Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first reported in 1991, and then behaviorally and biochemically characterized over the next 15–20 years. In this model of schizophrenia characterized by production of D2RSS in ontogeny, there are demonstrated alterations of signaling processes, as well as functional links between the biologic template of the animal model and ability of pharmacotherapeutics to modulate or reverse biologic and behavioral modalities toward normality. Another such animal model, featuring knockout of trace amine-associated receptor 1 (TAAR1), demonstrates D2RSS with an increase in the proportion of D2R in the high-affinity state. Currently, TAAR1 agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of D2RSS with substance use disorder. The aspect of adenosine A2A-D2heteroreceptor complexes in substance use disorder is highlighted, and the association of adenosine A2Areceptor antagonists in discriminative and rewarding effects of psychostimulants is outlined. In summary, these new animal models of schizophrenia have face, construct, and predictive validity, and distinct advantages over earlier models. While the review summarizes elements of D2RSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending D2RSS in schizophrenia and related clinical entities.

In a honey bee colony, the queen uses queen mandibular pheromone (QMP) to induce young worker bees to feed and groom her. Among its many behavioural and physiological effects, QMP reduces dopamine levels in the brains of young worker bees. Dopamine is a biogenic monoamine involved in numerous functions including motor control and aversive learning. This study investigates the effects of QMP on motor activities and aversive learning behaviour and the potential link between QMP and dopamine levels in the brain of young bees. In young bees under the age of 15-days, QMP dramatically reduced locomotor activity and inhibited aversive learning behaviour. Interestingly in older bees these behaviours were not affected by pheromone. Treating young bees with the dopamine precursor, L-dopa (3.25 [mu]g/mI), partially rescued the levels of locomotor activity in QMP-treated bees, and reduced QMP�s effects on aversive learning. This suggests that blocking effects of QMP on both locomotor activity and aversive learning result at least in part from QMP-induced changes in brain dopamine levels. Two components of the QMP blend, 4-hydroxy-3-methoxyphenylethanol (HVA) and methyl p-hydroxybenzoate (HOB) were examined more closely. Both HVA and HOB are structurally similar to dopamine. HVA was found to mimic the effects of the full QMP blend on aversive learning. Treating bees with HVA reduced aversive learning in young bees. In contrast, treatment with HOB did not affect learning ability. This strongly suggests that HVA is one of the key components that mediates the actions of QMP on aversive learning. The final section of this thesis investigates why it might be advantageous to honey bee queens to block aversive learning and reduce locomotor activity in young worker bees. The study reveals age-related differences in behaviours that individual worker bees display towards QMP. Young bees reared with QMP or collected from a queenright hive showed attraction to QMP. Conversely, older bees displayed avoidance behaviour towards QMP. By blocking the establishment of aversive memories, young bees may be prevented from forming an association between QMP and any unpleasant side effects induced by this pheromone. This may confer significant benefit to the queen by increasing the likelihood of young workers remaining in her attendance.

