Thesis (M.S.)--University of Central Florida, 2008. / Adviser: Michael Dunn. Includes bibliographical references (p. 50-57).

Thesis (Ph. D.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains xi, 130 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 127-130).

Thesis (Ph.D.)--Baylor University, 2006. / Includes bibliographic references (p. 163-189).

No description available.

Gamma Hydroxybutyrate (GHB) was banned from the consumer market by the Food and Drug Administration in 1991. Despite the ban, use of GHB has continued to contribute to thousands of emergency department visits and numerous fatalities in recent years. Efforts to reduce the use of this drug have had limited impact, which may be the result of using traditional prevention strategies that focus exclusively on educating people about of negative consequences of substance use rather than addressing the factors that motivate use. In an effort to identify motivational factors that could be targeted in future prevention efforts, the present study was designed to examine outcome expectancies for GHB that may promote use of this drug. Methodology that has led to successful strategies to reduce alcohol use was applied to identify GHB expectancies and model cognitive processes likely to encourage or discourage GHB use. Individual differences scaling was used to empirically model a two dimensional semantic network of GHB expectancies stored in memory, and preference mapping was used to model likely paths of expectancy activation for male and female GHB users and nonusers. Differences in expectancies between GHB users and nonusers followed patterns previously identified in relation to alcohol expectancies and alcohol use. Conclusions were limited by relatively low numbers of GHB users in the sample, despite the use of a very large number of participants, overall. Despite this limitation these findings lay the groundwork for development and validation of GHB expectancy based prevention strategies.

Objective: The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Methods: Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4- methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drugdrug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. Results: The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. Conclusion: Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. Scientific Significance: Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.

Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.

Drug dependence is a serious and increasing problem in our society, especially among adolescents. The use of the large variety of substances available can result in a range of physiological and psychological adverse effects on individuals and negative consequences on the society overall. Several different types of drugs induce neurotoxicological damages, which in turn can generate impairment in for example the reward system and affect cognitive parameters.  The drug gamma-hydroxybutyrate (GHB) is usually considered a harmless compound among abusers, but has now shown to be highly addictive. Furthermore, GHB can cause memory impairments in both humans and animals. On the contrary, growth hormone (GH) and its main mediator insulin-like growth factor 1 (IGF-1) have recently been suggested to improve memory and learning in several studies. The hormones exhibit certain neuroprotective capabilities and have also previously been demonstrated to reverse opioid induced apoptosis in hippocampal cells. These effects and the fact that GHB is shown to increase GH secretion, which attracted considerable attention among body builders, led us to initiate studies on GHB and its impact on relevant systems in the central nervous system (CNS). Thus, the main purpose of the present investigation was to elucidate some of the underlying mechanisms that could account for the effects exerted by GH and GHB in the CNS. We found that a) GH affects the density and functionality of GABAB-receptors and opioid receptors in the male rat brain, b) GHB induces cognitive deficits and down-regulates GABAB-receptors, c) GHB treatment creates an imbalance between the endogenous opioids Met-enkaphalin-Arg6Phe7 (MEAP) and dynorphin B and increases the levels of MEAP in regions of the brain that are associated with drug dependence, and d) GHB affects the expression of IGF-1 receptors but not the plasma levels of IGF-1. In conclusion, the present work demonstrates that GH interacts with both opioid and GABAB-receptors in the male rat CNS and that GHB has an impact on brain regions associated with cognition and the development of dependence. These observations may be of relevance in many aspects related to addiction and might be translated into humans.

In this project a LC-MS-method for the analysis of gamma-hydroxybutyrate, gamma-butyrolactone, 1,4-butanediol, amphetamine and methadone was developed. Initially, the efficiency of the ionisation of the analytes was evaluated with respect to the ionisation technique (ESI, APCI and APPI) and the composition of the mobile phase. In the next step a number of different columns was tested in order to find the one with the greatest potential for separation of the substances in question. Using the selected column, the separation was optimised by means of experimental design and the software The Unscrambler 7.8. The parameters studied were the flow rate, the column temperature and the mobile phase composition. The response variables were the resolution between the target compounds and the retention time of the last eluting compound. These experiments showed that, in order to obtain the best ionisation, the mobile phase should consist of 5 mM formic acid in water and acetonitrile. ESI should be used in the positive mode for all analytes except gamma-hydroxybutyrate, for which the negative mode should be applied. The Hypercarb column exhibited superior retention of the analytes and was therefore selected for further optimisation. The dimensions of this column were 2.1 x 50 mm and the particle size 5 μm, connected to a 2.1 x 10 mm precolumn containing the same packing material. The optimum of the flow rate and the column temperature were 250 μl/min and 20 ºC respectively. For the separation of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol the mobile phase consisted of 100% water with 5 mM formic acid. Thereafter a gradient, up to 70% acetonitrile with 5 mM formic acid, was used in order to elute amphetamine and methadone. Efforts were also made to find an internal standard for the method. However, none of the compounds tested was found suitable. In order to get the method usable for routine analysis, which is the goal, further work is required. A suitable internal standard needs to be added to the method and thereafter work remains with validation of the method.

<p>In this project a LC-MS-method for the analysis of gamma-hydroxybutyrate, gamma-butyrolactone, 1,4-butanediol, amphetamine and methadone was developed.</p><p>Initially, the efficiency of the ionisation of the analytes was evaluated with respect to the ionisation technique (ESI, APCI and APPI) and the composition of the mobile phase. In the next step a number of different columns was tested in order to find the one with the greatest potential for separation of the substances in question. Using the selected column, the separation was optimised by means of experimental design and the software The Unscrambler 7.8. The parameters studied were the flow rate, the column temperature and the mobile phase composition. The response variables were the resolution between the target compounds and the retention time of the last eluting compound.</p><p>These experiments showed that, in order to obtain the best ionisation, the mobile phase should consist of 5 mM formic acid in water and acetonitrile. ESI should be used in the positive mode for all analytes except gamma-hydroxybutyrate, for which the negative mode should be applied. The Hypercarb column exhibited superior retention of the analytes and was therefore selected for further optimisation. The dimensions of this column were 2.1 x 50 mm and the particle size 5 μm, connected to a 2.1 x 10 mm precolumn containing the same packing material. The optimum of the flow rate and the column temperature were 250 μl/min and 20 ºC respectively. For the separation of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol the mobile phase consisted of 100% water with 5 mM formic acid. Thereafter a gradient, up to 70% acetonitrile with 5 mM formic acid, was used in order to elute amphetamine and methadone. Efforts were also made to find an internal standard for the method. However, none of the compounds tested was found suitable.</p><p>In order to get the method usable for routine analysis, which is the goal, further work is required. A suitable internal standard needs to be added to the method and thereafter work remains with validation of the method.</p>