Glutamatergic Modulation of Cue-Induced Drug-Seeking Behavior in the Rat

The characteristics of drug addiction include compulsive drug use despite negative consequences and re-occurring relapses, returns to drug use after a period of abstinence. Therefore, relapse prevention is one of the major challenges for the treatment of drug addiction. There are three main factors capable of inducing craving for drugs and triggering relapse long after cessation of drug use and dissipation of physical withdrawal signs: stress, re-exposure to the drug, and environmental stimuli (cues) that have been previously associated with drug use. The neurotransmitters dopamine and glutamate have been implicated in the modulation of drug-seeking behavior. The aim of this project was to examine the role of glutamatergic neurotransmission in relapse triggered by conditioned drug-associated stimuli. The focus was on clarifying whether relapse to drug seeking can be attenuated by blockade of glutamate receptors. In addition, as the nucleus accumbens has been proposed to participate in the modulation of drug-seeking behavior, the effects of glutamate receptor blockade in this brain structure on cue-induced relapse were investigated. The studies employed animals models in which rats were trained to press a lever in a test cage to obtain alcohol or intravenous cocaine. Drug availability was paired with distinct olfactory, auditory, or visual stimuli. This phase was followed by extinction training, during which lever presses did not result in the presentation of the drug or the drug-associated stimuli. Extinction training led to a gradual decrease in the number of lever presses during test sessions. Relapse was triggered by presenting the rats with the drug-associated stimuli in the absence of alcohol or cocaine. The drug-associated stimuli were alone capable of inducing resumption of lever pressing and maintaining this behavior during repeated testing. The number of lever presses during a session represented the intensity of drug-seeking and relapse behavior. The results suggest that glutamatergic neurotransmission is involved in the modulation of drug-seeking behavior. Both alcohol and cocaine relapse were attenuated by systemic pretreatment with glutamate receptor antagonists. However, differences were found in the ability of ionotropic AMPA/kainate and NMDA receptor antagonists to regulate drug-seeking behavior. The AMPA/kainate antagonists CNQX and NBQX, and L-701,324, an antagonist with affinity for the glycine site of the NMDA receptor, attenuated cue-induced drug seeking, whereas the competitive NMDA antagonist CGP39551 and the NMDA channel blocker MK-801 were without effect. MPEP, an antagonist at metabotropic mGlu5 glutamate receptors, also decreased drug seeking, but its administration was found to lead to conditioned suppression of behavior during subsequent treatment sessions, suggesting that MPEP may have undesirable side effects. The mGluR2/3 agonist LY379268 and the mGluR8 agonist (S)-3,4-DCPG decreased both cue-induced relapse to alcohol drinking and alcohol consumption. Control experiments showed however that administration of the agonists was accompanied by motor suppression limiting their usefulness. Administration of the AMPA/kainate antagonist CNQX, the NMDA antagonist D-AP5, and the mGluR5 antagonist MPEP into the nucleus accumbens resulted also in a decrease in drug-seeking behavior, suggesting that the nucleus accumbens is at least one of the anatomical sites regulating drug seeking and mediating the effects of glutamate receptor antagonists on this behavior.

The effect of lignin content and lignin modification on Norway spruce wood properties and decay resistance