<p>Cellular biophysics deals with, among other things, transport processes within cells. This thesis presents two studies where mathematical models have been used to explain how two of these processes occur.</p><p>Cellular membranes separate cells from their exterior environment and also divide a cell into several subcellular regions. Since the 1970s lateral diffusion in these membranes has been studied, one the most important experimental techniques in these studies is <i>fluorescence recovery after</i> <i>photobleach</i> (FRAP). A mathematical model developed in this thesis describes how dopamine 1 receptors (D1R) diffuse in a neuronal dendritic membrane. Analytical and numerical methods have been used to solve the partial differential equations that are expressed in the model. The choice of method depends mostly on the complexity of the geometry in the model.</p><p>Calcium ions (Ca²⁺) are known to be involved in several intracellular signaling mechanisms. One interesting concept within this field is a signaling microdomain where the inositol 1,4,5-triphosphate receptor (IP₃R) in the endoplasmic reticulum (ER) membrane physically interacts with plasma membrane proteins. This microdomain has been shown to cause the intracellular Ca²⁺ level to oscillate. The second model in this thesis describes a signaling network involving both ER membrane bound and plasma membrane Ca²⁺ channels and pumps, among them store-operated Ca²⁺ (SOC) channels. A MATLAB^® toolbox was developed to implement the signaling networks and simulate its properties. This model was also implemented using<i> Virtual cell.</i></p><p>The results show a high resemblance between the mathematical model and FRAP data in the D1R study. The model shows a distinct difference in recovery characteristics of simulated FRAP experiments on whole dendrites and dendritic spines, due to differences in geometry. The model can also explain trapping of D1R in dendritic spines.</p><p>The results of the Ca²⁺ signaling model show that stimulation of IP3R can cause Ca²⁺ oscillations in the same frequency range as has been seen in experiments. The removing of SOC channels from the model can alter the characteristics as well as qualitative appearance of Ca²⁺ oscillations.</p> / <p>Cellulär biofysik behandlar bland annat transportprocesser i celler. I denna avhandling presenteras två studier där matematiska modeller har använts för att förklara hur två av dess processer uppkommer.</p><p>Cellmembran separerar celler från deras yttre miljö och delar även upp en cell i flera subcellulära regioner. Sedan 1970-talet har lateral diffusion i dessa membran studerats, en av de viktigaste experimentella metoderna i dessa studier är fluorescence recovery after photobleach (FRAP). En matematisk modell utvecklad i denna avhandling beskriver hur dopamin 1-receptorer (D1R) diffunderar i en neural dendrits membran. Analytiska och numeriska metoder har använts för att lösa de partiella differentialekvationer som uttrycks i modellen. Valet av metod beror främst på komplexiteten hos geometrin i modellen.</p><p>Kalciumjoner (Ca2+) är kända för att ingå i flera intracellulära signalmekanismer. Ett intressant koncept inom detta fält är en signalerande mikrodomän där inositol 1,4,5-trifosfatreceptorn (IP3R) i endoplasmatiska nätverksmembranet (ER-membranet) fysiskt interagerar med proteiner i plasmamembranet. Denna mikrodomän har visats vara orsak till oscillationer i den intracellulära Ca2+-nivån. Den andra modellen i denna avhandling beskriver ett signalerande nätverk där både Ca2+-kanaler och pumpar bundna i ER-membranet och i plasmamembranet, däribland store-operated Ca2+(SOC)-kanaler, ingår. Ett MATLAB®-verktyg utvecklades för att implementera signalnätverket och simulera dess egenskaper. Denna modell implementerades även i Virtual cell.</p><p>Resultaten visar en stark likhet mellan den matematiska modellen och FRAP-datat i D1R-studien. Modellen visar en distinkt skillnad i återhämtningsegenskaper hos simulerade FRAP-experiment på hela dendriter och dendritiska spines, beroende på skillnader i geometri. Modellen kan även förklara infångning av D1R i dendritiska spines.</p><p>Resultaten från Ca2+-signaleringmodellen visar att stimulering av IP3R kan orsaka Ca2+-oscillationer inom samma frekvensområde som tidigare setts i experiment. Att ta bort SOC-kanaler från modellen kan ändra karaktär hos, såväl som den kvalitativa uppkomsten av Ca2+-oscillationer.</p>

Prior work has shown important effects of the early life environment on development of adult stress response systems in both rats and humans. The present thesis is based on experiments that attempt to explore: 1) adolescent stress responding at hormonal and behavioural levels, and 2) the effects of repeated adolescent stressor exposure on adult stress responding (hormonal and behavioural) and levels of dopamine receptors expressed in prefrontal cortex, using both male and female rats. Defensive behaviours exhibited during stressor exposure and post-stress levels of circulating corticosterone were quantified as behavioural and hormonal measures of stress responding, respectively. In the first study, responses were compared among groups of adolescent rats exposed repeatedly to one of two different types of cat odour stressor stimuli (J-cloth coated in hair/dander or cat collar previously worn by a cat) or control stimuli, and long-term outcomes were examined in adulthood. Adolescent rats showed behavioural responses to both stressor stimuli, but behavioural inhibition was more consistent using repeated cat collar exposure, and this treatment resulted in long-term increases in anxiety-like behaviour in adulthood, whereas a stress-induced adolescent corticosterone elevation was observed only in the group that received exposure to the J-cloth stimuli. In the second study, adolescent and adult rats were compared directly using repeated exposure to the cat collar stressor or control stimuli. Adolescents were found to be more sensitive to the effects of the stressor stimuli, relative to adults. Finally, in the third study, repeated exposure to the J-cloth stressor or control stimuli was used, and stressor-exposed females showed elevated baseline corticosterone levels prior to the final exposure. Furthermore, stressor-exposed males and females showed lower levels of the D2 dopamine receptor in infralimbic and dorsopeduncular cortices of the prefrontal cortex in adulthood. In addition, these studies together provide evidence that sex differences in corticosterone levels emerge during the adolescent period. It may be concluded that adolescence should be considered a sensitive developmental timeframe for stress response programming.

