13-Cis-retinoic acid (13-cis-RA) is a synthetic retinoid and the active ingredient in the oral acne treatment Accutane. The medical literature has suggested that the use of 13-cis-RA for acne treatment can induce depression, but because acne itself can have a negative psychosocial impact on self esteem, whether or not 13-cis-RA can cause depression remains controversial. The purpose of this work was to examine whether chronic 13-cis-RA administration could induce depression-related behaviors in mice and to determine the impact 13-cis-RA has on regions of the brain thought to be associated with mood and depression. We found that chronic treatment of adolescent male mice with 13-cis-RA induced depression-related behaviors, as assessed by immobility in the tail suspension and forced swim tests. Although depression is a multifaceted disease in which many brain regions are involved, the regions that seem particularly vulnerable to the effects of 13-cis-RA are the serotonergic and hippocampal systems. In serotonergic cells in vitro, 13-cis-RA treatment increases protein levels of the serotonergic 5-HT[subscript 1A] autoreceptor and the serotonin reuptake transporter (SERT), two inhibitory components of serotonin (5-HT) signaling. In vivo, the median and dorsal raphe nuclei contain the main 5-HT producing cells. 13-Cis-RA uncoupled the functional connectivity of dorsal raphe nuclei from the hippocampal regions as measured by interregional correlations of cytochrome oxidase (CO) activity, a metabolic marker of neuronal activity. Decreased hippocampal neurogenesis is thought to occur in depression and is decreased by 13-cis-RA. 5-HT is also a known regulator of hippocampal neurogenesis. Uncoupling of the dorsal raphe nuclei from the regions of the hippocampus by 13-cis-RA treatment may be the cause of, or a result from, the decreased neurogenesis. Although retinoids are known regulators of apoptosis, the uncoupling of the dorsal raphe nuclei from the hippocampal regions was not due to serotonergic cell loss. Interestingly, 13-cis-RA treated animals with the lowest CO activity in the dentate gyrus have the highest immobility in the tail suspension and forced swim tests. Ultimately, the effects of 13-cis-RA on the serotonergic and hippocampal systems might be inducing depression-related behaviors. / text

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--Michigan State University. Dept. of Pharmacology and Toxicology, 2008. / Title from PDF t.p. (viewed on July 23, 2009) Includes bibliographical references (p. 278-302). Also issued in print.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007. / Title from first page of PDF file (viewed May 29, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 57-65).

An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential for rash development, is the link between 12-OH NVP and the skin rash. Female Brown Norway (BN) rats were co-treated with NVP or 12-OH NVP and sulfation inhibitors dehydroepiandrosterone (DHEA) and salicylamide. Co-treatment with salicylamide markedly decreased formation of the sulfate conjugate but did not prevent development of the rash suggesting that the sulfate is not involved. However, it is not known whether the sulfate formation in the skin was affected. Co-treatments with DHEA decreased the sulfate formation and prevented the rash but also had other effects on NVP metabolism. This implies that the sulfate metabolite is responsible for the rash. Additional studies will be required to resolve these conflicting results.

An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential for rash development, is the link between 12-OH NVP and the skin rash. Female Brown Norway (BN) rats were co-treated with NVP or 12-OH NVP and sulfation inhibitors dehydroepiandrosterone (DHEA) and salicylamide. Co-treatment with salicylamide markedly decreased formation of the sulfate conjugate but did not prevent development of the rash suggesting that the sulfate is not involved. However, it is not known whether the sulfate formation in the skin was affected. Co-treatments with DHEA decreased the sulfate formation and prevented the rash but also had other effects on NVP metabolism. This implies that the sulfate metabolite is responsible for the rash. Additional studies will be required to resolve these conflicting results.

