Functional recovery following peripheral nerve injuries is poor due to muscle atrophy and fibrosis being major contributing factors. Electrical muscle stimulation has been used for decades in some capacity to treat denervation related muscular changes. The research presented in this thesis explores a new stimulation paradigm and its effects on short and long term muscle denervation. The first part of this work describes the new stimulation paradigm and the design and development of the stimulator used to deliver this paradigm. The paradigm involved daily 1-hour stimulation sessions featuring 600 contractions at high stimulus frequencies (100 Hz) and low pulse durations (200 μs). To test the device and paradigm, a pilot study involving muscle stimulation throughout a one month period of denervation in rat lower limb muscles was carried out. The results showed that this short but intense stimulus session significantly reduced the rate of muscle atrophy compared to animals that did not receive stimulation. Furthermore, muscle weight and consequently muscle force were also significantly greater. The stimulus paradigm was then used to investigate muscle that was denervated and immediately repaired. Ideally, immediate nerve repair following nerve injuries produces the best outcome. One month of electrical muscle stimulation following nerve repair enhanced this outcome through significant increases in muscle weight and force. Additionally, contrary to many previous studies, the stimulus paradigm had no negative effects on reinnervation. Taken together, electrical muscle stimulation can provide significant improvements over the best case scenario of immediate nerve repair. The third part of this work investigated the use of chronic electrical muscle stimulation throughout three months of denervation and the impact on reinnervation. Results showed that reinnervation in chronically stimulated animals were no different than animals that were denervated and immediately repaired. The last part of this work combined the use of electrical muscle stimulation with sensory protection in chronically denervated muscle. Sensory protection involves suturing a sensory nerve to protect a muscle during denervation and was shown in previous studies to reduce muscle atrophy, preserve muscle spindles and the structure of the distal nerve stump. The results showed significantly greater muscle weights and force in the combined treatment compared to the individual treatments alone. Reinnervation in these animals was as good as those that were immediately repaired. This suggests that contractile support combined with sensory protection may provide superior functional outcomes in chronically denervated muscle. The findings presented in this thesis provide new evidence for the use of short duration daily electrical muscle stimulation immediately following nerve repair or throughout long term denervation. Evidence for a new therapy, muscle stimulation with sensory protection, is also presented and shown to provide superior functional outcomes compared to either therapy alone. The contributions made in this body of work may provide clinicians with evidence to pursue clinical use of the outlined strategies and ultimately help patients optimally recover from peripheral nerve injuries. / Doctor of Philosophy (PhD)

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Introdução: A hipertensão arterial sistêmica (HAS) é uma doença que pode determinar lesões em diversos órgãos inclusive nos olhos. As doenças vasculares oculares constituem a grande maioria das causas de cegueira na atualidade e a HAS tem contribuição importante nesta estatística. A variabilidade da pressão arterial tem sido implicada na gênese de uma série de lesões de órgãos-alvo. Na tentativa de compreender melhor a patogênese das doenças vasculares oculares testamos a hipótese de que não apenas os efeitos da HAS, mas também a variabilidade da pressão arterial (PA) poderia determinar lesão de órgão-alvo (ocular). Materiais e Métodos: A desnervação sino-aórtica (DSA), um modelo experimental de aumento da variabilidade da pressão arterial foi utilizado nos experimentos. Foram obtidas medidas da pressão intraocular e a partir destas medidas, a pressão de perfusão ocular. Foram analisados marcadores de estresse oxidativo (8-OHdG e nitrotirosina),VEGF e receptores AT1 na retina de animais normotensos e hipertensos com e sem DSA aguda (12 e 24 horas) e crônica (10 semanas). Resultados: Os animais desnervados apresentaram aumento da variabilidade da PA sem modificar a PA basal e redução da sensibilidade do barorreflexo. Houve aumento da modulação simpática vascular e da pressão de perfusão ocular (PPO), nos animais hipertensos, com aumento adicional da PPO nos hipertensos e desnervados crônicos.Observou-seestresse oxidativo retiniano nos animais desnervados agudos e noshipertensos desnervados crônicos, além do aumento da expressão de receptores AT1 da Angiotensina II nos animais hipertensos. Os níveis de VEGF retinianos dos animais desnervados crônicos, apresentaram comportamento inverso aos níveis de Caspase-3. Conclusão: Tais resultados indicam que só a HAS, mas também a variabilidade da PA podem determinar variações na pressão de perfusão ocular, assim como também podem induzir dano oxidativo às células retinianas. Além disso, pode-se sugerir efeito neuroprotetor retiniano do VEGF / Introduction: High blood pressure (HBP) is a disease that can determine lesions in many organs including the eyes. The ocular vascular diseases constitute the vast majority of causes of blindness and hypertension has important contribution in this statistic. Blood pressure variability has been implicated in the genesis of a series of end-organ damage. In an attempt to better understand the pathogenesis of ocular vascular diseases, we hypothesized that not only the effects of hypertension, but also the variability of blood pressure (BPV) could determine target end-organ damage (ocular). Materials and Methods: Sino-aortic denervation (SAD), an experimental model of increased blood pressure variability was used in the experiments. The intraocular pressure measurements were performed and from these measurements the ocular perfusion pressure was estimated. Oxidative stress markers (8-OHdG and nitrotyrosine), VEGF and AT1 receptor in rat retinas were analyzed inacute and chronic hypertensive and normotensiveSAD rats and in controls. Results: Denervated animals showed increased BP variability without altering the basal BP, while presenting reduced baroreflex sensitivity.There was an increase in sympatheticvascular modulation and in OPP,in hypertensive animals, that was additionally in chronic denervated hypertensive animals.Acute denervated and chronic hypertensive denervated animals showed retinal oxidative stress as well as hypertensive animals presented increased expression of AT1 receptors of angiotensin II. The levels of retinal VEGF of chronically denervated animals showed inverse behavior of levels of Caspase-3 Conclusion: These results suggest that, apart from the arterial hypertension, BP variability not only determines changes in ocular perfusion pressure, but also induces oxidative damage to retinal cells. Furthermore, one can suggest retinal neuroprotective effect of VEGF

Previous investigators demonstrated that epididymal white adipose tissue (EWAT) lipectomy suppressed spermatogenesis and caused atrophy of the seminiferous tubules. EWAT lipectomy, however, may disrupt testicular innervation, which reportedly compromises testicular function. To resolve this confound and better clarify the role of EWAT in spermatogenesis, three experimental groups of hamsters were created in which: i.) the superior and inferior spermatic nerves were transected (SSNx) at the testicular level, ii.) EWAT was extirpated (EWATx), and iii.) testicular nerves and EWAT were left intact (SHAM controls). It was hypothesized that transection of the superior and inferior spermatic nerves would disrupt normal spermatogenesis. The findings indicate a significant reduction in spermatogenic activity and marked seminal tubule atrophy within the EWATx testis, as compared to the SSNx and controls testes, which did not differ significantly from each other. From these data, it is concluded that EWAT, and not testicular innervation, is central to normal spermatogenesis.