In a honey bee colony, the queen uses queen mandibular pheromone (QMP) to induce young worker bees to feed and groom her. Among its many behavioural and physiological effects, QMP reduces dopamine levels in the brains of young worker bees. Dopamine is a biogenic monoamine involved in numerous functions including motor control and aversive learning. This study investigates the effects of QMP on motor activities and aversive learning behaviour and the potential link between QMP and dopamine levels in the brain of young bees. In young bees under the age of 15-days, QMP dramatically reduced locomotor activity and inhibited aversive learning behaviour. Interestingly in older bees these behaviours were not affected by pheromone. Treating young bees with the dopamine precursor, L-dopa (3.25 [mu]g/mI), partially rescued the levels of locomotor activity in QMP-treated bees, and reduced QMP�s effects on aversive learning. This suggests that blocking effects of QMP on both locomotor activity and aversive learning result at least in part from QMP-induced changes in brain dopamine levels. Two components of the QMP blend, 4-hydroxy-3-methoxyphenylethanol (HVA) and methyl p-hydroxybenzoate (HOB) were examined more closely. Both HVA and HOB are structurally similar to dopamine. HVA was found to mimic the effects of the full QMP blend on aversive learning. Treating bees with HVA reduced aversive learning in young bees. In contrast, treatment with HOB did not affect learning ability. This strongly suggests that HVA is one of the key components that mediates the actions of QMP on aversive learning. The final section of this thesis investigates why it might be advantageous to honey bee queens to block aversive learning and reduce locomotor activity in young worker bees. The study reveals age-related differences in behaviours that individual worker bees display towards QMP. Young bees reared with QMP or collected from a queenright hive showed attraction to QMP. Conversely, older bees displayed avoidance behaviour towards QMP. By blocking the establishment of aversive memories, young bees may be prevented from forming an association between QMP and any unpleasant side effects induced by this pheromone. This may confer significant benefit to the queen by increasing the likelihood of young workers remaining in her attendance.

[Truncated abstract] The mammalian cochlea receives an efferent innervation which originates in the superior olive. Known collectively as the olivocochlear system, this efferent innervation can be divided into lateral and medial systems. While the function of the lateral efferent system in the cochlea is still unknown, previous studies have identified both excitatory and inhibitory changes in sound-evoked and spontaneous cochlear responses attributable to the lateral efferent system. One of the neurotransmitters in the lateral efferents is the catecholamine dopamine, which in the central nervous system is known to exert inhibitory and excitatory effects by activating different receptor subtypes. The first experiments in this thesis were designed to determine if activation or blockade of different dopamine receptor subtypes in the cochlea could lead to both excitatory and inhibitory changes in sound-evoked and spontaneous cochlear responses. Adult guinea pigs were anaesthetised (Nembutal and Hypnorm) and highly specific D1/5 (SKF 38393, SKF 81297, SCH 23390), D2 ((+) PHNO, L 741, 626) and D3 (PD 128907, U 99194A) receptor agonists and antagonists were perfused through the cochlea for 15 minutes. Sound-evoked (compound action potential, summating potential, cochlear microphonic) and spontaneous cochlear responses were recorded before and after perfusion. Remarkably, activating or blocking D1/5 or D2 receptor subtypes resulted in the suppression of CAP amplitudes. These findings are paradoxical as the agonist data suggest that the D1/5 and D2 receptor subtypes are inhibitory, but the antagonist perfusions suggest that these receptors are excitatory. We propose that the presence of an agonist induces a process of receptor desensitisation which would elicit changes akin to receptor antagonism. If this is indeed the case then our agonist findings are spurious and require further interpretation. ... The suppression of the cochlear microphonic suggests that dopamine receptor influence is not confined to the primary afferent dendrite may also include the active process of the outer hair cells. The D1/5 and D2 antagonist data also suggests that dopamine receptors are activated by intrinsic dopamine. Therefore, we attempted to investigate the effects of putative dopamine depletion of the cochlea and found that application of the dopaminergic neurotoxin MPTP causes changes in both neural and hair cell responses which have not been reported before. However, we also demonstrated that tyrosine hydroxylase positive nerve fibres are still present in MPTP treated cochleae which suggests that dopamine is still present in these cochleae. Furthermore, we observed significant electrophysiological changes in these same cochleae when these were exposed to a D2 receptor antagonist which again supports the presence of intrinsic dopamine in these 'depleted cochleae'. These data suggest that the currently accepted method of acute dopamine depletion using MPTP is insufficient and different methods must be developed in the future.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 138-142).

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 56-68).

The effects of dopamine D1 and D2 antagonists on conditioned place preference (CPP) and locomotor activity were assessed. A total of three experiments were conducted. In each experiment there were two conditioning days followed by a test day. The results indicate that DA D1 and D2 receptors have distictly different roles in the mediation of behavior.