Three different Norway spruce cutting clones growing in three environments with different soil and climatic conditions were studied. The purpose was to follow variation in the radial growth rate, wood properties and lignin content and to modify wood lignin with a natural monolignol, coniferyl alcohol, by making use of inherent wood peroxidases. In addition, the incorporation of chlorinated anilines into lignin was studied with synthetic model compounds and synthetic lignin preparations to show whether unnatural compounds originating from pesticides could be bound in the lignin polymer. The lignin content of heartwood, sapwood and earlywood was determined by applying Fourier transform infrared (FTIR) spectroscopy and a principal component regression (PCR) technique. Wood blocks were treated with coniferyl alcohol by using a vacuum impregnation method. The effect of impregnation was assessed by FTIR and by a fungal decay test. Trees from a fertile site showed the highest growth rate and sapwood lignin content and the lowest latewood proportion, weight density and modulus of rupture (MOR). Trees from a medium fertile site had the lowest growth rate and the highest latewood proportion, weight density, modulus of elasticity (MOE) and MOR. The most rapidly growing clone showed the lowest latewood proportion, weight density, MOE and MOR. The slowest growing clone had the lowest sapwood lignin content and the highest latewood proportion, weight density, MOE and MOR. Differences between the sites and clones were small, while fairly large variation was found between the individual trees and growing seasons. The cutting clones maintained clone-dependent wood properties in the different growing sites although variation between trees was high and climatic factors affected growth. The coniferyl alcohol impregnation increased the content of different lignin-type phenolic compounds in the wood as well as wood decay resistance against a white-rot fungus, Coriolus versicolor. During the synthetic lignin preparation 3,4-dichloroaniline became bound by a benzylamine bond to β-O-4 structures in the polymer and it could not be released by mild acid hydrolysis. The natural monolignol, coniferyl alcohol, and chlorinated anilines could be incorporated into the lignin polymer in vivo and in vitro, respectively.

On the mechanical behavior of compacted pack ice : A theoretical and numerical investigation

Pack ice is an aggregate of ice floes drifting on the sea surface. The forces controlling the motion and deformation of pack ice are air and water drag forces, sea surface tilt, Coriolis force and the internal force due to the interaction between ice floes. In this thesis, the mechanical behavior of compacted pack ice is investigated using theoretical and numerical methods, focusing on the three basic material properties: compressive strength, yield curve and flow rule. A high-resolution three-category sea ice model is applied to investigate the sea ice dynamics in two small basins, the whole Gulf Riga and the inside Pärnu Bay, focusing on the calibration of the compressive strength for thin ice. These two basins are on the scales of 100 km and 20 km, respectively, with typical ice thickness of 10-30 cm. The model is found capable of capturing the main characteristics of the ice dynamics. The compressive strength is calibrated to be about 30 kPa, consistent with the values from most large-scale sea ice dynamic studies. In addition, the numerical study in Pärnu Bay suggests that the shear strength drops significantly when the ice-floe size markedly decreases. A characteristic inversion method is developed to probe the yield curve of compacted pack ice. The basis of this method is the relationship between the intersection angle of linear kinematic features (LKFs) in sea ice and the slope of the yield curve. A summary of the observed LKFs shows that they can be basically divided into three groups: intersecting leads, uniaxial opening leads and uniaxial pressure ridges. Based on the available observed angles, the yield curve is determined to be a curved diamond. Comparisons of this yield curve with those from other methods show that it possesses almost all the advantages identified by the other methods. A new constitutive law is proposed, where the yield curve is a diamond and the flow rule is a combination of the normal and co-axial flow rule. The non-normal co-axial flow rule is necessary for the Coulombic yield constraint. This constitutive law not only captures the main features of forming LKFs but also takes the advantage of avoiding overestimating divergence during shear deformation. Moreover, this study provides a method for observing the flow rule for pack ice during deformation.