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Made available in DSpace on 2016-06-02T20:18:20Z (GMT). No. of bitstreams: 1 5170.pdf: 1490860 bytes, checksum: e55ec88b5e46f4a697f05f0b01a4a9a5 (MD5) Previous issue date: 2013-04-24 / The literature presents many alternatives of physical training and frequently reiterates the use of animal models for studies on the effect of training, as the results in animals are similar to those in humans. There is also the possibility of evaluating variables such as volume and intensity. In addition, many studies have reported beneficial effects of estrogen as an important resource to minimize the deleterious effects of aging. As a means of understanding estrogen action and its influence on aerobic and anaerobic exercise, four experiments were carried out in this context. The first study was called The behavior of glycogen reserves in female rats denervated muscle, with different doses of estrogen and aimed at evaluating the estrogen action on the glycogenic profiles of denervated skeletal muscle.Methods: The animals were divided in 6 experimental groups (n=6): control (C), denervated for 15 days (D), denervated and treated with estrogen 20mg/weight/day (E20), denervated and treated with estrogen 40mg/weight/day (E40), denervated and treated with estrogen 80mg/weight/day (E80) and denervated and treated with estrogen 160mg/weight/day (E160). The treatment was realized by 15 days and the choice substance was estradiol cipionate. The following analyses were carried out: glycogen reserves in soleus (S), white (WG) and red gastrocnemius (RG), body and soleus weights. The statistical analysis included the Kolmogorov-Smirnov test, ANOVA and post-hoc Tukey test (p<0.05). Results: The denervation induced a reduction in glycogen content in the S, WG and RG muscles. The groups treated with estrogen we observed a progressive elevation in glycogen reserves concomitant with the elevation of dose and reinstate the glycogen reserves, but the dose that shows a better action is 160mg/weight/day were we observed the greatest quimiometabolic responses. Conclusions: These results suggest that estrogen may be an effective resource to minimize the metabolic compromising that follows the skeletal muscle atrophy induced by denervation. Subsequently, we conducted a study called Estrogen modulation of insulin secretion in isolated rat pancreatic islets , whose goal was to evaluate the sensitivity to glucose in pancreatic islets isolated from female rats treated with estradiol cypionate (160 mg/body weight/ 15 days) as well as its effect on concentration of protein kinase C and protein kinase A in isolated islets. For this purpose, islets were isolated from rats by the collagenase method to evaluate the secretory process in the presence of different concentrations of glucose. On the other hand, the concentration of the enzymes PKC and PKA was also performed by Western blotting. Statistical analysis was applied to normality test (Kolmogorov-Smirnov test) followed by Tukey test, p <0.05. The results showed that the group treated with estradiol cypionate had greater insulin secretion against the same concentration of glucose, and increase of concentration of PKA and PKC enzymes, compared to control. The results show insulinotropic properties of estrogen in synergy with glucose, which is the main insulin secretagogue, since the hormone did not alter the secretion at concentrations normoglycaemia. Possibly the focus of the secretagogue action of estrogen involves the activation of cytosolic enzyme pathways that determine the exudation of insulin. From these observations, we conducted the third study entitled "Electrocardiographic profile of aged rats trained and treated with estrogen , whose goal was to assess the eletrocardiographic profile of rats treated with the association of estrogen and physical activity. We used Wistar rats at 1 year of age, which were submitted to two programs of aerobic exercise (swimming 3 sessions weekly / 8 weeks) and anaerobic (climbing stairs of 80 cm, 3 sessions weekly / 8 weeks). We evaluated blood pressure and ECG intervals considering the QRS, QTc and PR. Data were compared by Student's t test followed by Tukey test, p <0.05. The findings of this study showed that the group treated with estrogen values were 21% lower compared to the control group. With respect to training, we observed that aerobic training promoted 25% reduction in FC, which reached 37.2% reduction in the presence of estrogen. In anaerobic training, we observed 28% reduction, which was accentuated to 40% when estrogen was present. Thus we conclude that treatment with estrogen alone or associated with physical activity was effective in maintaining and improving conditions in the metabolic and functional heart in the cardiac changes that accompany the aging process. Subsequently, we held the fourth paper entitled "Metabolic actions of estrogen in rats subjected to two types of physical training . The purpose of this study was to evaluate