Thesis (M. Sc.)--Carleton University, 2003. / Includes bibliographical references (p. 50-81). Also available in electronic format on the Internet.

El enamoramiento implica procesos bioquímicos en los que sustancias como neurotransmisores, neuromoduladores y hormonas  interaccionan con células nerviosas u otros órganos. Al estar enamorados, los niveles de dopamina aumentan generando atención, deseo y motivación en todo lo relacionado al ser amado. La serotonina, por el contrario, se presenta en concentraciones bajas en este estado. La oxitocina, por su parte, entra en juego cuando la demanda de dopamina no se logra suplir y es crucial al entablar relaciones de largo plazo. El entendimiento del mecanismo de la oxitocina en el ser humano es crucial no solo para el conocimiento académico sino también porque brinda luces para el tratamiento de algunos desórdenes psicológicos. / Romantic love involves biochemical processes in which substances such as neurotransmitters, neuromodulators and hormones interact with other nerve cells or organs. When being in love, dopamine levels increases, generating attention, desire and motivation in everything related to the beloved person. Serotonin, however, is present in low levels in this state. When the body does not supply the necessary amount of dopamine, oxytocin is released. Oxytocin is vital in long term relationships. Understanding the mechanism of oxytocin in humans is crucial not only for academic knowledge of the chemistry of love but also because it provides new lights for the treatment of some psychological disorders.

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Excitatory glutamatergic inputs from limbic regions such as the hippocampus and the basolateral amygdala (BLA), and dopaminergic inputs from the ventral tegmental area converge in the nucleus accumbens (NAc). It has been proposed that interactions between these glutamatergic and dopaminergic pathways play an important role in adaptive behaviors. The present thesis employed a multidisciplinary approach to study these interactions, with a specific emphasis on the importance of mesoaccumbens dopamine (DA) transmission, in order to obtain a better understanding of the neural mechanisms by which the NAc transforms signals from the temporal lobes into behavior. The experiments of Chapter 2 utilized extracellular single-unit recordings of individual NAc neurons in combination with electrochemical measures of DA efflux in the NAc. Recordings from NAc neurons which received input from the hippocampus but not the BLA revealed that increased efflux of mesoaccumbens DA, evoked by tetanic stimulation of the fimbria, potentiated hippocampal-evoked neural activity in these cells. These effects were mediated by both DA and NMDA receptors. Similar recordings from neurons which received converging input from both the hippocampus and the BLA revealed tetanic stimulation of the fimbria again potentiated hippocampal evoked spiking activity, while concurrently suppressing BLA-evoked spiking activity in the same neurons. The suppression of BLA-evoked spiking activity was activity-dependent, and was mediated by both D, and adenosine A, receptors. Chapter 3 showed that random foraging on a radial-arm maze, which is dependent on a neural circuit linking the hippocampus to the NAc, was correlated with an increase in mesoaccumbens DA extracellular levels, as measured with microdialysis. In Chapter 4, pharmacological blockade of DA or NMDA receptors in the NAc, or selective disruption of dopaminergic modulation of ventral subicular inputs to the NAc (using an asymmetrical infusion procedure) significantly disrupted random foraging. These effects were mediated by the Dl receptor. In Chapter 5, the present data are integrated with previous research to formulate a model of ventral striatal function. It is proposed that the NAc mediates behavior through distinct patterns of activity and inactivity driven by excitatory limbic input projecting to different groups of neural ensembles. Mesoaccumbens DA transmission plays an essential role in regulating the synchrony ensemble activity, augmenting activity in one ensemble while suppressing activity in another. It is argued that the modulatory effects of DA appears to be essential when an organism must switch from one form of adaptive behavior to another in response to a constantly changing environment. / Arts, Faculty of / Psychology, Department of / Graduate

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<p>Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.</p>

Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.

