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<p>Allosteric modulators are emerging as a new class of therapeutics for the treatment of complex disorders, including psychiatric illnesses such as schizophrenia. The disease is marked by hyperdopaminergic signaling in the striatum, which plays a role in the development of positive symptoms like delusions, hallucinations, and paranoia. Conventional antipsychotic drug therapy typically employs dopamine D2 receptor antagonists that compete with endogenous dopamine at the orthosteric, or dopamine-binding site, in an attempt to normalize these psychotic symptoms. However, they are often associated with adverse motor and metabolic side effects. Furthermore, only some antipsychotic drugs are able to treat the negative symptoms of schizophrenia, which include social withdrawal and anhedonia, and there is currently no treatment for the cognitive impairment associated with the disease.</p> <p>Allosteric modulators are safer alternatives to conventional orthosteric therapeutics as they interact with their receptor at a novel binding site and their mechanism involves modulation of endogenous signaling. Therefore, levels of endogenous ligand limit the activity of an allosteric modulator. Our lab has synthesized and evaluated over 185 compounds for their activity at the dopamine D2 receptor. Of these compounds, PAOPA is the most potent allosteric modulator, and has been shown to be effective in treating the MK-801 induced preclinical animal model of schizophrenia without causing the adverse effects induced by currently prescribed antipsychotic drugs. The objective of this study was to evaluate PAOPA’s ability to treat behavioural abnormalities in an amphetamine-sensitized model of schizophrenia.</p> <p>Four groups (n=10/group) of male Sprague Dawley rats received intraperitoneal injections three days per week on alternate days over three weeks. Group A received saline, group B received D-amphetamine (1mg/kg during week one, 2mg/kg during week two, 3mg/kg during week three), group C received PAOPA (1mg/kg), and group D received the same doses of amphetamine as group B with PAOPA (1mg/kg). Following a three-week withdrawal, each group was tested for prepulse inhibition, social interaction, and locomotor activity. Amphetamine-sensitized rats were subjected to the same tests following PAOPA administration (1mg/kg). To assess whether behavioural changes were associated with changes in brain chemistry, post-mortem dopamine levels were measured in the striatum, nucleus accumbens, and medial prefrontal cortex. Data were analyzed by one-way ANOVA or paired t test where appropriate.</p> <p>Amphetamine sensitization induced schizophrenic-like behavioural abnormalities, including deficits in prepulse inhibition and social interaction, as well as increased locomotor activity and sensitivity to amphetamine challenge. Concurrent amphetamine and PAOPA treatment prevented all amphetamine- induced behavioural abnormalities. Furthermore, amphetamine-induced deficits in prepulse inhibition and social interaction were reversed one hour following PAOPA treatment. PAOPA treatment alone had no effect on behaviour or post-mortem striatal dopamine. Behavioural changes in amphetamine-sensitized rats were accompanied by a reduction in post-mortem striatal dopamine levels. In correlation with behavioural results, PAOPA administration during amphetamine sensitization prevented this biochemical change.</p> <p>These results demonstrate that PAOPA can prevent and reverse behavioural and associated biochemical abnormalities in amphetamine-sensitized rats. PAOPA is a candidate for the development of treatments for schizophrenia.</p> / Master of Science (MSc)

This study was conducted in order to gain a better understanding of the phenomenon of drug trafficking with specific reference as to how South African drug mules are used in crossborder drug smuggling. Through media analysis, semi-structured interviews with drug trafficking experts and a literature study the researcher was able to make findings and recommendations as per the objectives of the study. The objectives of the study included examining how drug mules smuggle drugs across South African borders; what role drug mules play in drug trafficking syndicates and the motivations and reasons why South Africans are increasingly being recruited as drug mules. The researcher also attempted to determine the nature and extent of the drug demand supply in and to South Africa. By making the deduction that drug demand and drug supply are interrelated the researcher was ultimately able to conclude that drug mules will continue to engage in drug smuggling as long as there is a demand for drugs and readily available drug supply routes to and from a county. From the media reports analysed cocaine, methamphetamine and heroin were the drugs most smuggled by South African drug mules. It is