Roles of forced nicotine exposure and Comt gene disruption in the development of addiction-related behavioural and neurochemical changes in mice

Activation of midbrain dopamine systems is thought to be critically involved in the addictive properties of abused substances. Drugs of abuse increase dopamine release in the nucleus accumbens and dorsal striatum, which are the target areas of mesolimbic and nigrostriatal dopamine pathways, respectively. Dopamine release in the nucleus accumbens is thought to mediate the attribution of incentive salience to rewards, and dorsal striatal dopamine release is involved in habit formation. In addition, changes in the function of prefrontal cortex (PFC), the target area of mesocortical dopamine pathway, may skew information processing and memory formation such that the addict pays an abnormal amount of attention to drug-related cues. In this study, we wanted to explore how long-term forced oral nicotine exposure or the lack of catechol-O-methyltransferase (COMT), one of the dopamine metabolizing enzymes, would affect the functioning of these pathways. We also wanted to find out how the forced nicotine exposure or the lack of COMT would affect the consumption of nicotine, alcohol, or cocaine. First, we studied the effect of forced chronic nicotine exposure on the sensitivity of dopamine D2-like autoreceptors in microdialysis and locomotor activity experiments. We found that the sensitivity of these receptors was unchanged after forced oral nicotine exposure, although an increase in the sensitivity was observed in mice treated with intermittent nicotine injections twice daily for 10 days. Thus, the effect of nicotine treatment on dopamine autoreceptor sensitivity depends on the route, frequency, and time course of drug administration. Second, we investigated whether the forced oral nicotine exposure would affect the reinforcing properties of nicotine injections. The chronic nicotine exposure did not significantly affect the development of conditioned place preference to nicotine. In the intravenous self-administration paradigm, however, the nicotine-exposed animals self-administered nicotine at a lower unit dose than the control animals, indicating that their sensitivity to the reinforcing effects of nicotine was enhanced. Next, we wanted to study whether the Comt gene knock-out animals would be a suitable model to study alcohol and cocaine consumption or addiction. Although previous work had shown male Comt knock-out mice to be less sensitive to the locomotor-activating effects of cocaine, the present study found that the lack of COMT did not affect the consumption of cocaine solutions or the development of cocaine-induced place preference. However, the present work did find that male Comt knock-out mice, but not female knock-out mice, consumed ethanol more avidly than their wild-type littermates. This finding suggests that COMT may be one of the factors, albeit not a primary one, contributing to the risk of alcoholism. Last, we explored the effect of COMT deficiency on dorsal striatal, accumbal, and prefrontal cortical dopamine metabolism under no-net-flux conditions and under levodopa load in freely-moving mice. The lack of COMT did not affect the extracellular dopamine concentrations under baseline conditions in any of the brain areas studied. In the prefrontal cortex, the dopamine levels remained high for a prolonged time after levodopa treatment in male, but not female, Comt knock-out mice. COMT deficiency induced accumulation of 3,4-dihydroxyphenylacetic acid, which increased further under levodopa load. Homovanillic acid was not detectable in Comt knock-out animals either under baseline conditions or after levodopa treatment. Taken together, the present results show that although forced chronic oral nicotine exposure affects the reinforcing properties of self-administered nicotine, it is not an addiction model itself. COMT seems to play a minor role in dopamine metabolism and in the development of addiction under baseline conditions, indicating that dopamine function in the brain is well-protected from perturbation. However, the role of COMT becomes more important when the dopaminergic system is challenged, such as by pharmacological manipulation.

Community, Power, and Colonialism: The U.S. Army in Southern Arizona and New Mexico, 1866-1886

