This study analyzed sex differences in methylphenidate (MPH) sensitization and corresponding changes in glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotprhic factor protein (BDNF) in adolescent male and female rats. After habituation to a locomotor arena, animals were sensitized to MPH (5mg/kg) or saline from postnatal day (P) 33–49, tested every second day. On P50, one group of animals were injected with saline and behavior assessed for conditioned hyperactivity. Brain tissue was harvested on P51 and analyzed for GDNF protein. A second group of animals was also sensitized to MPH from P33 to 49, and expression of behavioral sensitization was analyzed on a challenge given at P60, and BDNF protein analyzed at P61. Females demonstrated more robust sensitization to MPH than males, but only females given MPH during sensitization demonstrated conditioned hyperactivity. Interestingly, MPH resulted in a significant increase in striatal and accumbal GDNF with no sex differences revealed. Results of the challenge revealed that females sensitized and challenged with MPH demonstrated increased activity compared to all other groups. Regarding BDNF, only males given MPH demonstrated an increase in dorsal striatum, whereas MPH increased accumbal BDNF with no sex differences revealed. A hierarchical regression analysis revealed that behavioral sensitization and the conditioned hyperactivity test were reliable predictors of striatal and accumbal GDNF, whereas sensitization and activity on the challenge were reliable predictors of accumbal BDNF, but had no relationship to striatal BDNF. These data have implications for the role of MPH in addiction and dopamine system plasticity.

Estrogens seem to play a role in the locomotor activating effects of cocaine. Japanese quail provide a good model for hormonal manipulation as alterations of their photoperiod controls hormone levels. The current study aims to examine the role of early life photoperiod manipulation in cocaine-induced behavioral sensitization in quail. It was expected that if quail were raised on a short photoperiod, they would have a reduction in gonadal hormones and this reduction in hormones would affect the acquisition of cocaine-induced behavioral sensitization. Quail were raised on an 8L:16D or a 16L:8D light cycle. Following 2 days of habituation, quail were administered saline, 5 mg/kg, or 10 mg/kg cocaine for 10 days. Restricted photoperiods in early life were correlated to lower gonadal hormone levels in females and males. Male quail raised on the short-light cycle developed a sensitized response to 10 mg/kg cocaine. Female quail raised on the short- or long-photoperiod developed behavioral sensitization to 5 mg/kg cocaine. Furthermore, early life reduction in estradiol in females modulated the amount of activity on day 10 of cocaine treatment. The current research extends previous research by finding a possible early life gonadal hormone control of behavioral sensitization in the quail.

Adolescent cannabis use has grown because of increased availability and higher societal acceptance. This increase in cannabis use is problematic as adolescents who experiment with cannabis are more likely to abuse cannabis and experiment with other illicit drugs such as cocaine. The reason for the greater susceptibility to drugs use is unclear and may be the result of altered drug sensitivity after cannabis exposure. Thus, the present investigation used the behavioral sensitization paradigm to examine the behavioral response of early adolescent rats to the cannabinoid agonist CP 55,940 (CP) or cocaine after repeated cannabinoid administration. It was hypothesized that: (1) CP would cause a sensitized response in both male and female adolescent rats, (2) female rats would have a greater behavioral response than male rats, (3) pretreatment with CP would induce cross-sensitization to cocaine, (4) pretreatment with cocaine would cause behavioral sensitization and conditioned activity in male and female adolescent rats. In the first experiment, 137 male and female Sprague-Dawley rats were given CP (4, 13.2, or 40 µg/kg, IP) or vehicle (50% DMSO/H2O) once daily for 5 consecutive days on postnatal day (PD) 30- PD 34. Distance traveled and stereotyped movement was assessed for 1 h after each drug injection. After a 48 h abstinence period (i.e., on PD 36), rats were given CP (4 or 13.2 µg/kg, IP) and distance traveled and stereotyped movement was monitored for 2 h. In the second experiment, 146 male and female rats were tested with the same protocol as in Experiment 1 except that rats were given CP (13.2 or 4 µg/kg), cocaine (20 mg/kg), or vehicle (saline or 50% DMSO/H2O) for five days and then tested with saline or cocaine (10 mg/kg) after 48 h. In the first experiment, no dose of CP altered distance traveled scores or stereotyped movement over the five pre-exposure days nor did CP cause behavioral sensitization on the test day. In the second experiment, pretreatment with cocaine led to enhanced distance traveled scores and stereotyped movement when challenged with cocaine (behavioral sensitization) or saline (conditioned activity) on test day. In contrast, CP-pretreated rats did not show greater activity when injected with cocaine or saline on test day. These data show that cannabinoids do not act like psychostimulant drugs, since CP did not cause the same changes in drug sensitivity as cocaine. The cocaine sensitization observed in adolescent rats indicates that this age group is particularly vulnerable to the rewarding effects of cocaine, and suggests that early cocaine exposure can augment drug seeking behavior. The failure to detect cannabinoid-induced sensitization, conditioned activity, or cocaine cross-sensitization during adolescence suggests that CP, when given at a consistent dose, does not increase the addictive properties of cannabinoids or cocaine. The results also indicate that cannabinoid use does not alter drug responsivity or lead to greater drug seeking and abuse in the adolescent population.

