Browsing by Subject "Relapse"

Now showing 1 - 4 of 4
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    The effects of progestins on animal models of cocaine bingeing and relapse.
    (2009-10) Anker, Justin Jack
    Female gonadal hormones influence responses to stimulant drugs, and estrogen (EST) facilitates while progesterone (PROG) attenuates these responses. The PROG metabolite allopregnanolone (ALLO) also suppresses responses to cocaine, and it may be responsible for PROG's attenuating effects. The research included in this thesis is concerned with the influence of PROG and its metabolite ALLO on animal models of escalation or bingeing of cocaine of intake (Experiments 1 and 2) and reinstatement of extinguished drug seeking or relapse (Experiments 3, 4, and 5). Experiment 1 focused on the influence of PROG on the escalation of cocaine self-administration that occurs with long (6 h) daily access in ovariectomized (OVX) and gonadally intact female rats treated with either EST or VEH. Following the escalation procedure, treatment groups were compared on a progressive ratio (PR) schedule for several doses of cocaine. This research was extended to the PROG metabolite ALLO in Experiment 2a. Gonadally intact female rats were treated with ALLO or VEH and allowed to earn either i.v. cocaine infusions or sucrose deliveries under a long-access (LgA) escalation procedure. In Experiment 2b sucrose was used to determine the specificity of ALLO's effects on the escalation of cocaine self-administration, and in Experiment 2c control conditions were used to examine the effect of ALLO on locomotor activity and operant behavior reinforced by food. In Experiment 3 the effects of PROG on the reinstatement of cocaine-seeking behavior were examined in OVX and intact female rats that received EST or VEH treatment. In Experiment 4 the mechanism of PROG's effects was further studied by using finasteride, a 5-alpha reductase inhibitor that prevents the metabolism of PROG into ALLO. Finasteride (FIN) was administered concurrently with PROG to determine whether it could block the attenuating effects of PROG on cocaine-primed reinstatement, thus implicating ALLO in PROG's actions. Allopregnanolone was also tested on cocaine-primed reinstatement in male and female rats to examine possible sex-specific treatment effects. In the final experiment (Experiment 5), the effects of ALLO were examined on stress-induced reinstatement by injecting rats with yohimbine (YOH) to generate a stressful condition. Results from Experiment 1 indicated that EST facilitated while PROG attenuated the escalation of cocaine self-administration during LgA, but neither hormone affected cocaine-maintained responding under a PR schedule. Experiment 2a confirmed that ALLO also attenuated the escalation of cocaine self-administration, and 2b indicated that ALLO did not affect the escalation of intake of a nondrug reward (i.e., sucrose). Experiment 2c revealed that ALLO also had no effect on locomotor activity or operant food-reinforced behavior. Experiments 3 and 4 demonstrated that PROG and ALLO also decreased the reinstatement of cocaine-seeking behavior precipitated by i.p. injections of cocaine. Results from Experiment 4 further indicated that the attenuation of cocaine seeking by PROG may be attributed to its conversion into ALLO, as blocking this conversion with FIN prevented PROG's attenuating effects. In addition, the effects of ALLO were specific to females and did not extend to males. Finally, in Experiment 5, female rats exhibited greater reinstatement of cocaine seeking following a stressful stimulus (YOH) than males, and the attenuating effects of ALLO on this behavior were specific to females. Taken together, these results demonstrated a role for PROG and ALLO in suppressing the bingeing and relapse associated with cocaine abuse. These effects were specific to cocaine seeking in females (vs. males) and did not extend to behavior maintained by a nondrug rewards (i.e., sucrose or food) or locomotor activity.
