Background Animal models can be used to mimic human conditions of psychopathology, and also as pre-clinical models to evaluate candidate drugs. With hormonal treatment it is possible to produce behavior in the rat which corresponds to the mental symptoms of pre-menstrual syndrome (PMS), and pre-menstrual dysphoric disorder (PMDD). PMS affects 25-30 % of all women in fertile age and 3-8% are diagnosed with the more severe condition PMDD. The cardinal mental symptoms are; irritability, mood-swings, depression, anxiety, fatigue, insomnia, difficulties with concentration and memory and learning difficulties. The symptoms of PMS/PMDD occur in the luteal phase in conjunction with increasing concentrations of progesterone (P4) and P4-metabolites. In anovulatory cycles the symptoms are absent. The hormones which produce the monthly reoccurring negative symptoms on mood are foremost the neuroactive metabolites; allopregnanolone (ALLO) and tetrahydro-deoxycorticosterone (THDOC). ALLO is produced by the corpus luteum, but can also be synthesized in the brain, both ALLO and THDOC can also be released from the adrenal cortex during stress. These steroids are active on the inhibitory GABA neurotransmitter system through the GABAA receptor, and the effects are similar to that of alcohol and benzodiazepines. These steroids have strong sedative and hypnotic effects. A paradox is that some individuals seem to react with negative mood on sex steroids while all fertile women have the cyclical steroid changes during the menstrual cycle. Some individuals are more sensitive to neuroactive steroids with influences of personality, heritability and stress factors. Aims The thesis aims were to develop pre-clinical animal models of PMS/PMDD and to investigate induction of ALLO tolerance, individual sensitivity to neurosteroids and the interactions between chronic social stress and neurosteroids. Methods In these studies male and female Wistar rats were used to test steroid hormone effects on learning and memory and behaviors analogous to negative mood symptoms. This was accomplished through hormonal treatment and a subsequent withdrawal period from P4 (P4) + estradiol (E2) (PEWD), or ALLO. To assess tolerance, memory and learning in the Morris water maze (MWM) was studied. Anxiety-like behaviors were tested with the elevated plus maze (EPM), open field test (OFT), and the intruder test (IT). The EPM or OFT was used to classify the rats as high or low responders on risk-taking and explorative behavior (HR/LR). For social ranking order assessment the tube test (TT) and food competition test (FCT) were used. Chronic social stress was accomplished through co-habituation with two older rats (chronic subordination stress). In female rats the estrous cycle followed using staining of vaginal smears. Concentration of corticosterone (CORT) was measured by radio-immuno-assay (RIA). Results In the MWM ALLO pre-treatment produced tolerance to the acute negative ALLO effects. Both male and female rats showed behavioral correlations between the EPM and OFT tests, and correlations were also seen in CORT levels. Individuals with the stable trait of high risk-taking and explorative behavior (HR) were more sensitive to PEWD induction of anxiety-like behavior. These animals also showed decreased CORT levels during withdrawal. Chronic subordination stress enhanced the response to PEWD on measures of locomotor activity and social anxiety-like behavior. Conclusions It is possible to induce tolerance to the negative ALLO effects on learning and memory. The animal models of anxiety-like behavior show an individual PEWD response profile where HR rats are more sensitive. Exposure to chronic social stress enhanced the PEWD response. Hence there are both inherent and environmental factors behind the behavioral response to steroid hormones in rats. / Stress- och könshormoners verkningar på centrala nervsystemet