whether rats supplemented with estrogen show better responses to the aerobic and anaerobic physical activity. We used aged Wistar rats (13 months), placed under ideal conditions of bioterism and divided into experimental groups called Control and Treated with estrogen (E, 160&#956;g/100g), Aerobically and Anaerobically trained, and Treated with estrogen or not. Blood samples were collected for biochemical evaluation and samples of different muscles of the anterior and posterior were collected for glycogen content assessment by the phenol sulfuric method. The outcomes show that both estrogen and the different workout programs promoted increase in muscle glycogen reserves. Besides, the association of hormone with exercise promoted an additional effect with further enhances in energy conditions. Additionally, we found lower plasma free fatty acids and abdominal fat, and there was also an increase in total protein concentration indicating adjustments in metabolic homeostasis, an important condition to be preserved in the aging process. / A literatura científica apresenta diversas maneiras de treinamento físico e constantemente reitera que a utilização de modelos animais em estudos sobre o efeito do treinamento visto a possibilidade de avaliar variáveis como volume e intensidade, já que as respostas encontradas nos animais são similares às encontradas em humanos. Por outro lado, diversos estudos têm relatado efeitos benéficos do estrógeno como um recurso importante para minimizar os efeitos deletérios do envelhecimento. Nesse contexto, com o objetivo precípuo de compreender as ações estrogênicas e suas influências no exercício aeróbio e anaeróbio foram realizados 2 trabalhos. O primeiro trabalho intitulado Perfil eletrocardiográfico de ratas envelhecidas treinadas e tratadas com estrógeno , cujo objetivo foi avaliar o perfil eletrocardiográfico de ratas tratadas com a associação de estrógeno e atividade física. Foram utilizadas ratas wistar com 1 ano e meio de idade, as quais foram submetidas a dois programas de exercício físico aeróbio (natação 3 sessões semanais/8 semanas) e anaeróbio (escalada em escada de 80 cm, 3sessões semanais/8 semanas), incluindo um período de 2 semanas de adaptação para cada protocolo de treinamento. Foram avaliados a pressão arterial e o ECG considerando os intervalos QRS, QTc e PR. Os dados foram comparados através do teste T de student seguido do teste de Tukey, p<0,05. Os resultados desse estudo mostraram que o grupo tratado com estrógeno apresentou valores 21% menores se comparado ao controle. Com relação ao treinamento foi observado que o treinamento aeróbio promoveu redução 25% na FC, redução que atingiu 37,2% na presença do estrógeno. No treinamento anaeróbio foi observado redução de 28% sendo acentuado para 40% quando o estrógeno esteve presente. Dessa forma conclui-se que nas alterações cardíacas que acompanham o processo de envelhecimento, o tratamento com estrógeno isoladamente ou associado a prática de atividade física mostrou-se eficiente na manutenção bem como na melhora das condições metabólicas cardíacas. Seqüencialmente foi realizado o segundo trabalho intitulado Ações metabólicas do estrógeno em ratas submetidas a dois tipos de treinamento físico. A proposta deste estudo foi avaliar se ratas suplementadas com estrógeno apresentam melhores respostas frente à atividade física aeróbia e anaeróbia. Foram utilizadas ratas Wistar envelhecidas (1 ano e meio de idade) acondicionadas sob condições ideais de bioterismo e divididas em grupos experimentais denominados Controle e Tratadas com estrógeno (E,160&#956;g/100g), Treinado aeróbio e treinado anaeróbio tratados ou não com estrógeno. Foram coletadas amostras de sangue para avaliação bioquímica e amostras de diferentes músculos dos membros anteriores e posteriores para avaliação do conteúdo de glicogênio pelo método do fenol sulfúrico. Os resultados mostram que tanto o estrógeno quanto os diferentes treinamentos promoveram elevação nas reservas musculares de glicogênio, por outro lado, na associação do hormônio com o exercício físico, foi verificado um efeito aditivo que promoveu a melhora ainda mais expressiva nas condições energéticas. Associado a isto, foi verificado menores concentrações plasmáticas de ácidos graxos livres e gordura abdominal e ainda houve elevação na concentração de proteínas totais indicando ajustes na homeostasia metabólica, condição importante a ser preservada no processo de envelhecimento.

