Class of 2007 Abstract / Objectives: To identify differences between patients diagnosed with a serious mental illness who test positive for cocaine and/or methamphetamine compared to patients who test positive or other abused substances. Methods: This retrospective study of clinical data obtained through a community mental health agency that provides outpatient services for patients with a serious mental illness. The study population was divided into two subgroups: positive cocaine and/or methamphetamine drug screen versus other positive drug screens and were compared over a 12- month period for the frequency and types of positive drug screens and blood alcohol levels, days of court-ordered treatment, the number of psychiatric hospitalizations and length of stay, primary psychiatric diagnosis, and the cost of care for services provided. Results: More females were in the “cocaine/methamphetamine” group versus more males in the “other substances of abuse” group, (p < 0.01). A higher proportion of patients diagnosed with psychotic disorders tested positive for “other substances” than for “cocaine and methamphetamine” (p < 0.01) and the “cocaine/methamphetamine” group had significantly more mood and anxiety disorders than the other group (p < 0.05). The frequency of patients testing positive for marijuana, methadone, and other opiates was higher in the “other substance abuse” group (p < 0.001). Patients in the “cocaine/methamphetamine” group had higher rates of polysubstance abuse (p < 0.001). The most commonly abused substance was cocaine (53.8%). Conclusions: Regular drug screening for substances of abuse and utilization of drug treatment programs should be recommended for SMI patients to improve their care and treatment outcomes.

In an effort to search for potential therapeutic agents for cocaine addiction, a novel class of compounds was synthesized and evaluated for in vitro dopamine and serotonin transporter affinities. These unique 3ƒÀ-aryl-3ƒ¿-arylmethoxytropane analogues incorporated the structure of dopamine selective 2-substituted-3-phenyltropanes and the design of serotonin selective meperidine derivatives. In general, the 3ƒÀ-aryl-3ƒ¿-arylmethoxytropane analogues exhibited greater potency for the serotonin transporter than the dopamine transporter. The most potent compounds of this series were 3ƒÀ-phenyl-3ƒ¿.(3, 4-dichlorophenyl)methoxy-8.azabicyclo [3.2.1]nortropane (Ki = 0.06 nM) and 3ƒÀ-(4Œ-chlorophenyl)-3ƒ¿.(4-chlorophenyl)methoxy-8. azabicyclo[3.2.1]nortropane (Ki = 0.09 nM) at the serotonin transporter and their binding affinities were equipotent with paroxetine and fluoxetine (Prozac). A series of 8-azabicyclo[3.2.1]oct-2-ene derivatives were synthesized from 3-tropinone based on the structure of triple re-uptake inhibitor, DOV 216, 303. The compounds were designed as potential triple re-uptake inhibitors which could exhibit equipotent affinities at the monoamine transporters for dopamine, serotonin and norepinephrine. A short and efficient synthetic methodology was developed for the synthesis of unique compounds which could exhibit potency for both the dopamine and serotonin transporters. The 3ƒÀ-aryl-3ƒ¿-(4Œ, 4-disubstituteddiphenylmethoxy)tropane analogues were designed as hybrid structures of the dopamine transporter selective benztropines and the serotonin transporter selective meperidine derivatives.

abstract: 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. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2018

Cocaine use disorder is a serious public health issue for which no approved pharmacotherapies exist. The development of a pharmacotherapy for cocaine use disorder is a priority for the National Institute on Drug Abuse. Amphetamine maintenance has been shown to be effective to reduce cocaine use in double-blind placebo controlled clinical trials, but has not been approved due to concerns over safety and abuse liability. Development of new pharmacotherapies is facilitated by preclinical testing for effectiveness and identification of new targets for medication development. The first part of this dissertation develops a novel non-human primate cocaine self-administration choice procedure that is modeled after a human laboratory cocaine self-administration choice procedure to improve translational research and facilitate medication development. The second part of this dissertation is devoted to examining the mechanisms of amphetamine maintenance-induced decreases in cocaine use. In the novel non-human primate choice procedure, monkeys chose between injections of cocaine or food pellets (0, 1, 3 or 10) in a 9-choice discrete trials procedure. The reinforcers were available on concurrent independent progressive-ratio schedules. Monkeys chose between cocaine and food in a dose- and magnitude-dependent manner. Maintenance on 7 days of lisdexamfetamine and amphetamine decreased cocaine choices without decreasing food responding, providing evidence that this model may be able to predict drugs that will have clinical efficacy to decrease cocaine use. The next set of experiments examined the effects of amphetamine maintenance on the abuse-related behavioral (intracranial self-stimulation, ICSS) and neurochemical [nucleus accumbens dopamine (DA) and serotonin (5-HT)] effects of cocaine, methylenedioxypyrovalerone, and methamphetamine in rats. Amphetamine maintenance produced sustained increases in ICSS baseline responding and nucleus accumbens DA levels without affecting 5-HT levels. Amphetamine maintenance also attenuated the behavioral and neurochemical abuse-related effects of cocaine but not those of methamphetamine, and with MDPV, amphetamine maintenance decreased the abuse-related neurochemical effect of MDPV, but not the abuse-related behavioral effect. This suggests that amphetamine would likely be most effective against cocaine, least effective against methamphetamine and between the two for MDPV. These data suggest targets that selectively release DA will be the most effective against cocaine use disorder.