A fundamental question in the neurobiological study of drug addiction concerns the mechanisms mediating the motivational effects of chronic drug withdrawal. According to one theory, drugs of abuse activate opposing motivational processes after both acute and chronic drug use. The negative experience of withdrawal is the opponent process of chronic drug use that drives relapse to drug-seeking and -taking, making the identification of the neurobiological substrates mediating withdrawal an issue of central importance in addiction research. In this thesis, I identify the involvement of the neurotransmitters dopamine (DA) and corticotropin-releasing factor (CRF) in the opponent motivational a- and b-processes occurring after acute and chronic nicotine administration. I report that acute nicotine stimulates an initial aversive a-process followed by a rewarding opponent b-process, and chronic nicotine stimulates a rewarding a-process followed by an aversive opponent b-process (withdrawal). These responses can be modeled using a place conditioning paradigm. I demonstrate that the acute nicotine a-process is mediated by phasic dopaminergic activity and the DA receptor subtype-1 (D1R) but not by tonic dopaminergic activity and the DA receptor subtype-2 (D2R) or CRF activity, and the opponent b-process is neither DA- nor CRF-mediated. I also demonstrate that the chronic nicotine a-process is DA- but not CRF-mediated, and that withdrawal from chronic nicotine (the b-process) decreases tonic but not phasic DA activity in the ventral tegmental area (VTA), an effect that is D2R- but not D1R-mediated. I show that a specific pattern of signaling at D1Rs and D2Rs mediates the motivational responses to acute nicotine and chronic nicotine withdrawal, respectively, by demonstrating that both increasing or decreasing signaling at these receptors prevents the expression of the conditioned motivational response. Furthermore, I report that the induction of nicotine dependence increases CRF mRNA in VTA DA neurons, and that blocking either the upregulation of CRF mRNA or the activation of VTA CRF receptors prevents the anxiogenic and aversive motivational responses to withdrawal from chronic nicotine. The results described in this thesis provide novel evidence of a VTA DA/CRF system, and demonstrate that both CRF and a specific pattern of tonic DA activity in the VTA are necessary for the aversive motivational experience of nicotine withdrawal.

El objetivo general de este trabajo ha sido estudiar la posible implicación de diferentes cascadas de proteín kinasas en las modificaciones cardiacas que se producen tras la administración de naloxona a ratas dependientes de morfina. Los datos obtenidos indican que durante la abstinencia a morfina se produce un aumento del turnover de NA, de la actividad TH y de su fosforilación en serina 40 y 31, lo que sugiere la puesta en marcha de mecanismos post-transcripcionales. Por otra parte, la vía de la PKA estaría implicada en el incremento del turnover de NA, en el aumento de TH total y en la fosforilación y activación de TH en serina 40 durante dicho síndrome. Por último, la vía de la PKC sería una de las vías implicadas en la expresión de c-fos, así como la de las ERK, que estaría también implicada en la activación de TH en serina 31. / The main aim of this work was to study the posible involvement of different protein kinases in the cardiac adaptive changes induced during morphine withdrawal. Our results show an increase of NA turnover, TH activity and TH phosphorylation at serine 31 and 40, suggesting starting post-trascriptional mechanisms. On the other hand, PKA transduction system could be implicated in the enhanced NA turnover, in the total TH increase and in the phosphorylation and activation of TH at serine 40 during this syndrome. Finally, PKC pathway would be involved in c-Fos expression as well as ERK system which would also be responsible for TH phosphorylation at serine 31.