also clear from the media reports that cocaine and methamphetamine are smuggled in the largest quantities by South African drug mules. The quantities of heroin found in the possession of South African drug mules were insignificantly small. This contradicts treatment centre data analysed that indicated heroin and methamphetamine users were almost double in numbers in comparison to cocaine users being treated at centres. Most South African drug mules are used to smuggle drugs to the cocaine markets in Europe and South Africa; the cannabis/marijuana (herb) market in Europe; the cannabis (resin) hashish market in Canada and the United States of America; the crystal methamphetamine market in the Far East (largely Japan and Korea) and the heroin market in South Africa. Using criminology theories as a basis, the researcher attempted to describe why people are vulnerable to being recruited as drug mules. Findings concluded that structural factors such as poverty and unemployment and substance abuse-related problems, particularly in marginalised and disadvantaged communities, all contribute to South Africans becoming drug mules. Recommendations by the researcher focused on identifying specific vulnerabilities associated with drug mule recruiting and its consideration in legislation relating to drug trafficking in South Africa. The recommendations focus on the specific prosecution of drug abusers, drug mules, drug distributors and drug mule recruiters. Lastly it is projected by the researcher that the drug demand in South Africa will continue to increase if the drug supply routes and drug smuggling operations by syndicates are not addressed more firmly / Criminology / M.A. (Criminology)

本研究藉由測量制約場地偏好行為及制約活動量兩種制約反應，透過制約期及後測期對藥物配對刺激之操弄，探討制約刺激與酬賞性藥物配對之歷程及其相關之神經機制。本文所使用的為低劑量(1.5 mg/kg)之安非他命，採腹腔注射方式給藥。實驗一探討後測日呈現不同的藥物配對刺激組合對兩種制約反應之影響效果，實驗結果發現受試只對與藥物配對過的兩個以上元素刺激同時出現才能引發受試表現制約場地偏好，且受試對複合刺激的活動量皆顯著高於對單一元素刺激的活動量。實驗二在制約期分別將視覺刺激與觸覺刺激與藥物配對，後測期於藥物配對箱單獨呈現視覺刺激或兩者所組成的複合刺激，測量受試兩種制約反應。實驗結果發現視覺刺激與複合刺激皆能引發制約場地偏好，受試對複合刺激的活動量亦高於對視覺刺激的活動量。實驗三則是於制約前分別破壞受試之杏仁核、背側海馬或腹側海馬，並進行實驗二之制約實驗程序。結果發現破壞杏仁核顯著的減抑單一元素刺激所引發之制約場地偏好，但不影響複合刺激引發之制約場地偏好。破壞背側海馬及腹側海馬減抑複合刺激引發之制約場地偏好。但在制約活動量表現方面，這三個腦組織均未獲得較一致性的結果。總而言之，本研究得到制約刺激之連結強度確實可以透過制約場地偏好及制約活動量反映出差異，且結果支持Rescorla-Wagner元素理論對制約刺激與非制約刺激配對歷程之假設。由破壞杏仁核及海馬對受試表現制約場地偏好造成不等程度之影響，可見杏仁核與海馬所參與以藥物配對的制約之行為功能不同。 關鍵字：心理藥物學，安非他命，制約場地偏好，制約活動，元素理論，整體理論，大白鼠 / By measuring of conditioned place preference (CPP) and conditioned locomotion, the present study manipulated various patterns of environment by composing three different contextual stimuli in the test chamber during different stages of conditioning to investigate behavioral processing and neural mechanisms underlying the association of conditioned stimulus and psychoactive drug. A relatively low dose of amphetamine (1.5 mg/kg) administered via intraperitoneal route was conducted as drug treatment throughout the study. In Experiment 1, the effects of CPP and conditioned locomotion were evaluated as different patterns of contextual stimuli composed in the test chamber presented during post-conditioning stage. The results showed CPP was significantly induced in the environment with context stimuli composed by at least two elements. And, the magnitude of conditioned locomotion induced by compound stimulus was higher than that induced by a single elemental stimulus. In Experiment 2, the effects of CPP and conditioned locomotion induced by a two-element compound stimulus were evaluated in the subjects received the drug pairing with both of each element stimulus in separate during the conditioning stage. The CPP was reliable induced by that compound stimulus. Although such CPP effect could also induced by an elemental stimulus specifically regarding to visual modality, it was not true for the other elemental stimulus manipulated on tactual modality. In Experiment 3, behavioral effects tested on the procedures of Experiment 2 were re-evaluated in the subjects received neurotoxic lesions in the amygdala, the dorsal hippocampus, or the ventral hippocampus before conditioning. While amygdaloid lesion significantly attenuated the CPP induced by elemental stimulus, such lesion did not inhibit the CPP induced by the compound stimulus. Lesions on those two hippocampal subareas disrupted the formation of CPP induced by compound stimulus. Regarding the conditioned locomotion, in contrast to what found on CPP, lesion treatment did not produce reliable effect induced by compound stimulus or elemental stimulus. In conclusion, the present findings on two conditioned responses measured support the assumption of Rescorla-Wagner Model on elemental theory. The lesion data indicate that amygdala and hippocampus are differentially involved in conditioned responses induced by psychoactive drug. Key words: psychopharmacology, amphetamine, conditioned place preference, conditioned locomotion, elemental theory, configural theory, rat.

