Behavioral analysis of conditions and treatments affecting movement and nociception

This thesis work includes three projects. First part deals with the investigation of novel D2 receptor ligands in Prepulse inhibition. The goal of this study is to establish a relationship between dopamine receptor antagonists and agonists and prepulse inhibition which can then serve as a working model for an in-vivo efficacy of novel dopamine D2 drugs. The second part of the thesis work deals with Niemann pick disease type C. Niemann pick disease type C is a progressive genetic disorder that is characterized by the lysosomal accumulation of lipids which causes neurodegeneration, dementia, ataxia, and death. NPC1nmf164 mutant mice (knockout) have a delayed acquisition of motor skills during development. The aim of our study was to identify cellular and molecular pathways involved in causing and progressing NPC in young patients from which effective therapeutic interventions can be designed and tested to prevent or delay the onset of the disease and prolong and improve the quality of life of young NPC patients. Finally, the last part of this thesis work includes studies on synergistic anithyperalgesic and antinociceptive effects of morphine and MP-III-024, a positive allosteric modulator at α2GABAA and α3GABAA receptors. The purpose of this study was to examine the interactive effects of the μ-opioid agonist morphine and the α2GABAA and α3GABAA receptor positive allosteric modulator MP-III-024 in preclinical models of mechanical hyperalgesia and thermal nociception

Comparative Analysis of the Effects of Actual Versus Assumed Opioid Experience on the Regulation of Ventral Striatal Opioid Receptor Gene Expression

Rationale: We conducted experiments to assess the effect of prior opioid experience on gene expression changes. We compared the current experimenter-imposed short versus extended-access conditions of opioid self-administration and developed a new quantitative method to determine their effectiveness in identifying the role of opioid experience in regulating opioid receptor expression levels in the ventral striatum (VS) using an oxycodone self-administration/abstinence model. Methods: In this study, male Sprague-Dawley rats (n=36) were trained for 20 days to self-administer oxycodone at 0.1 mg/kg/infusion under short access (n=15, or saline as controls n=3, for 3h/day) or extended access (n=15, or saline as controls n=3, for up to 9h/day). After 31 days of abstinence, the animals were sacrificed, 8and PCR was used to evaluate mu- and kappa-opioid receptor (MOR and KOR) gene expression levels in the ventral striatum (VS). Biochemical/behavioral profiles of short versus extended access conditions were compared using current methods and a new quantitative model based on normal mixtures clustering analysis. Data were analyzed using ANOVA and regression analysis to explore the relationship between opioid experience and VS opioid receptor expression levels Results: Our study found that experimenter-determined grouping was inadequate in representing opioid experience and failed to identify distinct biochemical/behavioral groups. However, our quantitative model identified two distinct biochemical/behavioral types related to experience, revealing significant differences in the relationship between opioid experience and MOR/KOR expression and their interactions. Conclusion: The quantitative model is more sensitive than the current experimenter-determined approach in studying the effect of prior opioid experience on VS opioid receptor gene expression