The neurobiological mechanisms underlying chronic pain in bone-metastasized breast and prostate cancer are not well understood although it is hypothesized that factors released in the tumor microenvironment may modulate sensory nociceptive sensory nerve fibers innervating the bone increasing pain sensation. Advanced metastatic breast and prostate cancer cells secrete high levels of parathyroid hormone-related peptide (PTHrP), which plays a critical role in metastasis to bones and subsequent tumor growth. PTHrP can activate parathyroid hormone receptor 1 (PTH1R), which signaling can activate either protein kinase C (PKC) and/or protein kinase A (PKA) depending on the tissue type. Both of these kinases are well known to modulate the nociceptive ion channel transient receptor potential vanilloid member 1 (TRPV1) due to which PTHrP constitutes an intriguing candidate that could modulate nociceptors, for pain sensitization related to cancer. TRPV1 can be activated by temperatures greater than 43°C and moderately acidic pH, less than pH 6. However, PKC and PKA phosphorylation of TRPV1 can potentiation channel activity by reducing the temperature of activation to 37°C and proton activation to pH 6.8 resulting in a channel that is constitutively active at body temperature or in the mildly acidic tumor microenvironment. Additionally, Src kinase, which under certain circumstances can be activated by PKC, can increase trafficking of TRPV1 to the plasma membrane, and enhance TRPV1-mediated signaling. Therefore, I hypothesize that PTHrP can sensitize TRPV1 and lead to an increase in nociceptive signaling. First I show that intraplantar PTHrP injection causes a TRPV1-dependent increase in thermal and mechanical hypersensitivity in mice. PTHrP treatment of cultured mouse dorsal root ganglion (DRG) neurons enhances TRPV1 activation and increases action potential firing, which was dependent on PKC activation. Furthermore, co-injection of PKC inhibitor attenuated PTHrP-induced thermal hypersensitivity. I also observed that PTHrP activated Src which led to an increase in the number of TRPV1-responsive neurons and an increase in TRPV1 protein level in the plasma membrane. While investigating the role of PTHrP-induced Src phosphorylation of TRPV1 I made a startling observation. Inhibition of Src phosphorylation of TRPV1 completely abolished PKC-induced potentiation of TRPV1. I found that Src phosphorylation of TRPV1 regulated PKC-induced potentiation of channel activity elicited by bradykinin, nerve growth factor and PMA. However, it did not regulate PKA induced potentiation of TRPV1 channel activity. In summary, my results suggest that PTHrP in the tumor microenvironment could induce constitutive pathological sensitization of adjacent nociceptive sensory fibers via upregulation of TRPV1 function, trafficking and expression. These actions are dependent on Src and PKC phosphorylation of TRPV1. Additionally, I found that Src regulates PKC-induced phosphorylation of TRPV1 by PTHrP as well as other inflammatory mediators, suggesting a crucial role for Src in PKC-induced sensitization of TRPV1.