La adicción es un trastorno crónico de la conducta caracterizado por la búsqueda y el consumo compulsivos de la droga, la pérdida de control para limitar dicho consumo, a aparición de un estado emocional negativo cuando el acceso a la droga está impedido y la recaída en el proceso incluso tras largos períodos de abstinencia. El sistema dopaminérgico mesolímbico cortical ha sido propuesto como la principal base neurobiológica de la adicción, sin embargo existen otros sistemas de neurotransmision que participan en la consolidación del proceso adictivo.El sistema endocannabinoide, a traves del receptor CB1, participa en las propiedades adictivas de diferentes drogas de abuso como el delta9-tetrahidrocannabinol, la nicotina y la morfina. Sin embargo, hasta el momento de iniciar este trabajo, pocos estudios han demostrado una clara implicación del sistema endocannabinoide en las propiedades reforzantes de los psicoestimulantes. Mediante el uso de ratones CB1 knockout, hemos demostrado que el receptor CB1 participa en la eficacia reforzante de la cocaína. Además, la presencia de dicho receptor es necesaria para los procesos de consolidación de una conducta operante mantenida por la autoadministración de cocaína. Este estudio demuestra la importancia de dicho receptor CB1 en las propiedades adictivas de la cocaína, confirmando que el sistema endocannabinoide es un sustrato común para la adicción de drogas de abuso. Por otra parte, el sistema purinérgico modula numerosos sistemas de neurotransmisión en el SNC. La estrecha relación a nivel celular y funcional entre los receptores de adenosina y los receptores dopaminérgicos proporciona evidencias de que el sistema purinérgico podría modular los sistemas de recompensa. Utilizando diferentes modelos animales, hemos demostrado que los receptores de adenosina A2A son necesarios para que las propiedades adictivas de las drogas de abuso como los cannabinoides, los opioides, la nicotina y los psicoestimulantes se produzcan de un modo completo.Nuestros estudios nos permiten afirmar que ambos sistemas, el cannabinoide y el purinérgico podría suponer la existencia de nuevos sistemas de modulación común de los procesos adictivos. Asi, sería de gran interés desarrollar nuevas estrategias de bloqueo de los receptores A2A y CB1 para atenuar e incluso prevenir el desarrollo de la adicción. / Drug addiction is a chronically relapsing disorder that is defined by a compulsion to take the drug intake, a loss of control in limiting intake and a withdrawal-negative affect state when the access to the drug is interrupted. Mesolimbic dopaminergic system has been proposed as a fundamental neurobiological substrate for drug addiction. However, there is evidence for other neurotransmitter systems involved in the consolidation of the addictive process. The endocannabinoid system, through the activation of CB1 receptor, participates in the addictive properties of different drugs of abuse such as delta9-tetrahydrocannabinol, morphine and nicotine. Nevertheless, few studies have revealed an important implication of CB1 receptor in the reinforcing properties of psychostimulants. By using CB1 knockout mice, we have demonstrated that CB1 receptor participates in the reinforcing efficacy of cocaine. Moreover, this receptor is necessary for the consolidation processes involved in cocaine maintained intravenous self-administration. Therefore, this study reveals an essential role of CB1 receptor in cocaine addictive properties, confirming that the endocannabinoid system is a common substrate of addiction to drugs of abuse.On the other hand, the purinergic system modulates different neurotransmitter systems in the CNS. Adenosine receptors are closely related to dopaminergic receptors at both cellular and functional levels, suggesting that purinergic system could modulate the reward systems. By using different animal models, we have demonstrated that A2A adenosine receptors are necessary for the development of the addictive properties of drugs of abuse such as opioids, cannabinoids, nicotine and cocaine. Our studies suggest that both cannabinoid and purinergic systems could represent new and common modulatory systems of addictive processes. Thus, it would be of interest to develop new therapeutic targets blocking CB1 and A2A receptors to attenuate the development of addiction.

From the Proceedings of the 1975 Meetings of the Arizona Section - American Water Resources Assn. and the Hydrology Section - Arizona Academy of Science - April 11-12, 1975, Tempe, Arizona / Conclusions drawn from a water resources study of the woody mountain area are: the average coefficients of transmissibility and of storage of the principal aquifer are approximately 30,000 gpd/ft and 0.05 respectively; drawdown in wells is greater than predicted using theoretical calculations due to the turbulent flow near the well bore in the fractured Coconino aquifer; the computed interference between pumped wells in the field ranges from 10.5 ft. To 19.7 ft. Interference would be negligible between wells spaced at distances greater than 6,000 ft. For pumping periods as long as two hundred days; the negative boundary effect of off-set on the oak creek fault may be balanced by the recharge effect of groundwater located in the highly permeable fractured zone adjacent to the fault; and the quantity of recharge water to the well field is greater than withdrawals from the wells.

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.

A fundamental question in the neurobiological study of drug addiction concerns the mechanisms mediating the motivational effects of chronic drug withdrawal. According to one theory, drugs of abuse activate opposing motivational processes after both acute and chronic drug use. The negative experience of withdrawal is the opponent process of chronic drug use that drives relapse to drug-seeking and -taking, making the identification of the neurobiological substrates mediating withdrawal an issue of central importance in addiction research. In this thesis, I identify the involvement of the neurotransmitters dopamine (DA) and corticotropin-releasing factor (CRF) in the opponent motivational a- and b-processes occurring after acute and chronic nicotine administration. I report that acute nicotine stimulates an initial aversive a-process followed by a rewarding opponent b-process, and chronic nicotine stimulates a rewarding a-process followed by an aversive opponent b-process (withdrawal). These responses can be modeled using a place conditioning paradigm. I demonstrate that the acute nicotine a-process is mediated by phasic dopaminergic activity and the DA receptor subtype-1 (D1R) but not by tonic dopaminergic activity and the DA receptor subtype-2 (D2R) or CRF activity, and the opponent b-process is neither DA- nor CRF-mediated. I also demonstrate that the chronic nicotine a-process is DA- but not CRF-mediated, and that withdrawal from chronic nicotine (the b-process) decreases tonic but not phasic DA activity in the ventral tegmental area (VTA), an effect that is D2R- but not D1R-mediated. I show that a specific pattern of signaling at D1Rs and D2Rs mediates the motivational responses to acute nicotine and chronic nicotine withdrawal, respectively, by demonstrating that both increasing or decreasing signaling at these receptors prevents the expression of the conditioned motivational response. Furthermore, I report that the induction of nicotine dependence increases CRF mRNA in VTA DA neurons, and that blocking either the upregulation of CRF mRNA or the activation of VTA CRF receptors prevents the anxiogenic and aversive motivational responses to withdrawal from chronic nicotine. The results described in this thesis provide novel evidence of a VTA DA/CRF system, and demonstrate that both CRF and a specific pattern of tonic DA activity in the VTA are necessary for the aversive motivational experience of nicotine withdrawal.

