A Virola surinamensis, também conhecida como ucuúba branca, é muito difundida na floresta amazônica e, popularmente, usada no tratamento de erisipelas, cólicas e dispepsias. Estudos experimentais demonstraram atividades anti-parasitárias de diferentes componentes da planta contra Schistosoma mansoni, Plasmodium falciparum, Leishmania donovani e Trypanosoma cruzi. Com a possibilidade de utilização farmacológica da planta evidencia-se a necessidade de avaliar os possíveis efeitos sobre o sistema hematopoético. O presente trabalho teve por objetivo verificar os efeitos da grandisina, uma lignana extraída da Virola surinamensis, sobre o sistema hematopoético, em camundongos. Para tanto, foram avaliados os seguintes parâmetros: números globais de eritrócitos, leucócitos e plaquetas no sangue periférico, celularidade na medula óssea e baço (utilizando câmara de Neubauer); contagem diferencial de leucócitos no sangue periférico e medula óssea (em extensões coradas com May-Grünwald/ Giemsa); caracterização da população de linfócitos da medula óssea e baço (por imunocitoquímica). A grandisina, em dose única de 100?g/g de peso corpóreo induziu, no sangue periférico, diminuição significativa do número de leucócitos totais, linfócitos e neutrófilos, após 7 e 14 dias, e redução significativa do número de monócitos, após 14 dias do tratamento. Houve uma tendência de aumento do número de células nucleadas da medula óssea após 7 dias da administração da substância, com aumento significativo após 14 dias do tratamento, mas não ocorreu nenhuma alteração na celularidade do baço. Foi observado aumento das células da linhagem linfocítica e monocítica em evolução, na medula óssea, após 7 e 14 dias do tratamento, enquanto no sangue periférico, o número de linfócitos e monócitos continuaram reduzidos. A grandisina, na dose de 100?g/g de peso corpóreo, por cinco dias, provocou uma redução no número de leucócitos, linfócitos, monócitos e neutrófilos no sangue periférico após 7 dias do tratamento. Houve uma tendência de redução do número de leucócitos, linfócitos e monócitos, com redução significativa do número de neutrófilos, após 14 dias da administração da substância. O número de células da medula óssea reduziu, após 7 e 14 dias do tratamento. Quanto a celularidade do baço, não foi observado qualquer alteração. Ocorreu ainda uma redução no número de células mononucleares e polimorfonucleares em evolução na medula óssea, após 7 e 14 dias do tratamento. No experimento de dose única, a imunohistoquímica dos sedimentos medulares mostrou uma tendência de diminuição do número de Linfócitos T totais, Linfócitos T imaturos e Linfócitos B, após 14 dias do tratamento. No experimento de dose seriada houve redução destas populações de linfócitos, após 7 e 14 dias do tratamento, somente na medula óssea. Os resultados obtidos neste estudo demonstram que a dose de 100?g/g de peso corpóreo, tanto em dose única como seriada, causa importantes alterações nas células sanguíneas indicando que, para o uso terapêutico, doses inferiores a estas devem ser avaliadas. / Virola surinamensis, also known as ucuuba branca, is widespread in the Amazon forest and, popularly, used in the treatment of erysipelas, colic and dyspepsia. Experimental studies have shown antiparasitic activities of different components of the plant against Schistosoma mansoni, Plasmodium falciparum, Leishmania donovani and Trypanosoma cruzi. The potential pharmacological use of the plant points towards the need to evaluate the possible effects on the hematopoietic system. The present work aims to verify the effects of grandisin, a lignan extracted from Virola surinamensis, on the hematopoietic system of mice. The following parameters were evaluated: the number of erythrocytes, leukocytes and platelets on peripheral blood, cell counts on bone marrow and spleen (with Neubauer chamber); differential leukocyte count on peripheral blood and bone marrow (on smears stained with May-Grünwald/Giemsa); the characterization of lymphocytes on bone marrow and spleen (by immunocytochemistry). The