Memoria para optar al Título Profesional de Ingeniero Forestal / La presente Memoria de Título tiene como propósito formular estrategias que orienten una futura campaña de prevención de incendios forestales basadas en la sensibilización, en las comunas de la provincia de Melipilla, Región Metropolitana. Para tales efectos, se realizó un análisis de la población respecto al conocimiento sobre el medio ambiente, su percepción sobre los incendios forestales, la prevención y su participación en el control de incendios forestales. El estudio contempló a las comunas de Alhué, Curacaví, María Pinto, Melipilla y San Pedro, que, en su totalidad, abarcan una superficie de 406.570 ha, en las cuales se describió y analizó la ocurrencia y causalidad de incendios forestales para un período de 17 temporadas (1999/00 a 2015/16, inclusive), basándose en la información registrada por el Programa de Manejo del Fuego de la Región Metropolitana de CONAF. Las percepciones sobre la ocurrencia y causalidad de incendios forestales, así como las medidas de prevención realizadas, se evaluaron a través de encuestas y entrevistas, en donde los resultados sirvieron de base para realizar un análisis que permitiese fundamentar las propuestas para futuras campañas de prevención basados en la sensibilización. Los resultados demostraron que la población estudiada posee escaso conocimiento en materia de prevención de incendios forestales y, además, se puede constatar que las campañas anteriormente realizadas han sido de escaso aporte, en cuanto a la identificación del público objetivo, su mensaje, el medio por el cual se ha entregado el mensaje, la cobertura y el impacto deseado para sensibilizar a las personas. Las instituciones que más relaciona la población como organismos activos en la prevención de incendios forestales son CONAF y Bomberos, los que destacan por su constancia y por ser las que demuestran más interés en el tema. Por otra parte, Bomberos es identificada como la organización a la que se acude cuando se origina un incendio forestal. Finalmente, los resultados obtenidos permitieron sustentar la formulación de la propuesta de estrategia de prevención. Al respecto, se definió la línea de acción básica identificada como Educación y Difusión, en la cual se propone un protocolo del ámbito de su aplicación, con las estrategias específicas correspondientes y por último, la secuencia de acciones a desarrollar para llevar a cabo su implementación y ejecución. / The present Title Memory aims to formulate strategies for a future campaign to prevent forest fires based on sensitization, in the communes of the Province of Melipilla, Metropolitan Region, based on the sociological characterization of the population. For this purpose, an analysis of the behavior of the population was made regarding knowledge about the environment, their perception of forest fires, their perception about prevention and their participation in the prevention of forest fires. The study contemplated at the communes of Alhué, Curacaví, María Pinto, Melipilla and San Pedro, all belonging to the Province of Melipilla, which, in their totality, cover an area of 406.570 ha, in which the occurrence and causality of forest fires for a period of 17 seasons (1999/00 to 2015/16), based on information recorded by the Fire Management Program of the Metropolitan Region from CONAF. The perceptions about the occurrence and causality of forest fires and the done prevention measures were evaluated through surveys and interviews, where the results served as the basis for an analysis that would allow basing the proposals for future fire prevention campaigns based on sensibilization. The results showed that there is a population with little knowledge about forest fire prevention and it is also possible to verify that the previous campaigns have been of little contribution, as to the identification of the target public, its message, the medias by which has been delivered the message, the coverage and the impact that has been wished to achieve in the sensitivity of people. The institutions that most closely relate the population to the organisms active in the prevention of forest fires are the CONAF and the Fire Department, which stand out for their constancy and for being the ones that show more interest in the subject. The Fire Department is identified as the organization that people come to when a forest fire occurs. Finally, the obtained results allowed to support the formulation of the proposed prevention strategy. In this regard, the basic line of action identified as Education and Dissemination was defined, in which, is proposed a definition of the scope of application, the corresponding specific strategies and, finally, the protocol of actions to be developed to carry out its implementation and execution.

Prior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.

<p>This qualitative study was conducted from June to November 2009, using designed questionnaires for sixty three (63) registered students and five (5) HIV program staff .The main reason for this study was to understand the underlying factors for why students may utilize or may not utilize the available HIV services on campus. The willingness of students to express their views was a positive finding in this study. Majority students who answered the questionnaires were quite aware of these HIV services. They also agreed that services provided are good. The study also found out that females utilized these services more than males and majority of students learnt of the HIV services from the HIV programs pamphlets and website thus indicating that the HIV program at UWC is function. However the research study also found out that the though students are aware of these services few utilize them and majority are females thus leaves a question why males do not utilize.</p>