The resistant hypertension is a disease difficult to diagnose and is associated with higher risk of cardiovascular events such as heart attack, stroke and sudden death. A considerable number of patients do not get effective control of the disease, despite the use of multiple drugs and high doses. Hyperactivation of the sympathetic nervous system is the pathophysiological basis for the ablation of afferent fibers, by applying radiofrequency energy in the renal arteries. This procedure, known as percutaneous sympathetic denervation has been shown to be a promising therapy and in recent years the results, with limited number of patients showed significant drop in blood pressure levels and cardiovascular risk. However, much of the reduction in risk can not be explained only by lowering blood pressure, emerging questions about treatment outcomes (use of multiple drugs / high doses) and assigning any failure of medication on independent effect vascular properties pressure. Vascular changes in micro and macrocirculation can not be fully observed by the peripheral measures, which required the understanding of endothelial dysfunction. The vascular endothelium is considered an active, dynamic tissue, so this dysfunction, in cases of high blood pressure, contributes to the development of atherosclerosis by promoting thrombosis, arterial stiffness and reduce tone and in the regulation of arterial flow. The identification of endothelin as a vasoconstrictor and the discovery of his release from the vascular endothelium suggested their involvement in the pathogenesis of hypertension and vascular disease, currently the most potent vasoconstrictor agent ever identified. We evaluated the reduction of blood pressure by sympathetic denervation in resistant hypertensive and one correlated their levels of endothelin of patients with cardiovascular disease. There were no complications, and at 18 months the average drop was 18 mmHg in systolic 24-ABPM and 19mmHg in central pressure. These two methods were shown to be equal in the assessment of therapeutic success. Higher levels of endothelin were present in cardiovascular disease may be a new marker of endothelial damage in heart disease. / A hipertensão arterial resistente é uma doença de difícil diagnóstico e está relacionada ao maior risco de eventos cardiovasculares, como infarto, acidente vascular cerebral e morte súbita. Uma parcela considerável dos pacientes não obtém controle efetivo da doença, a despeito do uso de múltiplos fármacos e doses elevadas. A hiperativação do sistema nervoso simpático constitui a base fisiopatológica para a ablação das fibras aferentes, através da aplicação de energia por radiofrequência nas artérias renais. Esse procedimento, conhecido como denervação simpática percutânea, tem se mostrado uma terapia promissora e nos últimos anos os resultados, com número limitado de pacientes, mostraram queda significativa dos níveis tensionais e do risco cardiovascular. No entanto, boa parte da redução do risco não pode ser explicada apenas pela redução da pressão arterial, surgindo questionamentos sobre os resultados dos tratamentos (uso de múltiplos fármacos/doses elevadas) e atribuindo-se eventuais falhas da medicação sobre propriedades vasculares independentes do efeito pressórico. As alterações vasculares da micro e macrocirculação não podem ser totalmente observadas pelas medidas periféricas, sendo necessário o entendimento da disfunção endotelial. O endotélio vascular é considerado um tecido ativo e dinâmico portanto, a disfunção deste, em casos de hipertensão arterial, contribui para o desenvolvimento da aterosclerose, promovendo trombose, rigidez arterial e redução da regulação do tônus e fluxo arteriais. A identificação da endotelina como um vasoconstritor e a descoberta da sua liberação a partir do endotélio vascular sugeriu seu envolvimento na patogênese da hipertensão e da doença vascular, sendo atualmente o agente vasoconstritor mais potente já identificado. Avaliou-se a redução dos níveis pressóricos através da denervação simpática em um hipertenso resistente e correlacionou-se seus níveis de endotelina com pacientes portadores de doenças cardiovasculares. Não houve complicações, sendo que aos 18 meses a queda média foi de 18mmHg na PAS da MAPA 24h e 19mmHg na pressão central. Estes dois métodos mostraram-se iguais na aferição do sucesso terapêutico. Níveis maiores de endotelina estiveram presentes na doença cardiovascular, podendo ser um novo biomarcador de lesão endotelial na doença cardíaca.