Of the findings, the European Commission established in its report on Energy Sector Inquiry, market manipulation constituted a major concern for the functioning and integrity of EU energy sectors. The Commission argued that the responsibility for high prices in wholesale energy markets could be attributed to manipulative practices of energy incumbents and the trust in the operation of operation of sector was largely compromised, due to these practices. Remedies, EU competition law provided, were considered as insufficient to resolve these shortcomings and thus should be supplemented with regulatory-based tools. The findings of the Energy Sector Inquiry and subsequent consultation documents by multiple EU institutions paved the way for the adoption of the Regulation on wholesale energy market integrity and transparency, REMIT, which incorporated into an anti-manipulation rule, specifically designed to prohibit and prosecute manipulative practices in EU wholesale energy markets. Nevertheless, as EU case law on market manipulation has yet to develop and there are uncertainties with respect to the concept of market manipulation. Furthermore REMIT does not preclude the jurisdiction of EU competition law, questions arise as to the scope and the extent of the application of this prohibition. Throughout its chapters, this book explores the scope of and the case law on market manipulation to determine what types of market practices are regarded as manipulative and thus prohibited under anti-manipulation rules. It also focuses on the interplay between REMIT and EU competition law and evaluates factors and circumstances that determine when and what market misconduct can be subject to enforcement proceedings under both anti-manipulation and antitrust rules. As the development of a single, coherent, rulebook that can be relied upon by market participant is fundamental for the functioning of EU wholesale energy markets, the book, finally, provides proposals and measures that can mitigate and resolve the legal uncertainties regarding the regulatory framework REMIT established.

The aim of this thesis is to show that Emily Dickinson was not concerned with the publication of her poems and she herself decided to withdraw from the outside world, a decisive event which contributed to the original production of her almost eighteen hundred poems and over eleven hundred letters. Emily Dickinson withdrew into her untouched private world – which here is called “the bubble” – and developed the contemplation process based on the approach of apprehending perceptions which resulted in the instant captions that have enchanted readers. Since her withdrawal was as a result of her own free choice and own writing and living conventions, she was able to be the craftsperson that enjoyed living and writing. Her perception of nature by taking instant captions of the observable natural objects is perfected by the process of contemplation developed in some of her poems. The theoretical and methodological basis of the study comes from the analysis of the complete edition of poems edited by Thomas H. Johnson, the letters edited by Mabel Loomis Todd, and the concept of Nature by Hans Georg Schenk. For the analyses of different issues related to Dickinson’s verses, withdrawal, and apprehension of perceptions, the works of the biographer Richard Benson Sewall and critics such as Albert Gelpi, Barton Levi Armand, Karl Keller, Sharon Cameron, among others, were consulted. This study aims to demonstrate that Emily Dickinson was not concerned with publication and her withdrawal within her bubble was a positive event for her life and poetry. Such conclusion might contribute to enlighten the knowledge about the life and work of such an amazing personage of American Literature and American society as Emily Dickinson has been so far.

The aim of this thesis is detailed description of solved reclamation in the selected location Cep II after gravel extraction. The part of thesis solves property settlements on the parcels concerned. The literary review outlines generally issue of mining and its impact on the landscape and ways of deal with these negative impacts. Besides the classical methods of reclamation (agricultural, forestry and hydrological reclamation) is described a method of using spontaneous restoration. There is also particularised the possibility of incorporating suitably reclaimed parcels into territorial system of ecological stability in terms of land adjustment.