Empire is central to U.S. history. When we see the U.S. projecting its influence on a global scale in today s world it is important to understand that U.S. empire has a long history. This dissertation offers a case study of colonialism and U.S. empire by discussing the social worlds, labor regimes, and culture of the U.S. Army during the conquest of southern Arizona and New Mexico (1866-1886). It highlights some of the defining principles, mentalities, and characteristics of U.S. imperialism and shows how U.S. forces have in years past constructed their power and represented themselves, their missions, and the places and peoples that faced U.S. imperialism/colonialism. Using insights from postcolonial studies and whiteness studies, this work balances its attention between discursive representations (army stories) and social experience (army actions), pays attention to silences in the process of historical production, and focuses on collective group mentalities and identities. In the end the army experience reveals an empire in denial constructed on the rule of difference and marked by frustration. White officers, their wives, and the white enlisted men not only wanted the monopoly of violence for the U.S. regime but also colonial (mental/cultural) authority and power, and constructed their identity, authority, and power in discourse and in the social contexts of the everyday through difference. Engaged in warfare against the Apaches, they did not recognize their actions as harmful or acknowledge the U.S. invasion as the bloody colonial conquest it was. White army personnel painted themselves and the army as liberators, represented colonial peoples as racial inferiors, approached colonial terrain in terms of struggle, and claimed that the region was a terrible periphery with little value before the arrival of white civilization. Officers and wives also wanted to place themselves at the top of colonial hierarchies as the refined and respectable class who led the regeneration of the colony by example: they tried to turn army villages into islands of civilization and made journeys, leisure, and domestic life to showcase their class sensibilities and level of sophistication. Often, however, their efforts failed, resulting in frustration and bitterness. Many blamed the colony and its peoples for their failures. The army itself was divided by race and class. All soldiers were treated as laborers unfit for self-government. White enlisted men, frustrated by their failures in colonial warfare and by constant manual labor, constructed worlds of resistance, whereas indigenous soldiers sought to negotiate the effects of colonialism by working in the army. As colonized labor their position was defined by tension between integration and exclusion and between freedom and colonial control.

Psychological consequences of cancer from the salutogenic and dyadic perspective

Previous empirical research has shown that positive, i.e. salutogenic, psychological resources and social support, have health-promoting effects in stressful life situations. In the present study the associations between sense of coherence (SOC), dispositional optimism, partner support, psychological distress, and quality of life among cancer patients and their partners were examined. The data was collected from Helsinki University Central Hospital in 1997 2000 by self-report questionnaires approximately 2, 8, and 14 months post diagnosis. Participants in studies I-IV were 155, 123, 153, and 147 cancer patients and their partners, respectively. The sample of the present study consisted of physically relatively well-functioning patients, whose overall psychological wellbeing was generally good as compared to the healthy population. Partners in this study, however, reacted more strongly to their partners illness and treatment. The partners displayed e.g. higher levels of anxiety and depression than the patients. The results of this study indicated that cancer patients and their partners with strong SOC and who are optimistic report fewer symptoms of distress. Moreover, patients who display an optimistic attitude to life, who receive support from their partner, and who control how they express anger have a better quality of life. The findings also confirmed that the role of the partner is significant in coping with cancer. The symptoms of depression and anxiety in patients and partners were associated, and the partner s optimism seemed to protect also the patient from elevated levels of anxiety. The role of the partner was also highlighted in the couples anger-expression styles. The patients and partners tendency to inhibit anger was associated with decreased partner support and worse patient quality of life. Finally, in the present study we found substantial gender differences. For the patients, partner support was more significant for the women than for the men. Furthermore, for the female patients, the husband s tendency to openly express anger (anger-out) had a negative impact on their psychological quality of life, whereas the wives high anger-out seemed to predict good psychological quality of life in the men. Also, in this study the female partners reported higher levels of anxiety and depression as compared to the male partners. The results of the present study extend the previous literature on positive psychological resources and psychological wellbeing among cancer couples. Furthermore, these findings support the theory on SOC and optimism as health-promoting factors. However, the construct of SOC seems to include other important elements besides optimism. The findings of this study are applicable in designing new rehabilitation programmes for cancer patients and their partners.

Kahdestaan kotona : Tutkimus vanhoista pariskunnista

In this study, which pertains to the field of social gerontology and family research, I analyse the meaning of everyday life as perceived by elderly couples living at home. I use the ethnographic approach, with the aim of interpreting meanings from the elderly people s personal point of view and to increase understanding of their way of life. The study deepens our conception of what gives purpose to the everyday life of elderly people. The number of elderly couples is growing and, to an increasing extent, a couple will live and cope together to a ripe old age. Such coping can also be viewed as an important resource for society. Ethnography tries to get close to people's life practices. I examine the day-to-day life of elderly couples based on textual data, which I obtained by visiting the homes of 16 couples in a total of five small municipalities in Southern Finland. The couples had married soon after the war or in the early 1950s. I found that the aspiration towards continuity, which unites the concepts of place and home, housework and a long marriage, is the most important notion connecting the discussion themes. The results show that in the opinion of the elderly, the concept of a good life is intertwined with a long marriage spent at home, as well as its values. Old people find that they lead an independent life if they feel that they can hold on to the key features of their way of life. Elderly couples ability to cope with everyday life involves taking care of housework and other tasks around the home together. This means that they support one another and have common goals and aspirations. Daily tasks provide substance in the lives of elderly couples. Each day has its rhythm, and the pace of this rhythm is set by routine and habits. Satisfaction stems from the fact that you can do something you are good at. The couples have also revised the division of housework. Men have learned to perform new tasks around the house when their wives can no longer manage them by themselves. Some tasks are given up. Day-to-day life at home and around the house provides room for men s participation. Mutual support and care between husband and wife can also protect them from having to resort to outside or official help. Old couples integrate their life experiences and memories, as well as present and future risks and opportunities. They wish to carry on their lives as before, and still think that their present life corresponds with their idea of a good life. Key words: elderly couples, continuity theory of aging, everyday life, social gerontology, family research