The neuropeptide, corticotropin-releasing factor (CRF), plays a critical role in the central regulation of various stress-related behaviours, including those unique to subjects with prior cocaine experience. The three series of experiments presented in this dissertation explored the role of two neurochemical systems, the teneurin C-terminal associated peptides (TCAP) and the endocannabinoids (eCBs), in several cocaine- and anxiety-related behaviours induced or mediated by CRF. The first series of experiments examined the effects of TCAP-1 on the reinstatement of cocaine seeking and expression of cocaine-induced behavioural sensitization. Repeated (5-day), but not acute, TCAP-1 treatment blocked the reinstatement of cocaine seeking induced by central injections of CRF. TCAP-1 was, however, without effect on footshock- or cocaine-induced reinstatement. Repeated TCAP-1 further interfered with the expression of behavioural sensitization to a CRF, but not a cocaine, challenge. These findings suggest that TCAP-1 normalizes CRF signaling dysregulated by cocaine exposure to interfere in the subsequent effects of CRF on cocaine-related behaviours. A parallel series of experiments investigated the role of eCB signaling at CB1 receptors in the reinstatement of cocaine seeking and cocaine-sensitized locomotion. Pretreatment with the CB1 receptor antagonist, AM251, selectively interfered with CRF-, but not footshock- or cocaine-induced reinstatement. AM251 further blocked the expression of behavioural sensitization induced by challenge injections of both CRF and cocaine. These findings reveal a mediating role for CB1 receptor transmission in the effects of CRF on cocaine-related behaviours. A final series of experiments examined the role of CB1 receptor transmission in the behavioural anxiety induced by central injections of CRF, and by withdrawal from chronic cocaine exposure. AM251, although itself anxiogenic, reversed anxiety induced by CRF and cocaine withdrawal. Furthermore, AM251 elevated plasma corticosterone levels, indicative of increased HPA axis activity, irrespective of CRF treatment or cocaine withdrawal. These findings suggest that CRF- and cocaine withdrawal-induced anxiety are mediated, at least in part, by CB1 receptor transmission, independent of HPA axis regulation. The collective findings are discussed within a framework of CRF-TCAP-eCB interactions, wherein TCAP-1 and AM251 are proposed to act in parallel to modulate amygdalar CRF transmission, and thus regulate the expression of cocaine- and anxiety-related behaviours.

The neuropeptide, corticotropin-releasing factor (CRF), plays a critical role in the central regulation of various stress-related behaviours, including those unique to subjects with prior cocaine experience. The three series of experiments presented in this dissertation explored the role of two neurochemical systems, the teneurin C-terminal associated peptides (TCAP) and the endocannabinoids (eCBs), in several cocaine- and anxiety-related behaviours induced or mediated by CRF. The first series of experiments examined the effects of TCAP-1 on the reinstatement of cocaine seeking and expression of cocaine-induced behavioural sensitization. Repeated (5-day), but not acute, TCAP-1 treatment blocked the reinstatement of cocaine seeking induced by central injections of CRF. TCAP-1 was, however, without effect on footshock- or cocaine-induced reinstatement. Repeated TCAP-1 further interfered with the expression of behavioural sensitization to a CRF, but not a cocaine, challenge. These findings suggest that TCAP-1 normalizes CRF signaling dysregulated by cocaine exposure to interfere in the subsequent effects of CRF on cocaine-related behaviours. A parallel series of experiments investigated the role of eCB signaling at CB1 receptors in the reinstatement of cocaine seeking and cocaine-sensitized locomotion. Pretreatment with the CB1 receptor antagonist, AM251, selectively interfered with CRF-, but not footshock- or cocaine-induced reinstatement. AM251 further blocked the expression of behavioural sensitization induced by challenge injections of both CRF and cocaine. These findings reveal a mediating role for CB1 receptor transmission in the effects of CRF on cocaine-related behaviours. A final series of experiments examined the role of CB1 receptor transmission in the behavioural anxiety induced by central injections of CRF, and by withdrawal from chronic cocaine exposure. AM251, although itself anxiogenic, reversed anxiety induced by CRF and cocaine withdrawal. Furthermore, AM251 elevated plasma corticosterone levels, indicative of increased HPA axis activity, irrespective of CRF treatment or cocaine withdrawal. These findings suggest that CRF- and cocaine withdrawal-induced anxiety are mediated, at least in part, by CB1 receptor transmission, independent of HPA axis regulation. The collective findings are discussed within a framework of CRF-TCAP-eCB interactions, wherein TCAP-1 and AM251 are proposed to act in parallel to modulate amygdalar CRF transmission, and thus regulate the expression of cocaine- and anxiety-related behaviours.

Adverse childhood events have been identified as a risk factor for developing chronic pain conditions in adulthood. However, previous studies have inconsistently supported the link between adverse childhood events and hypersensitivity to laboratory-induced pain. Therefore, this study intended to investigate the effects of adverse childhood events on temporal summation of second pain (TSSP). A group of 38 healthy and pain-free college students participated in laboratory pain tests after being screened for childhood trauma history. Half of participants (47.5% female) were positive for childhood trauma and the other half (63.2% female) reported no adverse childhood event. The laboratory pain tests measured TSSP using 10 thermal pulses per trial over four consecutive trials. The trauma group showed a tendency of greater sensitization within TSSP trials and lack of habituation over repeated TSSP trials. In sum, adverse childhood events predisposed adults to enhanced TSSP, which is potentially linked to an increased likelihood to develop chronic pain problems.