Growth and Modification of Cluster-Assembled Thin Films

Thin film applications have become increasingly important in our search for multifunctional and economically viable technological solutions of the future. Thin film coatings can be used for a multitude of purposes, ranging from a basic enhancement of aesthetic attributes to the addition of a complex surface functionality. Anything from electronic or optical properties, to an increased catalytic or biological activity, can be added or enhanced by the deposition of a thin film, with a thickness of only a few atomic layers at the best, on an already existing surface. Thin films offer both a means of saving in materials and the possibility for improving properties without a critical enlargement of devices. Nanocluster deposition is a promising new method for the growth of structured thin films. Nanoclusters are small aggregates of atoms or molecules, ranging in sizes from only a few nanometers up to several hundreds of nanometers in diameter. Due to their large surface to volume ratio, and the confinement of atoms and electrons in all three dimensions, nanoclusters exhibit a wide variety of exotic properties that differ notably from those of both single atoms and bulk materials. Nanoclusters are a completely new type of building block for thin film deposition. As preformed entities, clusters provide a new means of tailoring the properties of thin films before their growth, simply by changing the size or composition of the clusters that are to be deposited. Contrary to contemporary methods of thin film growth, which mainly rely on the deposition of single atoms, cluster deposition also allows for a more precise assembly of thin films, as the configuration of single atoms with respect to each other is already predetermined in clusters. Nanocluster deposition offers a possibility for the coating of virtually any material with a nanostructured thin film, and therein the enhancement of already existing physical or chemical properties, or the addition of some exciting new feature. A clearer understanding of cluster-surface interactions, and the growth of thin films by cluster deposition, must, however, be achieved, if clusters are to be successfully used in thin film technologies. Using a combination of experimental techniques and molecular dynamics simulations, both the deposition of nanoclusters, and the growth and modification of cluster-assembled thin films, are studied in this thesis. Emphasis is laid on an understanding of the interaction between metal clusters and surfaces, and therein the behaviour of these clusters during deposition and thin film growth. The behaviour of single metal clusters, as they impact on clean metal surfaces, is analysed in detail, from which it is shown that there exists a cluster size and deposition energy dependent limit, below which epitaxial alignment occurs. If larger clusters are deposited at low energies, or cluster-surface interactions are weaker, non-epitaxial deposition will take place, resulting in the formation of nanocrystalline structures. The effect of cluster size and deposition energy on the morphology of cluster-assembled thin films is also determined, from which it is shown that nanocrystalline cluster-assembled films will be porous. Modification of these thin films, with the purpose of enhancing their mechanical properties and durability, without destroying their nanostructure, is presented. Irradiation with heavy ions is introduced as a feasible method for increasing the density, and therein the mechanical stability, of cluster-assembled thin films, without critically destroying their nanocrystalline properties. The results of this thesis demonstrate that nanocluster deposition is a suitable technique for the growth of nanostructured thin films. The interactions between nanoclusters and their supporting surfaces must, however, be carefully considered, if a controlled growth of cluster-assembled thin films, with precisely tailored properties, is to be achieved.

Very Low Birth Weight Infants as Young Adults : Focus on aspects of cognition, behavior and sleep

Major advances in the treatment of preterm infants have occurred during the last three decades. Survival rates have increased, and the first generations of preterm infants born at very low birth weight (VLBW; less than 1500 g) who profited from modern neonatal intensive care are now in young adulthood. The literature shows that VLBW children achieve on average lower scores on cognitive tests, even after exclusion of individuals with obvious neurosensory deficits. Evidence also exists for an increased risk in VLBW children for various neuropsychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and related behavioral symptoms. Up till now, studies extending into adulthood are sparse, and it remains to be seen whether these problems persist into adulthood. The aim of this thesis was to study ADHD-related symptoms and cognitive and executive functioning in young adults born at VLBW. In addition, we aimed to study sleep disturbances, known to adversely affect both cognition and attention. We hypothesized that preterm birth at VLBW interferes with early brain development in a way that alters the neuropsychological phenotype; this may manifest itself as ADHD symptoms and impaired cognitive abilities in young adulthood. In this cohort study from a geographically defined region, we studied 166 VLBW adults and 172 term-born controls born from 1978 through 1985. At ages 18 to 27 years, the study participants took part in a clinic study during which their physical and psychological health was assessed in detail. Three years later, 213 of these individuals participated in a follow-up. The current study is part of a larger research project (The Helsinki Study of Very Low Birth Weight Adults), and the measurements of interest for this particular study include the following: 1) The Adult Problem Questionnaire (APQ), a self-rating scale of ADHD-related symptoms in adults; 2) A computerized cognitive test battery designed for population studies (CogState®) which measures core cognitive abilities such as reaction time, working memory, and visual learning; 3) Sleep assessment by actigraphy, the Basic Nordic Sleep Questionnaire, and the Morningness-Eveningness Questionnaire. Actigraphs are wrist-worn accelerometers that separate sleep from wakefulness by registering body movements. Contrary to expectations, VLBW adults as a group reported no more ADHD-related behavioral symptoms than did controls. Further subdivision of the VLBW group into SGA (small for gestational age) and AGA (appropriate for gestational age) subgroups, however, revealed more symptoms on ADHD subscales pertaining to executive dysfunction and emotional instability among those born SGA. Thus, it seems that intrauterine growth retardation (for which SGA served as a proxy) is a more essential predictor for self-perceived ADHD symptoms in adulthood than is VLBW birth as such. In line with observations from other cohorts, the VLBW adults reported less risk-taking behavior in terms of substance use (alcohol, smoking, and recreational drugs), a finding reassuring for the VLBW individuals and their families. On the cognitive test, VLBW adults free from neurosensory deficits had longer reaction times than did term-born peers on all tasks included in the test battery, and lower accuracy on the learning task, with no discernible effect of SGA status over and above the effect of VLBW. Altogether, on a group level, even high-functioning VLBW adults show subtle deficits in psychomotor processing speed, visual working memory, and learning abilities. The sleep studies provided no evidence for differences in sleep quality or duration between the two groups. The VLBW adults were, however, at more than two-fold higher risk for sleep-disordered breathing (in terms of chronic snoring). Given the link between sleep-disordered breathing and health sequelae, these results suggest that VLBW individuals may benefit from an increased awareness among clinicians of this potential problem area. An unexpected finding from the sleep studies was the suggestion of an advanced sleep phase: The VLBW adults went to bed earlier according to the actigraphy registrations and also reported earlier wake-up times on the questionnaire. In further study of this issue in conjunction with the follow-up three years later, the VLBW group reported higher levels of morningness propensity, further corroborating the preliminary findings of an advanced sleep phase. Although the clinical implications are not entirely clear, the issue may be worth further study, since circadian rhythms are closely related to health and well-being. In sum, we believe that increased understanding of long-term outcomes after VLBW, and identification of areas and subgroups that are particularly vulnerable, will allow earlier recognition of potential problems and ultimately lead to improved prevention strategies.