Sikiöaikana päihteille altistuneiden lasten kasvuympäristö ja kehitys

Life of children exposed to alcohol or drugs in utero This study focused on the growth environment, physical development and socio-emotional development of children, aged 16 and under, who had been exposed to alcohol (n=78) or drugs (n=15) in utero. The aim of the study was to obtain a comprehensive picture of the living conditions of these children and to examine the role of the growth environment in their development. The study was carried out using questionnaires, written life stories and interviews. Attachment theory was used as a background theory in the study. Over half of the children exposed to alcohol were diagnosed with foetal alcohol syndrome (FAS), one quarter was diagnosed with foetal alcohol effects (FAE), and one fifth had no diagnosis. Most of the children exposed to drugs had been exposed to either amphetamines or cannabis, and a smaller number to heroin. Some of the children exposed to alcohol were mentally handicapped or intellectually impaired. The children exposed to drugs did not exhibit any serious learning difficulties but a considerable number of them had socio-emotional development problems. Language and speech problems and attention, concentration and social interaction problems were typical among both the children exposed to alcohol and those exposed to drugs. Only one child had been placed into long-term foster care in a family immediately after leaving the maternity hospital. In biological families there had been neglect, violence, mental health problems, crime and unemployment, and many parents were already dead. Two of the children had been sexually abused and four were suspected of having been abused. From the point of view of the children's development, the three most critical issues were 1) the range of illnesses and handicaps that had impaired their functional capacity as a result of their prenatal exposure to alcohol, 2) child's age at the time of placement on a long-term basis, and 3) the number of their traumatic experiences. The relationship with their biological parents after placement also played a role. Children with symptoms were found in all diagnosis categories and types of exposure. Children with the smallest number of symptoms were found among those who had never lived with their biological parents. Almost all children were exhibiting strong symptoms at the time of placement in foster care. In most cases, they were behaving in a disorderly manner towards others, but some children were withdrawn. The most conspicuous feature among those with the most severe symptoms was their disorganized behaviour. Placement in a foster family enhanced the children's development, but did not solve the problems. The foster parents who brought these children up did not receive as much therapy for the children and support for the upbringing as they appear to have needed. In Finland, transfer to long-term custody is based on strict criteria. The rights of children prescribed in the child protection law are not fulfilled in practice. Key words: FASD, FAS, FAE, alcohol exposure, drugs exposure, illegal drugs, early interaction, child development, attachment

Uloimmalla rannalla : Luotsi- ja majakkamiesperheet asemayhdyskunnissaan

The subject of the present research is historical lighthouse and maritime pilot stations in Finland. If one thinks of these now-abandoned sites as an empty stage, the dissertation aims to recreate the drama that once played out there. The research comprises three main themes. The first, the family problematic, focuses on the relationship between the family members concerned and the public service positions held, as well as the islands on which these people were stationed. The role of the male actors becomes apparent through an examination of the job descriptions of pilots and lighthouse keepers, but the role of the wives appears more problematic: running a household and the insularity of the community came with their own challenges, and the husbands were away for much of the time. In this context the children emerge as crucial. What was their role in the family of a public official? What were the effects of having to move to the mainland for school? The second theme is the station community. A socioecological examination is undertaken which defines the islands as plots allowing the researcher to study the social behaviours of the isolated communities in question. The development of this theme is based on interpretations of interviews revealing starkly opposed views on the existing neighbourly relations. The premise is that social friction is inevitable among people living within close proximity of each other, and the study proceeds to become an analysis that seeks to uncover the sociocultural strategies designed to control the risks of communal living either by creating distance between neighbours or by enhancing their mutual ties. In connection with this, the question of why some neighbourhoods were open and cooperative while others were restrained and quarrelsome is addressed. Finally, the third main theme discusses the changes in piloting and lighthouse keeping that took place increasingly numerous towards the end of the 20th century. How did individuals react to the central management s technocratic strivings and rationalisations, such as the automation of lighthouses and the intense downsizing of the network of pilot stations? How was piloting, previously very comprehensive work, splintered into specialisations, and how did the entire occupation of lighthouse keeping lose its status before completely disappearing, as the new technology took over?