This study was conducted in order to gain a better understanding of the phenomenon of drug trafficking with specific reference as to how South African drug mules are used in crossborder drug smuggling. Through media analysis, semi-structured interviews with drug trafficking experts and a literature study the researcher was able to make findings and recommendations as per the objectives of the study. The objectives of the study included examining how drug mules smuggle drugs across South African borders; what role drug mules play in drug trafficking syndicates and the motivations and reasons why South Africans are increasingly being recruited as drug mules. The researcher also attempted to determine the nature and extent of the drug demand supply in and to South Africa. By making the deduction that drug demand and drug supply are interrelated the researcher was ultimately able to conclude that drug mules will continue to engage in drug smuggling as long as there is a demand for drugs and readily available drug supply routes to and from a county. From the media reports analysed cocaine, methamphetamine and heroin were the drugs most smuggled by South African drug mules. It is also clear from the media reports that cocaine and methamphetamine are smuggled in the largest quantities by South African drug mules. The quantities of heroin found in the possession of South African drug mules were insignificantly small. This contradicts treatment centre data analysed that indicated heroin and methamphetamine users were almost double in numbers in comparison to cocaine users being treated at centres. Most South African drug mules are used to smuggle drugs to the cocaine markets in Europe and South Africa; the cannabis/marijuana (herb) market in Europe; the cannabis (resin) hashish market in Canada and the United States of America; the crystal methamphetamine market in the Far East (largely Japan and Korea) and the heroin market in South Africa. Using criminology theories as a basis, the researcher attempted to describe why people are vulnerable to being recruited as drug mules. Findings concluded that structural factors such as poverty and unemployment and substance abuse-related problems, particularly in marginalised and disadvantaged communities, all contribute to South Africans becoming drug mules. Recommendations by the researcher focused on identifying specific vulnerabilities associated with drug mule recruiting and its consideration in legislation relating to drug trafficking in South Africa. The recommendations focus on the specific prosecution of drug abusers, drug mules, drug distributors and drug mule recruiters. Lastly it is projected by the researcher that the drug demand in South Africa will continue to increase if the drug supply routes and drug smuggling operations by syndicates are not addressed more firmly / Criminology and Security Science / M. A. (Criminology)

本研究以心理興奮性藥物(psychosimulants)引發之行為致敏化作為探討環境與藥物的配對學習如何影響個體長期使用藥物後對藥物的反應。首先於實驗一建立安非他命引發自發活動致敏化基本模式，以及不同的重複注射情境下致敏化的表現，結果顯示經由本實驗操弄注射情境的程序可有效引發在測試箱、飼養籠，和第三處的安非他命致敏化表現，並且致敏化自發活動表現量在測試箱組顯著高於飼養籠組和第三處組。實驗二對致敏化形成歷程中可能與安非他命配對的刺激進行消除，以釐清致敏化形成歷程中連結學習的要素，結果顯示消除程序沒有降低致敏化活動量的效果。實驗三使用中樞注射麩胺酸受體拮抗劑NBQX於依核以影響致敏化的連結學習歷程，結果顯示該操弄可阻斷在飼養籠重複注射安非他命引發的行為致敏化。測試箱組經過該操弄後其致敏化活動量顯著降低但仍有顯著的致敏化活動量表現。實驗四分別破壞前額葉皮質兩處次級區塊以瞭解其在致敏化連結學習歷程中扮演的角色，結果顯示破壞背側前額葉皮質只阻斷在飼養籠注射安非他命所引起的行為致敏化，破壞腹側前額葉皮質只阻斷測試箱組行為致敏化。綜合上述研究結果顯示安非他命引發致敏化的形成深受藥物配對的環境影響而可區分環境相依與環境獨立之行為致敏化，環境相依行為致敏化的行為機制可由場合建立的觀點加以解釋。在依核內之麩胺酸傳導和前額葉皮質次級區塊之功能在兩種行為致敏化上的差異可以反應環境相依和環境獨立行為致敏化的潛在神經機制可能有所不同。 / The present study investigated the neurobehavioral mechanisms of d-amphetamine (AMP) induced behavioral sensitization, with the aim to elucidate the role of associative learning between the context and drug. Experiment 1 compared the sensitization effects of repeated (AMP) conducted in three different contexts by the measurement of locomotion activity. The results showed that behavioral sensitization of locomotion was significantly induced AMP repeatedly injected in each of the contexts. However, the magnitudes of behavioral sensitization were different among those three conditions. The highest degree of sensitized locomotion was observed in the group with repeated AMP conducted in the test box in comparing to the other two groups with drug administration in the home cage and a third place, Experiment 2 was designed to examine the effects of extinction on the injection procedure and the contextual cue on the behavioral sensitization of AMP induced in the test box, the home cage, and a third place. The resu lts clearly indicate all three types of locomotion sensitization were resistant to the manipulation of extinction. Experiment 3 tested the effects of NBQX, a glutamatergic AMPA receptor antagonist, infused into the nucleus accumbens on the establishment of behavioral sensitization of AMP induced in the test box and the home