Browsing by Subject "Tolerance"

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Affective responses in cocaine-experienced rats reveal cue-induced drug craving and cocaine reward magnitude
(2011-08) Maier, Esther Yvonne; Duvauchelle, Christine L.; Schallert, Timothy; Gonzales, Rueben A.; Gore, Andrea C.; Monfils, Marie H.
The development and persistence of cocaine dependence are greatly influenced by emotional affect and cocaine associative learning. Cocaine is known to enhance nucleus accumbens (NAcc) dopamine, serve as a positive reinforcer and produce negative effects, such as anxiety that may influence cocaine intake behavior. In the first study, I investigated the effects of the anxiolytic, diazepam on NAcc dopamine levels and cocaine self-administration behavior. These are two factors associated with cocaine rewarding effects. Diazepam has no effect on NAcc dopamine, but affects cocaine self-administration. This supports the notion that decreasing the anxiogenic effects of cocaine increases the rewarding value in a dopamine independent manner. Therefore, increasing the aversive effects of cocaine might be a novel approach to fight cocaine dependence. In the second study, I studied cocaine-induced associative learning and changes in affect during cocaine conditioning and extinction. 50-kHz ultrasonic vocalizations (USVs) in rats are thought to reflect positive affect and occur upon appetitive stimuli and with cocaine delivery. First, I explored whether USVs might be elicited in anticipation of impending drug delivery. Shortly into conditioning, rats elicited USVs when placed in the cocaine-associated environment. USVs progressively increased, indicating a growing learned association between cocaine intake and cocaine-associated cues. This suggests that USVs may be a useful model for investigating cocaine craving and serve as a pharmacological target for interventions aimed to reduce cocaine craving and relapse. I then examined the effects of short-term deprivation of cocaine and cocaine cues on cocaine-conditioned USVs, which were both exaggerated after abstinence. The results may have clinical implications, in that intermittently avoiding cues or context may enhance drug cue salience and increase the probability of relapse. Motivational aspects of cocaine were assessed comparing commonly measured lever response rate and locomotion with cocaine-induced USVs during cocaine administration and extinction. In agreement with prevailing findings, lever responding for cocaine and cocaine-induced locomotor activity increased across conditioning sessions. However, the number of USVs evoked in response to cocaine infusion decreased with cocaine experience. These findings suggest growing tolerance to the rewarding properties of cocaine. These studies underscore the value of USV assessment during drug dependence studies.
A compilation of design principles and guidelines for selective laser sintering
(2016-05) Pradhan, Nivedita; Seepersad, Carolyn; Crawford, Richard H
The term Additive Manufacturing (AM) is used to describe several manufacturing technologies that share the same basic principle of producing parts directly from their CAD models without the need for special tooling, by adding material selectively one layer at a time. Current research focuses on one such technology called Selective Laser Sintering (SLS) where thin layers of powdered thermoplastic material are fused using a laser beam. With no part-specific tooling required, the product development cycle is drastically shortened. This lack of tooling, coupled with freedom of placement of material, opens the door to several design opportunities unique to AM such as increased geometrical design freedom and the ability to manufacture low production volumes economically. Gradual improvements in process accuracy and selection of materials over time have resulted in a shift in application of AM from rapid prototyping to direct manufacturing and even ‘democratization’ of the product development process in which even non-professional users can rapidly manufacture products as long as there is a CAD model for the part. However, the move to direct manufacturing of end-use parts also means that part quality in terms of conformance to product specification becomes important for the product to successfully perform its function. The research in this thesis is focused on documenting these manufacturability capabilities and limitations for Selective Laser Sintering. It focuses specifically on thermoplastics, especially Nylon 12 polyamide materials known by the trade names PA 2200 and Duraform PA. While several design resources have been created based on industry best practices developed through experience, they are scattered throughout the literature and are not readily available to designers. It is also difficult to compare and draw quantitative inferences from existing guidelines as they are developed independently under dissimilar process conditions. Therefore, a prime focus of this research is to synthesize and compile existing guidelines into a comprehensive document. The first objective of this research is to compile a user-friendly resource, in the form of design principles and guidelines, to help designers make early process selection decisions, optimize part quality and minimize manufacturing cost. A systematic literature review of available guidelines, exploratory studies and case studies is conducted to develop actionable design recommendations that are within the scope of the designer. The second objective of this research is to address the lack of adequate process tolerance information that can reliably predict the quality of parts produced by the selective laser sintering process. This information is important to accurately evaluate the process during early process selection. A test part is proposed to measure dimensional deviations for various features (such as holes, gaps, cylinders, walls, clearances, etc.) across a range of dimensions and along different orientations. Finally, a sampling plan that represents sources of variability in the process is put forward to collect statistical data in an economical manner.