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    Effects of wheel running on cocaine seeking in rats: behavior and neurobiology
    (2014-12) Zlebnik, Natalie
    Cocaine addiction is a pervasive public health problem, but currently there are no highly effective treatments to reduce its extent or duration. Emerging research in humans and animals suggests that aerobic exercise may decrease drug use and prevent relapse. This set of experiments focused on the use of exercise as a behavioral treatment for cocaine addiction using rodent (rat) models of relapse. Concurrent access to a voluntary running wheel decreased reinstatement of cocaine-seeking behavior in response to a cocaine injection (Experiments 1-3), cocaine-paired cues (Experiment 2-3), and the pharmacological stressor yohimbine (Experiment 2). Wheel running during the withdrawal period also prevented incubation of cocaine seeking or time-dependent increases in reactivity to cocaine-paired cues, a situation that often precipitates relapse (Experiment 5). Further, using pharmacological treatments such as progesterone (Experiment 2) or atomoxetine (Experiment 3) in combination with wheel running led to an additive treatment effect, suggesting a larger role for exercise as a singular or adjunct treatment in the prevention of cocaine relapse. While these behavioral models have revealed exercise to be an efficacious method to attenuate cocaine-motivated behaviors, long-term wheel running also changed cocaine-induced activation of brain reward circuitry (Experiment 4). Using c-Fos immunohistochemistry to evaluate neuronal activation, results demonstrated that exercising and control rats showed differential activation of the nucleus accumbens, caudate putamen, and prefrontal cortex in response to an acute cocaine injection. These results suggest that exercise may alter reactivity to cocaine by inducing plasticity in the mesolimbic dopamine system. Overall, results across these experiments have demonstrated that aerobic exercise has the ability to attenuate activation of the neurobiological substrates of addiction in addition to robustly reducing relapse to cocaine-seeking behavior.
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    Oncogenic roles of RAS in acute myeloid leukemia cooperated with Mll-AF9.
    (2008-07) Kim, Won-il
    Three main sections are presented in this thesis. First, we investigated which hematopoietic cells express TRE -driven transgenes when combined with Vav-tTA , because mastocytosis was developed in Vav-tTA ; TRE-NRAS G12V transgenic mice without detectable other diseases. We assayed Vav-tTA -driven luciferase expression in hematopoietic cells including bone marrow-derived mast cells (BMMC) and CD34 positive hematopoietic progenitor cells (HPC) as well as myeloid and lymphoid lineages by live mouse imaging and relative light unit measurement before or after treating Vav-tTA ; TRE -luciferase co-transgenic mice with doxycycline (Dox). We found that B cells in the bone marrow and T cells in the thymus expresses Vav-tTA -driven luciferase at much higher levels than in myeloid cells, BMMC and CD34 positive HPC, which showed relatively low levels. Thus, we conclude that Vav-tTA -driven NRAS G12V expression is sufficient for mastocytosis development but not for myeloid leukemia, and lymphoid cells are resistant to NRAS G12V transformation despite high level of expression. Second, experiments were performed to study the oncogenic role of the NRAS oncogene ( NRAS G12V ) in the context of acute myeloid leukemia (AML). We transplanted AML, which was developed in Vav-tTA TRE-NRASG12V ; Mll-AF9 transgenic ( TRM -transgenic) mice, into recipient SCID mice. Conditional repression of NRAS G12V expression greatly reduced peripheral white blood cell (WBC) counts in leukemia recipient mice and induced apoptosis in the transplanted AML cells correlated with reduced Ras/Erk signaling. After marked decrease of AML blast cells, myeloproliferative disease (MPD)-like AML relapsed characterized by cells that did not express NRAS G12V . In comparison with primary AML, the MPD-like AML showed significantly reduced aggressiveness, reduced myelosuppression and a more differentiated phenotype. We conclude that, in AML induced by an Mll-AF9 transgene, NRAS G12V expression contributes to acute leukemia maintenance by suppressing apoptosis and reducing differentiation of leukemia cells. Moreover, NRAS G12V oncogene has a cell non-autonomous role in suppressing erythropoiesis that results in the MPD-like AML showed significantly reduced ability to induce anemia. Third, based on the results finding the relapse of NRAS G12V -independent AML, we tested a hypothesis that chemotherapeutic cytarabine (AraC) treatment in addition to the RAS oncogene suppression would prevent or delay the relapse of AML. After the establishment of full-blown AML. We treated recipient mice with Dox and/or AraC (50 mg/kg/day). Compared with recipient mice treated with either Dox or AraC, we found that co-treatment significantly postponed the relapse of resistant AML and increased the survival days of the TRM -transgenic AML recipient mice. These results suggest that oncogenic RAS-targeting therapy may increase the therapeutic potential against drug-resistant AML when combined with chemotherapeutic AraC treatments. Consequently, we conclude the oncogenic roles of NRAS G12V expression in AML induced in cooperation with Mll-AF9 are; (1) to induce proliferation of AML blast cells, (2) to induce cell non-autonomous myelosuppression, (3) to suppress apoptosis in AML blast cells, and (4) to inhibit differentiation of AML blast cells. In treatment of AML, oncogenic RAS suppression combined current chemotherapy may improve the therapeutic potential and achieve longer remission period.
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