Introdução: A hipertensão arterial sistêmica (HAS) é uma doença que pode determinar lesões em diversos órgãos inclusive nos olhos. As doenças vasculares oculares constituem a grande maioria das causas de cegueira na atualidade e a HAS tem contribuição importante nesta estatística. A variabilidade da pressão arterial tem sido implicada na gênese de uma série de lesões de órgãos-alvo. Na tentativa de compreender melhor a patogênese das doenças vasculares oculares testamos a hipótese de que não apenas os efeitos da HAS, mas também a variabilidade da pressão arterial (PA) poderia determinar lesão de órgão-alvo (ocular). Materiais e Métodos: A desnervação sino-aórtica (DSA), um modelo experimental de aumento da variabilidade da pressão arterial foi utilizado nos experimentos. Foram obtidas medidas da pressão intraocular e a partir destas medidas, a pressão de perfusão ocular. Foram analisados marcadores de estresse oxidativo (8-OHdG e nitrotirosina),VEGF e receptores AT1 na retina de animais normotensos e hipertensos com e sem DSA aguda (12 e 24 horas) e crônica (10 semanas). Resultados: Os animais desnervados apresentaram aumento da variabilidade da PA sem modificar a PA basal e redução da sensibilidade do barorreflexo. Houve aumento da modulação simpática vascular e da pressão de perfusão ocular (PPO), nos animais hipertensos, com aumento adicional da PPO nos hipertensos e desnervados crônicos.Observou-seestresse oxidativo retiniano nos animais desnervados agudos e noshipertensos desnervados crônicos, além do aumento da expressão de receptores AT1 da Angiotensina II nos animais hipertensos. Os níveis de VEGF retinianos dos animais desnervados crônicos, apresentaram comportamento inverso aos níveis de Caspase-3. Conclusão: Tais resultados indicam que só a HAS, mas também a variabilidade da PA podem determinar variações na pressão de perfusão ocular, assim como também podem induzir dano oxidativo às células retinianas. Além disso, pode-se sugerir efeito neuroprotetor retiniano do VEGF / Introduction: High blood pressure (HBP) is a disease that can determine lesions in many organs including the eyes. The ocular vascular diseases constitute the vast majority of causes of blindness and hypertension has important contribution in this statistic. Blood pressure variability has been implicated in the genesis of a series of end-organ damage. In an attempt to better understand the pathogenesis of ocular vascular diseases, we hypothesized that not only the effects of hypertension, but also the variability of blood pressure (BPV) could determine target end-organ damage (ocular). Materials and Methods: Sino-aortic denervation (SAD), an experimental model of increased blood pressure variability was used in the experiments. The intraocular pressure measurements were performed and from these measurements the ocular perfusion pressure was estimated. Oxidative stress markers (8-OHdG and nitrotyrosine), VEGF and AT1 receptor in rat retinas were analyzed inacute and chronic hypertensive and normotensiveSAD rats and in controls. Results: Denervated animals showed increased BP variability without altering the basal BP, while presenting reduced baroreflex sensitivity.There was an increase in sympatheticvascular modulation and in OPP,in hypertensive animals, that was additionally in chronic denervated hypertensive animals.Acute denervated and chronic hypertensive denervated animals showed retinal oxidative stress as well as hypertensive animals presented increased expression of AT1 receptors of angiotensin II. The levels of retinal VEGF of chronically denervated animals showed inverse behavior of levels of Caspase-3 Conclusion: These results suggest that, apart from the arterial hypertension, BP variability not only determines changes in ocular perfusion pressure, but also induces oxidative damage to retinal cells. Furthermore, one can suggest retinal neuroprotective effect of VEGF