Diazepam binding inhibitor and tolerance to ethanol in Drosophila melanogaster
(2012-12) Robles, Roseanna Beth; Atkinson, Nigel (Nigel S.); Aldrich, Richard; Duvauchelle, Christine; Mihic, John; Zakon, Harold
Tolerance to ethanol is an endophenotype of alcoholism, allowing the study of a complex psychiatric condition using animal models. To identify new genes involved in the acquisition of tolerance, I designed an automated and high-throughput tolerance assay and screened a collection of deficiency mutants for the inability to develop tolerance. The screen yielded several “regions of interest” where more than one overlapping deficiency failed to develop tolerance. One of these regions comprised nine genes, and testing the expression levels of each gene revealed that diazepam binding inhibitor (Dbi) showed grossly increased expression in the deficiency mutant compared to wild type. Another mutant stock, with a P-element transposon inserted downstream of the Dbi gene, both failed to develop tolerance and showed further increased expression of Dbi. There are two insulator binding sites flanking Dbi, and the P-element transposon also contains insulator binding sites. Based on these results, it was hypothesized that an insulator complex kept Dbi expression low in wild type flies and that disrupting the insulator complex allowed aberrantly high expression of Dbi in the mutants. Furthermore, we assumed that induction of Dbi blocked tolerance by making the mutants resistant prior to the first sedation. A UAS-DBI transgene was constructed to over-express Dbi. Induction of the UAS-DBI with a heat shock gal4 driver induced resistance to ethanol sedation; a similar response was observed in the parental control, but the effect was smaller. Although driving UAS-DBI with the neural elav-gal4 driver did not block tolerance, the experimental stock was resistant to ethanol sedation compared to the parental controls, indicating that increased Dbi expression produced “pre-tolerance.” To confirm the theory that insulator disruption was responsible for the increase in Dbi and the resulting no-tolerance phenotype, the P-element in the second mutant was mobilized by introducing a transposase source. These offspring lines were analyzed using qualitative PCR to determine whether the transposon excised precisely, left a portion of the transposon behind, or removed some of the flanking region. A precise excision mutant was identified, but this mutation did not rescue tolerance as predicted. This result might indicate that genetic background was the cause of the no-tolerance phenotype, or it might indicate that the excision was not exactly precise and removed the native insulator binding site, causing the insulator complex to remain disrupted.
Mechanisms of benzyl alcohol tolerance in Drosophila melanogaster
(2009-12) Alhasan, Yazan Mahmoud; Atkinson, Nigel (Nigel S.); Zakon, Harold; Gonzales, Rueben A.; Singer, Michael C.; Bergeson, Susan E.
Proper neuronal function requires the preservation of appropriate neural excitability. An adaptive increase in neural excitability after exposure to agents that depress neuronal signaling blunts the sedative drug effects upon subsequent drug exposure. This adaptive response to drug exposure leads to changes in drug induced behaviors such as tolerance, withdrawal and addiction. Here I use Drosophila melanogaster to study the cellular and neuronal components which mediate behavioral tolerance to the anesthetic benzyl alcohol. I demonstrate that rapid tolerance to benzyl alcohol is a pharmacodynamic mechanism independent of drug metabolism. Furthermore, tolerance is a cell autonomous response which occurs in the absence of neural signaling. Using genetic and pharmacological manipulations I find the synapse to play an important role in the development of tolerance. In addition, the neural circuits that regulate arousal and sleep also alter benzyl alcohol sensitivity. Beyond previously described transcriptional mechanisms I find a post-translational role of the Ca2+-activated K+-channel, slowpoke in the development of tolerance. Finally, I explore a form of juvenile onset tolerance, which may have origins that differ from rapid tolerance. The implications of this study go beyond tolerance in Drosophila melanogaster to benzyl alcohol and can shed light on human drug tolerance, withdrawal and addiction.