grandisin in a single dose of 100?g/g of body weight induced, on peripheral blood, significant decrease in the total count of leukocytes, lymphocytes and neutrophils, after 7 and 14 days and a significant decrease in the number of monocytes, after 14 days of treatment. A tendency in the increase of nucleated bone marrow cells occurred after 7 days of administration of the substance, with a significant increase after 14 days of treatment, but no alteration in the spleen cells occurred. An increase in the cells of lymphocytic and monocytic lineages was observed in evolution, in bone marrow after 7 and 14 days of treatment whereas in peripheral blood the number of lymphocytes and monocytes maintained low. Grandisin, administered during five consecutive days with a daily dose of 100?g/g of body weight, caused a decrease in the number of leukocytes, lymphocytes, monocytes and neutrophils in peripheral blood after 7 days of treatment. A tendency of decrease in the number of leukocytes, lymphocytes and monocytes occurred with a significant decrease in the number of neutrophils, after 14 days of administration of the substance. The number of bone marrow cells decreased after 7 and 14 days of treatment. For the spleen cells no alterations were observed. A decrease in the number of mononuclear and polimorfonuclear cells in evolution on bone marrow after 7 and 14 days of treatment was observed. In a single dose experiment, the immunocytochemistry of medullar sediments showed a tendency of decrease in the total number of T lymphocytes, T immature lymphocytes and B lymphocytes after 14 days of treatment. The serial dose caused a decrease in the population of lymphocytes after 7 and 14 days of treatment in bone marrow. The results obtained in this study demonstrated that the dose of 100?g/g of body weight, either in single or in serial doses, cause important alterations on blood cells indicating that for therapeutic use inferior doses must be evaluated.

Made available in DSpace on 2014-06-11T19:31:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-05-14Bitstream added on 2014-06-13T19:01:28Z : No. of bitstreams: 1 godoy_av_dr_jabo.pdf: 494650 bytes, checksum: d27d9898dce60f32a0eece2e8cdaf032 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O presente estudo teve como objetivos avaliar seqüencial e temporalmente o quadro leucocitário de dez cães portadores de linfoma em remissão, submetidos à alta dose de ciclofosfamida, durante o uso do estimulador de colônia de granulócitos (GCSF, filgrastine) seguido ou não do transplante autólogo de medula óssea (TMO), bem como quantificar células CD34+ no sangue periférico dos referidos cães. Para tal avaliação foram utilizados três grupos experimentais, sendo o grupo 1 (G1) formado por cinco animais em remissão de linfoma que passaram por alta dose de ciclofosfamida e TMO seguido do uso de G-CSF; o grupo 2 (G2) formado por cinco animais em remissão de linfoma que sofreram alta dose de ciclofosfamida seguida do uso de G-CSF e o grupo 3 (G3) formado por dez animais saudáveis que receberam apenas o G-CSF. O transplante consistiu na colheita de medula óssea, preparo e congelamento da bolsa que continha células medulares em suspensão, condicionamento do paciente com 500mg/m2 de ciclofosfamida, infusão das células hematopoéticas e aplicação do G-CSF. Para avaliar a recuperação hematopoética pós-transplante foi realizado leucograma e análise citométrica do sangue nos dias 7, 8, 9, 10 e 11 após condicionamento. O nadir médio dos neutrófilos segmentados (NS) no grupo com transplante de medula óssea (G1) foi 425 NS/mL, e no grupo sem TMO (G2) foi 637,4 NS/μL e ocorreu sete dias após alta-dose de quimioterápico em ambos os grupos. A duração média da neutropenia foi de três dias. Nenhum animal apresentou febre ou sepse após a alta dose de ciclofosfamida. A dose de 5μg/kg/dia durante quatro dias de filgrastine foi insuficiente na mobilização adequada de células CD34+ nos três grupos estudados, sendo necessários novos estudos para este propósito. Desta maneira, pode-se