The aim of the present investigation was to study the influence of the sympathetic nervous system and of various adrenoceptor agents on enzyme secretion and morphology in rat parotid and guinea-pig submandibular glands. Biochemical methods were combined with electron microscopical techniques. Two different in vitro systems were employed, batch-incubation and microperifusion, to characterize the sympathetically evoked amylase release and its correlation to cyclic AMP. By using various selective β-adrenoceptor agonists and antagonists a dominance of the β1-adrenoceptor over the β2 - in regulating amylase release - was establ ished. Continuous noradrenaline perifusion caused a rapid initial amylase discharge, closely correlated to tissue levels of cyclic AMP; no correlation between the two was observed during the later phase. Prenalterol (a β1-agonist) failed to elevate glandular cyclic AMP. This was in contrast to its potent secretagogic effect. On the other hand, terbutaline (a β2-agonist) was a weak secretagogue but markedly raised the levels of cyclic AMP. Thus, β-adrenoceptor activation may lead to release of large amounts of amylase despite minimal or no increase in cyclic AMP. Moreover, these effects seemed to be dissociated in salivary glands with regard to the β-adrenoceptor subtypes. This was further substantiated by the findings that repeated injections of prenalterol induced qualitative changes in the granule populations, similar to those caused by the non-selective β-agonist isoprenaline. Terbutaline was without effect. However, acinar cells size was increased following both prenalterol and terbutaline treatment. The data suggest that the 3-adrenergic effects on acinar cell size and granule population may be independently regulated. A decreased sympathetic activity of long duration was induced by neonatal or adult extirpation of the superior cervical ganlion on one side. Acinar cell size, as well as granule and amylase content was reduced 9 weeks after neonatal denervation. Ganglionectomy performed in adult animals was without significant effects. The secretory behaviour of neonatally denervated glands was characterized by an increased postjunctional sensitivity to 3-adrenoceptor agonists. Of special interest was the finding that neonatal denervation seemed to transform terbutaline from a partial to a full secretory agonist, thus changing its effects in the direction of those of prenalterol and noradrenaline. Moreover, increased levels of cyclic AMP as well as an enhanced response to DBcAMP were noted in the denervated glands as were intracellular changes. The denervation supersensitivity after neonatal denervation seems to differ from that observed in adult denervated glands. The results of the studies on denervated glands suggest that the sympathetic nervous system plays a fundamental role in the early maturation of the rat parotid gland as well as for the development of the β-adrenoceptor subtypes. / <p>S. 1-34: sammanfattning, s. 35-128: 6 uppsatser</p> / digitalisering@umu

Dopamine receptor supersensitivity (DARSS) often is invoked as a mechanism possibly underlying disordered thought processes and agitation states in psychiatric disorders. This review is focused on identified means for producing DARSS and associating the role of other monoaminergic systems in modulating DARSS. Dopamine (DA) receptors, experimentally, are prone to become supersensitive and to thus elicit abnormal behaviors when coupled with DA or a receptor agonist. In intact (control) rats repeated DA D1 agonist treatments fail to sensitize D1 receptors, while repeated D 2 agonist treatments sensitize D2 receptors. D2 RSS is attenuated by a lesion with DSP-4 (N-(2-chlorethyl)-N-ethyl-2- bromobenzylamine) in early postnatal ontogeny, indicating that noradrenergic nerves have a permissive effect on D2 DARSS. However, if DSP-4 is co-administered with 5,7-dihydroxytryptamine to destroy serotonin (5-HT) nerves, then D2 RSS is restored. In rats treated early in postnatal ontogeny with the neurotoxin 6-hydroxydopamine to largely destroy DA innervation of striatum, both repeated D1 and D2 agonists sensitize D1 receptors. 5-HT nerves appear to have a permissive effect on D1 DARSS, as a 5-HT lesion reduces the otherwise enhanced effect of a D1 agonist. The series of findings demonstrate that DARSS is able to be produced by repeated agonist treatments, albeit under different circumstances. The involvement of other neuronal phenotypes as modulators of DARSS provides the potential for targeting a variety of sites in the aim to prevent or attenuate DARSS. This therapeutic potential broadens the realm of approaches toward treating psychiatric disorders.