Thesis (MSc)--Stellenbosch University, 2005. / ENGLISH ABSTRACT: This study (2 x 2 factor design) describes an investigation into the physiological interaction between the peripheral endocrine and cytokine systems after the organism has been exposed to psychological stress. An in vivo rodent model with two interventions was used: (1) mild psychological stress (immobilisation for 2 hours per day, for 4 days); (2) an antiinterleukin (IL)-6-antibody injection. Thirty-nine male Wi star rats were divided into 4 groups and given either the antibody (CA, control antibody) or stress (IP, immobilisation placebo), or both (IA, immobilisation antibody), or neither (CP, control placebo). Antibody and placebo (saline) were injected intraperitoneally. Differences between groups for the following parameters were determined in blood or metabolic tissues, viz. skeletal muscle and liver: 1) corticosterone concentrations, 2) glucocorticoid receptor (GR) binding capacity and 3) activities of metabolic enzymes, tyrosine aminotransferase (TAT) and glutamine synthetase (GS). Groups lP and lA showed a significant loss in body mass (CP vs. lP, p<O.01; CA vs. lA, p<O.001), indicating a main effect of stress. The corticosterone concentrations of only group lP were significantly elevated compared to that of group CP (CP vs. lP, p<O.01), again indicating a main effect of stress. All three intervention groups (CA, lP, lA) had decreased GR binding capacity, with group lA showing a statistically greater decrease (CP vs. CA, p<O.05; IP vs. IA, p<O.01; CP vs. IP, p<O.001; CA vs. IA, p<O.001), indicating main effects of stress and antibody treatment. In groups IP and IA increased activities of both enzymes (TAT and GS) were measured (main effect of stress), with IA again showing the greatest statistically significant increase for both enzymes. The liver tissue displayed greater sensitivity to the stress and antibody regimes. This study provides the first conclusive in vivo evidence for IL-6 modulation of glucocorticoid action in peripheral tissues in response to mild psychological stress. / AFRIKAANSE OPSOMMING: Hierdie studie (met 'n 2 X 2 faktorontwerp) beskryf 'n ondersoek oor die fisiologiese interaksie tussen die perifere endokrien- en sitokiensisteme in organismes blootgestel aan psigologiese stres. Daar word gebruik gemaak van 'n in vivo-rotmodel met twee intervensies: (1) matige psigologiese stres (immobilisering vir 2 uur per dag vir 4 dae); (2) 'n anti-interleukin (IL)-6-antiliggaam inspuiting. Nege-en-dertig manlike Wistar rotte is in vier groepe verdeel en het óf antiliggaam (CA, antiliggaam kontrole), óf stres (IP, immobilisasie placebo), óf beide stres en antiliggaam (lA, immobilisasie antiliggaam) of geen behandeling ontvang (CP, placebo kontrole). Die antiliggaam- en placebo (soutoplossing)- inspuitings is intraperitoneaal toegedien. Verskille tussen die groepe van die volgende parameters, in metaboliese weefsels (skeletspier en lewer), was bepaal: 1) kortikosteroon konsentrasies, 2) glukokortikoïed reseptor (GR) bindingskapasiteit en 3) aktiwiteite van die metaboliese ensieme, tirosien aminotransferase (TAT) en glutamien sintetase (GS). Groepe IP en IA het 'n beduidende afname in gewig getoon (CP vs. IP, p<O.01;CA vs. IA, p<O.001), wat 'n hoof-effek van stres aandui. Die kortikosteroon konsentrasies van slegs IP het beduidend toegeneem in vergelyking met CP (CP vs. IP, p<O.01),wat weereens 'n hoof-effek van stres aandui. AI drie intervensiegroepe (CA, IP, IA) het verlaagte GR bindingskapasiteit getoon, met lA wat 'n groot statistiese afname getoon het (CP vs. CA, p<O.05; IP vs. IA, p<O.01;CP vs. IP, p<O.001;CA vs. IA, p<O.001),wat hoof-effekte van beide stres en antiliggaam-behandeling aandui. In groepe IP and IA is toenames in beide ensiemaktiwiteitvlakke (TAT en GS ensieme) getoon (hoof-effek van stres), met IA wat weereens die grootste toename gewys het. Die lewer het ook verhoogde sensitiwiteit tot die stres- en antiliggaamregimente. Hierdie studie lewer die eerste daadwerklike in vivo bewyse vir IL-6 modulering van glukokortikoïedaksie in perifere weefsels na reaksie op psigologiese stres.