comprovar o fato de que o uso do G-CSF leva a reduções significativas na incidência... / The aims of this research were to provide an analysis of several counts of leucocytes values in dogs with lymphoma in remission phase, undergone to high-dose chemotherapy with cyclophosphamide, during treatment with granulocyte colonystimulating factor (G-CSF, filgrastine), followed or not by autologous bone marrow transplantation (BMT), as well to quantify CD34+ cells of peripheral blood from that dogs. For this purpose, three experimental groups were considered. Five dogs in clinical remission undergone to high-dose chemotherapy with cyclophosphamide and BMT, followed by G-CSF use were included in group 1 (G1), while group 2 (G2) was consisted by five dogs undergone to high-dose chemotherapy with cyclophosphamide, followed by G-CSF. Group 3 (G3) was composed of ten healthy dogs undergone to GCSF only. Transplantation consisted of bone marrow harvest, managing and freezing bags containing lifted marrow cells, cyclophosphamide conditioning (500mg/m2), hematopoietic cells infusion and treatment with G-CSF. After transplantation, hematopoietic recovery was evaluated by means of leukograms and flow cytofluorimetrical analysis on days 7, 8, 9, 10 and 11 after conditioning. Mean nadir neutrophil (NS) counts in group undergone transplantation (G1) was 425 NS/mL versus 637,4 NS/μL in group without BMT (G2). Nadir was observed on the seventh day after high-dose chemotherapy in both groups and neutropenia mean time was three days. Fever or sepsis was not observed in any dog after high-dose cyclophosphamide. Four days of filgrastine treatment in dose of 5μg/Kg, daily, was not enough to mobilize CD34+ cells appropriately in three groups analyzed, requiring new studies for this purpose. Considering these results, it is possible to conclude that G-CSF significantly reduces the incidence, severity and duration of neutropenia

O objetivo deste estudo foi avaliar os efeitos da concentração subletal de 0,3 ppm da FSA de petróleo em parâmetros do sistema imune inato e hepático de Rachycentron canadum após o período de 7 e 14 dias. Observou-se uma diminuição do fator de condição dos animais expostos por 14 dias, comparado ao grupo controle. A contagem diferencial de leucócitos mostrou um aumento do número de leucócitos após 7 dias, e uma diminuição destes após 14 dias. A atividade da enzima lisozima no grupo exposto por 14 dias foi maior em comparação ao grupo controle. Foram observadas, ainda, alterações nos tecidos branquiais, renais e hepáticos, após análises histológicas nos grupos expostos a FSA. Notou-se um aumento do índice hepatossomático e da atividade da enzima AST dos animais expostos a FSA. Não foi observada atividade da enzima ALT em todos os grupos. Conclui-se que a concentração de 0,3 ppm da FSA de petróleo altera parâmetros do sistema imune inato e hepáticos de R. canadum, podendo causar imunossupressão e comprometimento do sistema de biotransformação. / The objective of this study was to evaluate the effects of sublethal concentration of 0.3 ppm of the petroleum WSF in parameters of the innate immune system and hepatic of Rachycentron canadum, after the periods of 7 and 14 days. It was observed a decrease in condition factor of animals exposed for 14 days compared to control group. The differential leukocyte count showed an increased number of total leukocytes after 7 days and decreased after 14 days. The activity of the lysozyme enzyme in group exposed for 14 days was higher compared to the control group. There were, also, changes in gill, kidney and liver tissues in groups exposed to WSF of petroleum for 7 and 14 days. It was noted an increase of the hepatosomatic index and AST enzyme activity of animals exposed WSF. It was not observed activity of the enzyme ALT in all groups. It was concluded that the sublethal concentration of 0.3 ppm of the WSF of petroleum alters parameters of the innate immune system and hepatic of R. canadum that may cause immunosuppression and biotransformation system impairment.