Drug epidemiology, interactions and pharmacogenetics : A post-mortem database study

Use of adverse drug combinations, abuse of medicinal drugs and substance abuse are considerable social problems that are difficult to study. Prescription database studies might fail to incorporate factors like use of over-the-counter drugs and patient compliance, and spontaneous reporting databases suffer from underreporting. Substance abuse and smoking studies might be impeded by poor participation activity and reliability. The Forensic Toxicology Unit at the University of Helsinki is the only laboratory in Finland that performs forensic toxicology related to cause-of-death investigations comprising the analysis of over 6000 medico-legal cases yearly. The analysis repertoire covers most commonly used drugs and drugs of abuse, and the ensuing database contains also background information and information extracted from the final death certificate. In this thesis, the data stored in this comprehensive post-mortem toxicology database was combined with additional metabolite and genotype analyses that were performed to complete the profile of selected cases. The incidence of drug combinations possessing serious adverse drug interactions was generally low (0.71%), but it was notable for the two individually studied drugs, a common anticoagulant warfarin (33%) and a new generation antidepressant venlafaxine (46%). Serotonin toxicity and adverse cardiovascular effects were the most prominent possible adverse outcomes. However, the specific role of the suspected adverse drug combinations was rarely recognized in the death certificates. The frequency of bleeds was observed to be elevated when paracetamol and warfarin were used concomitantly. Pharmacogenetic factors did not play a major role in fatalities related to venlafaxine, but the presence of interacting drugs was more common in cases showing high venlafaxine concentrations. Nicotine findings in deceased young adults were roughly three times more prevalent than the smoking frequency estimation of living population. Contrary to previous studies, no difference in the proportion of suicides was observed between nicotine users and non-nicotine users. However, findings of abused substances, including abused prescription drugs, were more common in the nicotine users group than in the non-nicotine users group. The results of the thesis are important for forensic and clinical medicine, as well as for public health. The possibility of drug interactions and pharmacogenetic issues should be taken into account in cause-of-death investigations, especially in unclear cases, medical malpractice suspicions and cases where toxicological findings are scarce. Post-mortem toxicological epidemiology is a new field of research that can help to reveal problems in drug use and prescription practises.

Operationalizing Supply Chain vs. Supply Chain Competion

Competition is an immensely important area of study in economic theory, business and strategy. It is known to be vital in meeting consumers’ growing expectations, stimulating increase in the size of the market, pushing innovation, reducing cost and consequently generating better value for end users, among other things. Having said that, it is important to recognize that supply chains, as we know it, has changed the way companies deal with each other both in confrontational or conciliatory terms. As such, with the rise of global markets and outsourcing destinations, increased technological development in transportation, communication and telecommunications has meant that geographical barriers of distance with regards to competition are a thing of the past in an increasingly flat world. Even though the dominant articulation of competition within management and business literature rests mostly within economic competition theory, this thesis draws attention to the implicit shift in the recognition of other forms of competition in today’s business environment, especially those involving supply chain structures. Thus, there is popular agreement within a broad business arena that competition between companies is set to take place along their supply chains. Hence, management’s attention has been focused on how supply chains could become more aggressive making each firm in its supply chain more efficient. However, there is much disagreement on the mechanism through which such competition pitching supply chain against supply chain will take place. The purpose of this thesis therefore, is to develop and conceptualize the notion of supply chain vs. supply chain competition, within the discipline of supply chain management. The thesis proposes that competition between supply chains may be carried forward via the use of competition theories that emphasize interaction and dimensionality, hence, encountering friction from a number of sources in their search for critical resources and services. The thesis demonstrates how supply chain vs. supply chain competition may be carried out theoretically, using generated data for illustration, and practically using logistics centers as a way to provide a link between theory and corresponding practice of this evolving competition mode. The thesis concludes that supply chain vs. supply chain competition, no matter the conceptualization taken, is complex, novel and can be very easily distorted and abused. It therefore calls for the joint development of regulatory measures by practitioners and policymakers alike, to guide this developing mode of competition.