cage. This intra-accumbens NBQX treatment significantly suppressed the formation of behavioral sensitization of AMP induced in the home cage, but not in the test box. Experiment 4 investigated the lesion effects of medial prefrontal cortex (mPFC) on the establishment of behavioral sensitization of AMP induced in the test box and the home cage. Two subareas of the mPFC, dorsal and ventral parts, were lesioned by ibotenic acid. The findings indicated a double dissociation existing in the mPFC subareas for the behavioral sensitization of AMP induced in different contexts. The lesion of ventral mPFC inhibited the formation of behavioral sensitization of AMP induced in the test box, whereas the lesion of dorsal mPFC attenuated the AMP sensitization induced at the home cage. Together, these data suggest that the association of the repeated drug effects pairing to the context is critical for the development of behavioral sensitization. Such sensitization can further be differentiated into the context-depentdent and context-independent forms based on the uniqueness of contextual cue in the environment where drug is administered. Different neural substrates are involved in the establishment of behavioral sensitization of AMP.

There has been an awareness of nerve poisons from ancient times. At the dawn of the twentieth century, the actions and mechanisms of these poisons were uncovered by modern physiological and biochemical experimentation. However, the era of selective neurotoxins began with the pioneering studies of R. Levi-Montalcini through her studies of the neurotrophin "nerve growth factor" (NGF), a protein promoting growth and development of sensory and sympathetic noradrenergic nerves. An antibody to NGF, namely, anti-NGF - developed in the 1950s in a collaboration with S. Cohen - was shown to produce an "immunosympathectomy" and virtual lifelong sympathetic denervation. These Nobel Laureates thus developed and characterized the first identifiable selective neurotoxin. Other selective neurotoxins were soon discovered, and the compendium of selective neurotoxins continues to grow, so that today there are numerous selective neurotoxins, with the potential to destroy or produce dysfunction of a variety of phenotypic nerves. Selective neurotoxins are of value because of their ability to selectively destroy or disable a common group of nerves possessing (1) a particular neural transporter, (2) a unique set of enzymes or vesicular transporter, (3) a specific type of receptor or (4) membranous protein, or (5) other uniqueness. The era of selective neurotoxins has developed to such an extent that the very definition of a "selective" neurotoxin has warped. For example, (1) N-methyl-D- aspartate receptor (NMDA-R) antagonists, considered to be neuroprotectants by virtue of their prevention of excitotoxicity from glutamate receptor agonists, actually lead to the demise of populations of neurons with NMDA receptors, when administered during ontogenetic development. The mere lack of natural excitation of this nerve population, consequent to NMDA-R block, sends a message that these nerves are redundant - and an apoptotic cascade is set in motion to eliminate these nerves. (2) The rodenticide rotenone, a global cytotoxin that acts mainly to inhibit complex I in the respiratory transport chain, is now used in low dose over a period of weeks to months to produce relatively selective destruction of substantia nigra dopaminergic nerves and promote alpha-synuclein deposition in brain to thus model Parkinson's disease. Similarly, (3) glial toxins, affecting oligodendrocytes or other satellite cells, can lead to the damage or dysfunction of identifiable groups of neurons. Consequently, these toxins might also be considered as "selective neurotoxins," despite the fact that the targeted cell is nonneuronal. Likewise, (4) the dopamine D2-receptor agonist quinpirole, administered daily for a week or more, leads to development of D2-receptor supersensitivity - exaggerated responses to the D2-receptor agonist, an effect persisting lifelong. Thus, neuroprotectants can become "selective" neurotoxins; nonspecific cytotoxins can become classified as "selective" neurotoxins; and receptor agonists, under defined dosing conditions, can supersensitize and thus be classified as "selective" neurotoxins. More examples will be uncovered as the area of selective neurotoxins expands. The description and characterization of selective neurotoxins, with unmasking of their mechanisms of action, have led to a level of understanding of neuronal activity and reactivity that could not be understood by conventional physiological observations. This chapter will be useful as an introduction to the scope of the field of selective neurotoxins and provide insight for in-depth analysis in later chapters with full descriptions of selective neurotoxins.