Canine parvoviral enteritis is an economically important disease in South Africa and globally. Although treatment of dogs with parvoviral enteritis is often successful, many dogs die of complications related to septicaemia or are euthanized because of anticipated high costs. More effective prediction of the outcome of this disease will have an economic impact if a prognosis can be determined early in the course of the disease. Although leukocyte responses seldom are pathognomonic for a specific disease, they can provide clinical information to establish a fairly reliable prognosis. A prospective study was performed on 62 puppies presented to the OVAH with typical clinical signs of canine parvoviral enteritis that subsequently was confirmed on electron microscopy. Full haematology was performed at admission as well as every consecutive day until death or discharge. Of the 11 puppies that died (18%), nine died due to complications of the disease and two were euthanized due to financial restrictions and a poor prognosis. The puppies that died due to the disease died within the first three days of hospitalization. All the puppies that died were sent for a full post mortem examination and histopathological evaluation. Statistical analysis of the data showed that there was a definite difference between the puppies that died and those that survived in several of the leukocyte parameters. These parameters included the total leukocyte, lymphocyte, monocyte and eosinophil counts. In none of the puppies that died from the disease did the total leukocyte count rise above 2.0 × 10 9 /l (normal reference range: 6.0-15.0 × 10 9 /l). In the puppies that survived, the total leukocyte count started rising within 24 – 48 hours after admission and often resulted in a rebound leukocytosis. The puppies that died did not develop lymphocytosis to indicate an immune response, whereas the surviving puppies developed lymphocytosis within 24 – 48 hours after admission. The puppies that died also did not develop monocytosis and remained severely eosinopaenic during the course University of Pretoria etd – Goddard, A (2006) xii of the disease. Evidence of impaired leukocyte production was found on histopathology. Most of the puppies that died from the disease showed marked to severe thymic and lymphoid atrophy and marked to severe bone marrow hypocellularity. These results show that a reliable prognosis can be obtained at 24 and 48 hours after admission by evaluation of the leukocytes, specifically the total leukocyte, lymphocyte, monocyte and eosinophil counts. / Dissertation (Master in Veterinary Medicine(Clinical Laboratory Diagnostics))--University of Pretoria, 2006. / Companion Animal Clinical Studies / unrestricted

Phagocytosis of Bacteroides fragilis and Bacteroides thetaiotaomicron by human polymorphonuclear leukocytes (PMNL) was studied using a modified fluorochrome assay. Bacteria were grown overnight, washed and opsonized in normal, human, pooled serum. Preopsonized bacteria, either in suspension or preadhered onto a glass cover slip, were then incubated with PMNL. Afer appropriate incubation, the mixtures were centrifuged onto the cover glasses. The cover glasses were stained with acridine orange, while duplicate cover glasses were also stained with Giemsa solution. The total number and distribution of bacteria and PMNL, as well as morphological changes in PMNL, were observed with the Giemsa stain. The acridine orange stained only ingested bacteria which provided an accurate indication of phagocytosis. Bacteroides cells adhered to a glass surface were phagocytized significantly more efficiently than Bacteroides in suspension.

OBJECTIVE:: To examine peripheral leukocyte Dectin-1 regulation in clinically relevant models of fungal and polymicrobial sepsis. DESIGN:: Prospective animal study. SETTING:: University medical school research laboratory. SUBJECTS:: Age, weight, and sex matched ICR/HSD mice. INTERVENTIONS:: Mice were infected with Candida albicans (1 × 10, intravenously) or were subjected to cecal ligation and puncture to induce polymicrobial sepsis. MEASUREMENTS:: Blood, spleen, and peritoneal exudate were harvested and leukocytes were isolated. Leukocytes were evaluated for membrane-associated Dectin-1 expression and cell phenotype by flow cytometry. MAIN RESULTS:: In C. albicans infection, Dectin-1-positive blood and splenic leukocytes were increased from 23.5% to 58.9% over the course of infection. The increased percentage of Dectin-1-expressing cells was primarily attributable to neutrophilia. However, the amount of Dectin-1 expressed by blood and splenic neutrophils in C. albicans-infected mice was decreased by a range of 49.0% to 53.3%. C. albicans infection also resulted in an infiltration of Dectin-1-positive macrophages and neutrophils into the kidney. In contrast, polymicrobial sepsis decreased blood leukocyte Dectin-1-expressing cells by up to 51.4%. This reduction was due to a decrease in Dectin-1-positive neutrophils in the periphery. However, the percentage of Dectin-1-expressing cells in the peritoneal cavity increased by 774% with cecal ligation and puncture. Treatment of isolated neutrophils with three soluble glucans, mannan, lipopolysaccharide, or a variety of cytokines revealed that glucans, alone or in combination, were the only treatment that resulted in a decrease in Dectin-1-positive neutrophils. CONCLUSIONS:: We conclude that peripheral leukocyte Dectin-1 expression is differentially regulated in fungal vs. polymicrobial sepsis. These data demonstrate that leukocyte Dectin-1 levels are modulated in response to infections of fungal and nonfungal origin.