The effects of stall surfaces and milk yield on the lying behavior of dairy cow

The importance of lying behavior to dairy cows and the feasible definition of lying has attracted many studies on the subject. Cattle show both behavioral and physiological stress responses when subjected to thwarting of their lying behavior. If cows are unable to lie down they later compensate for lost lying time when possible. Environmental factors such as housing and bedding systems have been noted to affect the time spent lying, but there is usually large variation in lying time between individuals. Internal factors such as the reproductive stage, age and health of cows affect their lying time and can cause variation. However, the effect of higher milk production on behavior has not previously been illuminated. The objective of this study was to provide data applicable for the improvement of resting conditions of cows. The preference of stall surface material, differences in normal behavior per unit time and various health measures were observed. The aim was to evaluate lying behavior and cow comfort on different stall bedding materials. In addition, the effect of milk yield on behavior was examined in a tie stall experiment. The preferences for surface materials were investigated in 5 experiments using 3 surface materials with bedding manipulations. According to the results, the cows preferred abundant straw bedding and soft rubber mats. However, they showed an aversion to sand bedding. Some individuals even refused to use stalls with sand when no organic bedding material was present. However, this study was unable to determine the reason for the avoidance, as neither the sand particle size nor thermal properties appeared critical. However, previous exposure to particular surface materials increased the preference for them. The amount of straw bedding was found to be an important factor affecting the preferences for stalls, and the lying time in stalls increased when the flooring softness was improved by applying straw or by installing elastic mats. Despite sand being the least preferred flooring material in preference tests, the health of legs improved during exposure to sand-floored stalls. Moreover cows using sand were cleaner than those that used straw stalls. Thus, sand bedding entailed some health benefits despite the contradictory results of preference tests, which more strongly reflected the perceptions of individual animals. Milk yield was observed to affect behavior by reducing the lying time, possibly due to factors other than longer duration of eating. High yielding cows seemed to intensify their lying bouts, as they were observed to lie with the neck muscles relaxed sooner after lying down than lower yielding cows. In conclusion, cows were found to prefer softer stall surface materials and organic bedding material. In addition, the lying time was reduced by a high milk yield, although the lying time seemed to be important for resting. Cows might differ in the needs for their lying environment. The management of dairy cows should eliminate any unnecessary prevention of lying, as even in tie-stalls high yielding cows seem to be affected by time constraints. Adding fresh bedding material to stalls increases the comfort of any stall flooring material.