Understanding the neural mechanisms underlying the extinction of maladaptive behaviors has become increasingly relevant. Extinction, or the reduction of a response due to lack of reinforcement, is believed to be “new learning.” Most extinction paradigms involve the performance of the previously reinforced response in the absence of reinforcement in order for extinction to occur. Conversely, latent extinction is a cognitive form of learning in which the previously rewarded response is not made during extinction training. However, until now the neurobiological basis of latent extinction has remained unknown. This dissertation has three aims to examine the neurobiological basis of latent extinction. Previous research has shown latent extinction to be impaired following hippocampal inactivation and the goal of Aim 1 was to examine other neural systems potentially involved in latent extinction through examination of brain structures such as the dorsal striatum, medial prefrontal cortex, and basolateral amygdala. Additionally, the neurochemical basis of latent extinction is unidentified; therefore Aim 2 addressed this question, specifically investigating the glutamatergic system through both NMDA receptor agonism and antagonism. Finally, understanding latent extinction may be useful for the extinction of drug addiction. Aim 3 was to examine some clinical implications for the extinction of drug addiction utilizing latent extinction following maze running for an oral cocaine reward. Reversible neural inactivation studies using the sodium channel blocker bupivacaine demonstrated a selective impairment of response extinction following dorsal striatum inactivation, but no effect on either latent or response extinction following medial prefrontal cortex or basolateral amygdala inactivation. These results, coupled with previous data from our lab demonstrate a double dissociation for extinction behavior. Further, peripheral NMDA receptor agonism with D-cyloserine enhances latent extinction and intra-hippocampal NMDA receptor antagonism with AP5 impairs latent extinction, identifying a role for the glutamatergic system in latent extinction. Finally, oral cocaine administration during acquisition selectively impairs latent extinction indicating that drug use affects the relive use of multiple memory systems during extinction. Overall, the multiple memory systems theory and latent extinction provide a framework with which to further understand the neural mechanisms of extinction behavior.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Supervisor: Christine L. Duvauchelle. Vita. Includes bibliographical references. Available also from UMI Company.

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This project is designed as a case study investigating the relationship and practices between residents and police officers in the William Wells Brown neighborhood of Lexington, Kentucky toward the issue of drug-related crime. Employing Michel Foucault‘s work on governmentality and his concept of Splendor, I explore how governance is practiced within the daily negotiations of the WWB neighborhood. I approach this project through the lens of policing because some residents, especially those who comprise the William Wells Brown Neighborhood Association, form a limited partnership with the police department in combating the threat of drug crime in the neighborhood. Drug-related crime is defined as the purchasing, selling or using of illegal drugs. In my research, the illegal drug most commonly referred to is crack cocaine. Through my analysis, I explore the importance of visual appearances and spatial regulation in the policing of individuals.

The purpose of this inquiry was to explore recovery from drug abuse from a mother's perspective. Women's experiences of treatment and recovery are unique from men's and mothers' experiences have been studied little (Poole & Dell, 2005). A series of three interviews were conducted during which the participant was encouraged to deeply explore her experience of recovery as a woman and a mother. This project was carried out using both Consensual Qualitative Research (Hill, Thompson, Hess, Knox, Williams, Ladany, 2005) as well as The Wish and Fear List (Perry, 1997). These two types of analyses complemented one another and provided two complementary views of the participant's experiences as both a woman and a recovered drug user within the context of her parenting. The themes of mothering, recovery and identity development, and respective sub-themes are discussed. The proportions of wishes and fears expressed at two phases in the participant's recovery journey are also discussed.