Obesidade é fator de risco para a hipertensão arterial e os mecanismos envolvidos nesta doença não são totalmente esclarecidos. Camundongos C57BL/6J e transgênicos com com deleção em neurônios e glia da via inflamatória do receptor toll-like-NF&#954;B foram submetidos à dieta hiperlipídica (HL) por 8 e 15 semanas e avaliados parâmetros metabólicos, pressão arterial, frequência cardíaca, atividade do sistema nervoso autônomo, fatores inflamatórios e neuropeptídeos no hipotálamo e no tronco encefálico. Os camundongos expostos HL desenvolveram hipertensão arterial acompanhada de disfunção autonômica e aumento de CART no DMH. Os animais transgênicos quando submetidos à dieta HL desenvolveram um quadro de obesidade, porém não apresentaram hipertensão arterial e disfunção autonômica. Além disso, o grupo de animais HL aumentou o RNAm de CCL5 no hipotálamo e de CD86 no tronco-encefálico e a densidade de microglia no NTS caudal. Os resultados sugerem novos mecanismos para a hipertensão e disfunção autonômica secundárias à ingestão de dieta hiperlipídica mostrando o papel do CART o DMH e o envolvimento da via inflamatória do TLR-NF&#954;B em neurônios e glia nos mecanismos desta patologia. / Obesity is a risk factor for high blood pressure and the mechanisms involved in this disease are not fully clarified. C57BL/6J and transgenic mice with toll-like-NF&#954;B receptor inflammatory- pathway deletion in neurons and glia were fed with high-fat diet (HL) for 8 or 15 weeks and assessed metabolic parameters, blood pressure, heart rate, autonomic nervous system activity, inflammatory factors and neuropeptides in the hypothalamus and brainstem. The HL mice developed hypertension accompanied with autonomic dysfunction and increased CART in DMH. Transgenic animals when submitted to HL diet developed obesity, but not showed high blood pressure and autonomic dysfunction. In addition, HL animals had increased CCL5 mRNA in hypothalamus, CD86 mRNA in brainstem and micróglia density in caudal NTS. The results suggest new mechanisms for hypertension and autonomic dysfunction secondary to intake of high-fat diet by showing CART role in DMH and the involvement of the inflammatory pathway TLR-NF&#954;B in neurons and glia.

Obesidade é fator de risco para a hipertensão arterial e os mecanismos envolvidos nesta doença não são totalmente esclarecidos. Camundongos C57BL/6J e transgênicos com com deleção em neurônios e glia da via inflamatória do receptor toll-like-NF&#954;B foram submetidos à dieta hiperlipídica (HL) por 8 e 15 semanas e avaliados parâmetros metabólicos, pressão arterial, frequência cardíaca, atividade do sistema nervoso autônomo, fatores inflamatórios e neuropeptídeos no hipotálamo e no tronco encefálico. Os camundongos expostos HL desenvolveram hipertensão arterial acompanhada de disfunção autonômica e aumento de CART no DMH. Os animais transgênicos quando submetidos à dieta HL desenvolveram um quadro de obesidade, porém não apresentaram hipertensão arterial e disfunção autonômica. Além disso, o grupo de animais HL aumentou o RNAm de CCL5 no hipotálamo e de CD86 no tronco-encefálico e a densidade de microglia no NTS caudal. Os resultados sugerem novos mecanismos para a hipertensão e disfunção autonômica secundárias à ingestão de dieta hiperlipídica mostrando o papel do CART o DMH e o envolvimento da via inflamatória do TLR-NF&#954;B em neurônios e glia nos mecanismos desta patologia. / Obesity is a risk factor for high blood pressure and the mechanisms involved in this disease are not fully clarified. C57BL/6J and transgenic mice with toll-like-NF&#954;B receptor inflammatory- pathway deletion in neurons and glia were fed with high-fat diet (HL) for 8 or 15 weeks and assessed metabolic parameters, blood pressure, heart rate, autonomic nervous system activity, inflammatory factors and neuropeptides in the hypothalamus and brainstem. The HL mice developed hypertension accompanied with autonomic dysfunction and increased CART in DMH. Transgenic animals when submitted to HL diet developed obesity, but not showed high blood pressure and autonomic dysfunction. In addition, HL animals had increased CCL5 mRNA in hypothalamus, CD86 mRNA in brainstem and micróglia density in caudal NTS. The results suggest new mechanisms for hypertension and autonomic dysfunction secondary to intake of high-fat diet by showing CART role in DMH and the involvement of the inflammatory pathway TLR-NF&#954;B in neurons and glia.