Short-term Price Behavior and the Effect of Foreign Investors in Finnish Equity Markets (summary section only)

As globalization and capital free movement has increased, so has interest in the effects of that global money flow, especially during financial crises. The concern has been that large global money flows will affect the pricing of small local markets by causing, in particular, overreaction. The purpose of this thesis is to contribute to the body of work concerning short-term under- and overreaction and the short-term effects of foreign investment flow in the small Finnish equity markets. This thesis also compares foreign execution return to domestic execution return. This study’s results indicate that short-term under- and overreaction occurs in domestic-buy portfolios (domestic net buying) rather than in foreign-buy portfolios. This under- and overreaction, however, is not economically meaningful after controlling for the bid-ask bounce effect. Based on this finding, one can conclude that foreign investors do not have a destabilizing effect in the short-term in the Finnish markets. Foreign activity affects short-term returns. When foreign investors are net buyers (sellers) there are positive (negative) market adjusted returns. Literature related to nationality and institutional effect leads us to expect these kind of results. These foreign flows are persistent at a 5 % to 21 % level and the persistence of foreign buy flow is higher than the foreign sell flow. Foreign daily trading execution is worse than domestic execution. Literature which quantifies foreign investors as liquidity demanders and literature related to front-running leads us to expect poorer foreign execution than domestic execution.

Modification of ventricular repolarization in silent long QT syndrome mutation carriers

Congenital long QT syndrome (LQTS) is a familial disorder characterized by ventricular repolarization that makes carriers vulnerable to malignant ventricular tachycardia and sudden cardiac death. The three main subtypes (LQT1, LQT2 and LQT3) constitute 95% of cases. The disorder is characterized by a prolonged QT interval in electrocardiograms (ECG), but a considerable portion are silent carriers presenting normal (QTc < 440 ms) or borderline (QTc < 470 ms) QT interval. Genetic testing is available only for 60-70% of patients. A number of pharmaceutical compounds also affect ventricular repolarization, causing a clinically similar disorder called acquired long QT syndrome. LQTS carriers - who already have impaired ventricular repolarization - are especially vulnerable. In this thesis, asymptomatic genotyped LQTS mutation carriers with non-diagnostic resting ECG were studied. The body surface potential mapping (BSPM) system was utilized for ECG recording, and signals were analyzed with an automated analysis program. QT interval length, and the end part of the T wave, the Tpe interval, was studied during exercise stress testing and an epinephrine bolus test. In the latter, T wave morphology was also analyzed. The effect of cetirizine was studied in LQTS carriers and also with supra- therapeutic dose in healthy volunteers. At rest, LQTS mutation carriers had a slightly longer heart rate adjusted QTc interval than healthy subjects (427 ± 31 ms and 379 ± 26 ms; p<0.001), but significant overlapping existed. LQT2 mutation carriers had a conspicuously long Tpe-interval (113 ± 24 ms; compared to 79 ± 11 ms in LQT1, 81 ± 17 ms in LQT3 and 78 ± 10 ms in controls; p<0.001). In exercise stress tests, LQT1 mutation carriers exhibit a long QT interval at high heart rates and during recovery, whereas LQT2 mutation carriers have a long Tpe interval at the beginning of exercise and at the end of recovery at low heart rates. LQT3 mutation carriers exhibit prominent shortening of both QT and Tpe intervals during exercise. A small epinephrine bolus revealed disturbed repolarization, especially in LQT2 mutation carriers, who developed prolonged Tpe intervals. A higher epinephrine bolus caused abnormal T waves with a different T wave profile in LQTS mutation carriers compared to healthy controls. These effects were seen in LQT3 as well, a group that may easily escape other provocative tests. In the cetirizine test, the QT and Tpe intervals were not prolonged in LQTS mutation carriers or in healthy controls. Subtype-specific findings in exercise test and epinephrine bolus test help to diagnose silent LQTS mutation carriers and to guide subtype-specific treatments. The Tpe interval, which signifies the repolarization process, seems to be a sensitive marker of disturbed repolarization along with the QT interval, which signifies the end of repolarization. This method may be used in studying compounds that are suspected to affect repolarization. Cetirizine did not adversely alter ventricular repolarization and would not be pro-arrhythmic in common LQT1 and LQT2 subtypes when used at its recommended doses.