Idiosyncratic drug reactions (IDRs) are unpredictable adverse drug reactions. Their exact mechanisms are unknown but most appear to be immune-mediated. Mechanistic studies require valid animal models, but there are very few available and none for the study of drug-induced agranulocytosis. Thus, the first part of my thesis has focused on the development of an animal model of agranulocytosis. We pursued many attempts to develop one in rabbits, guinea pigs, and rats by treatment with aminopyrine, amodiaquine, and clozapine and manipulating the factors hypothesized to be involved in the mechanism of IDRs such as reactive metabolite formation/detoxication and immune stimulation. Clozapine-induced agranulocytosis is not associated with immune memory, which suggests that it may not be immune-mediated. Therefore, other factors, specifically selenium and vitamin C deficiencies, were assessed as possible risk factors for clozapine-induced agranulocytosis. Despite many attempts, we were not able to develop an animal model of idiosyncratic drug-induced agranulocytosis. The second part of this thesis was focused on investigating the effects of clozapine on neutrophils. It is known that the reactive metabolite of clozapine increases neutrophil apoptosis in vitro; however, it was not clear that the conditions of these experiments reflect in vivo conditions. Therefore, the effect of clozapine on neutrophil kinetics in vivo was examined. We found that clozapine treatment decreased the half-life of circulating neutrophils and increased the rate of release of neutrophils in rabbits. Thus, even though these animals did not develop agranulocytosis clozapine did appear to cause neutrophil damage that was compensated for by an increased production of neutrophils. Failure of the bone marrow to keep up with the increased rate of neutrophil destruction in certain individuals could result in agranulocytosis. Alternatively, damage to neutrophils could lead to an immune response in some patients that results in agranulocytosis. The failure to develop an animal model of drug-induced agranulocytosis despite many attempts using interventions based on the current mechanistic hypotheses suggests that these hypotheses are wrong. However, it is also possible that we are just unable to overcome the default response of immune tolerance; future studies will examine this possibility and the mechanism of clozapine-induced neutrophil damage.

Idiosyncratic drug reactions (IDRs) are unpredictable adverse drug reactions. Their exact mechanisms are unknown but most appear to be immune-mediated. Mechanistic studies require valid animal models, but there are very few available and none for the study of drug-induced agranulocytosis. Thus, the first part of my thesis has focused on the development of an animal model of agranulocytosis. We pursued many attempts to develop one in rabbits, guinea pigs, and rats by treatment with aminopyrine, amodiaquine, and clozapine and manipulating the factors hypothesized to be involved in the mechanism of IDRs such as reactive metabolite formation/detoxication and immune stimulation. Clozapine-induced agranulocytosis is not associated with immune memory, which suggests that it may not be immune-mediated. Therefore, other factors, specifically selenium and vitamin C deficiencies, were assessed as possible risk factors for clozapine-induced agranulocytosis. Despite many attempts, we were not able to develop an animal model of idiosyncratic drug-induced agranulocytosis. The second part of this thesis was focused on investigating the effects of clozapine on neutrophils. It is known that the reactive metabolite of clozapine increases neutrophil apoptosis in vitro; however, it was not clear that the conditions of these experiments reflect in vivo conditions. Therefore, the effect of clozapine on neutrophil kinetics in vivo was examined. We found that clozapine treatment decreased the half-life of circulating neutrophils and increased the rate of release of neutrophils in rabbits. Thus, even though these animals did not develop agranulocytosis clozapine did appear to cause neutrophil damage that was compensated for by an increased production of neutrophils. Failure of the bone marrow to keep up with the increased rate of neutrophil destruction in certain individuals could result in agranulocytosis. Alternatively, damage to neutrophils could lead to an immune response in some patients that results in agranulocytosis. The failure to develop an animal model of drug-induced agranulocytosis despite many attempts using interventions based on the current mechanistic hypotheses suggests that these hypotheses are wrong. However, it is also possible that we are just unable to overcome the default response of immune tolerance; future studies will examine this possibility and the mechanism of clozapine-induced neutrophil damage.

Thesis (Ph. D.)--Michigan State University. Dept. of Biochemistry and Molecular Biology, 2008. / Title from PDF t.p. (viewed on Mar. 30, 2009). Includes bibliographical references (p. 204-227). Also issued in print.