics (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS.
ContributorsLewis, Candace (Author) / Olive, M. Foster (Thesis advisor) / Hammer, Ronald (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015
Description
The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, opioids, and amphetamine. Methamphetamine (METH) causes great harm to both the individual user and to society; yet, no studies have examined the effects of MS on METH SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core were also investigated. Long-Evans pups and dams were separated on postnatal days (PND) 2-14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-hr daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.
ContributorsLewis, Candace (Author) / Olive, Micheal F (Thesis advisor) / Conrad, Cheryl (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
Serotonin 1B receptors (5-HT1BRs) are a novel target for developing pharmacological therapies to reduce psychostimulant craving. 5-HT1BRs are expressed in the mesolimbic pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which is involved in reward and motivation. 5-HT1BR agonists modulate both cocaine- and methamphetamine-seeking behaviors in rat models of psychostimulant craving. In this dissertation, I tested the central hypothesis that 5-HT1BRs regulate cocaine and methamphetamine stimulant and rewarding effects in mice. I injected mice daily with cocaine for 20 days and then tested them 20 days after their last injection. The results showed that the 5-HT1BR agonist CP94253 attenuated sensitization of cocaine-induced locomotion and cocaine-seeking behavior, measured as a decrease in the ability of a cocaine priming injection to reinstate extinguished cocaine-conditioned place preference (CPP). Subsequent experiments showed that CP94253 given prior to conditioning sessions had no effect on acquisition of methamphetamine-CPP, a measure of drug reward; however, CP94253 given prior to testing attenuated expression of methamphetamine-CPP, a measure of drug seeking. To examine brain regions and cell types involved in CP94253 attenuation of methamphetamine-seeking, I examined changes in the immediate early gene product, Fos, which is a marker of brain activity involving gene transcription changes. Mice expressing methamphetamine-CPP showed elevated Fos expression in the VTA and basolateral amygdala (BlA), and reduced Fos in the central nucleus of the amygdala (CeA). In mice showing CP94253-induced attenuation of methamphetamine-CPP expression, Fos was increased in the VTA, NAc shell and core, and the dorsal medial caudate-putamen. CP94253 also reversed the methamphetamine-conditioned decrease in Fos expression in the CeA and the increase in the BlA. In drug-naïve, non-conditioned control mice, CP94253 only increased Fos in the CeA, suggesting that the increases observed in methamphetamine-conditioned mice were due to conditioning rather than an unconditioned effect of CP94253 on Fos expression. In conclusion, 5-HT1BR stimulation attenuates both cocaine and methamphetamine seeking in mice, and that the latter effect may involve normalizing activity in the amygdala and increasing activity in the mesolimbic pathway. These findings further support the potential efficacy of 5-HT1BR agonists as pharmacological interventions for psychostimulant craving in humans.
ContributorsDer-Ghazarian, Taleen (Author) / Neisewander, Janet (Thesis advisor) / Olive, Foster (Committee member) / Newbern, Jason (Committee member) / Wu, Jie (Committee member) / Arizona State University (Publisher)
Created2018
Description
The combined use of methamphetamine and opioids has been reported to be on the rise throughout the United States (U.S.). However, our knowledge of this phenomenon is largely based upon reported overdoses and overdose-related deaths, law enforcement seizures, and drug treatment records; data that are often slow, restricted, and only track a portion of the population participating in drug consumption activities. As an alternative, wastewater-based epidemiology (WBE) has the capability to track licit and illicit drug trends within an entire community, at a low cost and in near real-time, while providing anonymity to those contributing to the sewer shed. In this study, wastewater was collected from two Midwestern U.S. cities (2017-2019) and analyzed for the prevalence of methamphetamine and the opioids oxycodone, codeine, fentanyl, tramadol, hydrocodone, and hydromorphone. Monthly 24-hour time-weighted composite samples (n = 48) from each city were analyzed using isotope dilution liquid chromatography tandem mass spectrometry. Results showed that methamphetamine and total opioid consumption (milligram morphine equivalents) in City 1 were strongly correlated only in 2017 (Spearman rank order correlation coefficient, ρ = 0.78), the relationship driven by fentanyl, hydrocodone, and hydromorphone. For City 2, methamphetamine and total opioid consumption were strongly positively correlated during the entire study (ρ = 0.54), with the correlations driven by hydrocodone and hydromorphone. In both cities, hydrocodone and hydromorphone mass loads were highly correlated, suggesting a parent and metabolite relationship. WBE provides important insights into licit and illicit drug consumption patterns in near real-time as they evolve; important information for community stakeholders in municipalities across the U.S.
ContributorsClick, Kathleen Grace (Author) / Halden, Rolf (Thesis director) / Gushgari, Adam (Committee member) / Driver, Erin (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution & Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Substance abuse has become a major problem in the USA in the past decade, with immense public health and societal consequences. Methamphetamine (meth) use has grown due to an increased number of meth production and distribution markets. Border states such as Arizona and California are especially concerned with Mexico’s production and distribution of meth to their residents. A mathematical model for meth use and markets was developed and then analyzed to track multiple types of drug markets and drug-related arrests for possession or distribution. The importance of social influences as a major causal factor in the onset of illicit drug use is explicitly incorporated. The model parameters are then estimated using meth-related data from California and Arizona. A parameter sensitivity analysis on the model output was carried out. The results suggest that law enforcement policy aimed at marketers will be significantly more effective than targeting current users. Moreover, local unorganized markets have a greater role in maintaining the endemic level of meth users. Whereas, global organized markets play a role in initiating meth use outbreaks. Some implications for interventions and health promotion for the two states are also discussed.
ContributorsChavez, Brianna (Author) / Mubayi, Anuj (Thesis director) / Shafer, Michael (Committee member) / Amol Thakur, Mugdha (Committee member) / Industrial, Systems & Operations Engineering Prgm (Contributor) / School of Human Evolution & Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05