Nicotine is a major psychoactive ingredient in tobacco that is thought to promote smoking behavior via nicotinic acetylcholine receptors (nAChRs) in the brain. Given reports that people smoke to relieve anxiety and that anxiety precipitates relapse, the overarching goal of this dissertation research is to assess beta 2 subunit containing nAChR (beta2*nAChR) contributions to anxiety-like behavior. Nicotine’s activity at beta2*nAChRs is concentration-dependent, with high concentrations facilitating activation followed by rapid desensitization and low concentrations preferentially desensitizing beta2*nAChRs; hence, activation or inhibition of beta2*nAChRs may support smoking behavior. Rodent studies reveal that nicotine affects anxiety-like behavior dose-dependently: low doses promote anxiolysis- and high doses support anxiogenic-like behavior. These pharmacological and genetic studies in mice test the hypothesis that nicotine administration promotes anxiolysis via inactivation of beta2*nAChRs and begin to identify which subunits, namely alpha 4 and alpha 6, work in concert with beta 2 to affect anxiety-like behavior. Low dose nicotine and inhibition of beta2*nAChRs supported anxiolysis-like behavior in a number of tasks with predictive validity for anxiolysis efficacy. These studies further suggest that activation of alpha6beta2*nAChRs is sufficient to produce anxiogenic-like behavior and that inhibition of alpha4beta2*nAChRs supports anxiolysis-like behavior. A secondary goal of these studies is to assess if beta2*nAChRs affect anxiety-like behavior during aging. Dysregulation of cholinergic tone can increase anxiety in the elderly, but little is known regarding beta2*nAChR contributions to anxiety in this population or where in the brain this may take place. These studies show that alpha4beta2*nAChR expression differentially affects anxiety-like behavior in adult and aged mice. With a focus on the lateral septum, a GABA-ergic limbic nucleus thought to regulate anxiety-like responses to external stimuli, a third goal of these studies is to elucidate the neuroanatomical and intracellular underpinnings of anxiety-like behavior that are affected by beta2*nAChR inhibition and expression. Previous studies demonstrate that exposure to stressors reduces phosphorylation of extracellular regulated kinase (ERK) in the lateral septum. In these studies, levels of pERK in the lateral septum were inversely associated with alpha4beta2*nAChR expression as well as anxiogenic-like behavior. In sum, these preclinical studies suggest that inhibition alpha4beta2*nAChRs may support cessation in those who smoke to relieve anxiety.

Major depressive disorder (MDD) is rapidly growing among the population. A widely believed neurobiological explanation is that the symptoms arise due to an imbalance of the neurotransmitter serotonin. Therefore, the most provided antidepressant is currently selective serotonin reuptake inhibitors (SSRI), which increase the serotonin in the synaptic cleft by inhibit the reuptake of serotonin. There are medications which challenge the serotonin hypothesis such as tianeptine. Tianeptine increases the reuptake of serotonin in the synaptic cleft and thus decreasing the serotonin levels. The thesis has three aims: First, to investigate what mechanisms tianeptine and SSRI work upon. Second, compare the efficiency of SSRI and tianeptine. Third, if the two agents display any differences in adverse side effects. A systematic review and search through relevant databases were made to obtain results. The main findings of this thesis were the two agents act differently of many aspects of the brain mechanisms and neurochemistry such as the cannabinoid system, expression of different cell types and their dependence of protein kinase. Even so, the results show that both agents are equally efficient in treating the depressive symptoms in the larger context, although some interesting findings are seen when zooming in. Anxiety is often comorbid with depression and even though both tianeptine and SSRI are shown to reduce these symptoms during chronic administration, SSRI can produce an anxiogenic effect in the beginning. Another noteworthy finding was that tianeptine showed to be clinically significant, but so did placebo. The third aim investigated the differences in side-effects between these two agents, and both agents were equally safe in number of adverse side-effects. Though tianeptine showed to have some slight advantages in manners of sexual dysfunction and the item 3 on the CGI scale.