Acute inflammatory response is caused by the rapid recruitment of leukocytes, mainly neutrophils and monocytes, from blood to the tissue site. Diverse agents, including invading pathogens, injured or dead cells, and other irritants, may stimulate this response. In the ensuing inflammatory response, the recruited leukocytes and their secreted molecules help in eliminating or containing the injurious agents and promoting tissue regeneration. But often this response is imprecise and can lead to bystander tissue damage. Unchecked neutrophil activation is implicated in the pathology of many inflammatory conditions. An in-depth understanding of the pathways regulating this response, therefore, becomes critical in identifying therapeutic targets for these diseases. In this study, we investigate the role of intestinal commensal bacteria in regulating the acute inflammatory response. Furthermore, we examine the mechanism by which Interleukin-1 (IL-1) controls the inflammatory response to sterile agents. Inflammatory responses have been studied in the context of host defense against pathogens. However, we report that the innate immune system needs to be primed by intestinal flora to enable neutrophil recruitment to diverse microbial or sterile inflammatory signals. This priming requires myeloid differentiation primary response gene (88) (MyD88) signaling. In antibiotic-treated mice, which have depleted intestinal flora, we show that neutrophils get released into the blood from the bone marrow, but have a specific defect in migration into the inflammed tissue. This deficiency can be restored by pre-stimulating the mice with a purified MyD88 ligand. Despite having reduced number of infiltrating neutrophils, antibiotic-treated mice make higher levels of pro-inflammatory cytokines in the tissue, after inflammatory challenge. This suggests that antibiotic-treated mice produce some anti-inflammatory molecule(s) that counteract the effect of the pro-inflammatory cytokines. However, this effect is not due to the overproduction of the anti-inflammatory cytokine, Interleukin-10 (IL-10). In summary, our findings highlight the role of commensals in the development of acute inflammatory responses to microbial and sterile particles. The inflammatory response to sterile dead cells has been shown to be critically dependent upon IL-1. However, several key aspects of the IL-1 signaling cascade including the source of IL-1 and the cellular target of IL-1 were unresolved. We find that in most cases, the injured cells are not a major contributor of IL-1 that is required to propagate the inflammatory signal. On the contrary, we demonstrate that both the isoforms of IL-1, IL-1α/IL-1β are generated by bone marrow-derived, tissue-resident responding cells, upon sensing the injury. We also sought to determine the identity of the cellular target of IL-1 signaling. Previous studies have shown that for cell death-induced neutrophil recruitment, interleukin-1 receptor (IL-1R) expression is required on parenchymal cells. To identify this parenchymal cell, we are currently in the process of making the conditional knockout mouse of IL-1R. The latter would facilitate the parenchymal tissue-specific deletion of IL-1R. In summary, this study reports our progress in unraveling key aspects of IL-1 signaling during sterile inflammation. Taken together, we have identified key modulators of the acute inflammatory response and their mechanisms of regulation. These findings would facilitate the development of new therapies for inflammatory diseases triggered by both microbe and sterile agents.

Chronic peritonitis contributes to technique failure in peritoneal dialysis (PD), an effective replacement therapy for chronic kidney failure. Staphylococcus aureus infection is one of the most common causes of peritonitis in PD. Interestingly, mice deficient in the cell surface heparan sulfate proteoglycan, syndecan-1, were reported to clear S. aureus corneal infection more effectively than wild-type mice. The objectives of this study were to examine the protein expression and role of syndecan-1 in leukocyte recruitment, chemokine presentation and S. aureus infection in the microcirculation underlying the parietal peritoneum in wild-type and syndecan-1-/- mice. Immunofluorescence intravital microscopy (IVM) of the parietal peritoneum microcirculation revealed that syndecan-1 was localized to the subendothelial region of venules and the mesothelial layer but does not regulate leukocyte recruitment and is not necessary for presentation of the chemokine MIP-2 in peritoneal venules. IVM was also used to study the effects of a conventional PD solution injected through a peritoneal catheter in a mouse PD model. After 6 weeks of dialysis, the peritoneal catheter implant increased leukocyte rolling and extravasation, fibrosis and angiogenesis in the parietal peritoneum independently from the dialysis solution treatment. Furthermore, the role of syndecan-1 was examined using a 4 week PD model. Four hours after infection with S. aureus through the dialysis catheter or intraperitoneal injection, the dialyzed syndecan-1-/- mice were more susceptible to S. aureus infection than undialyzed syndecan-1-/- controls and wild-type animals. IVM showed that in S. aureus infection, syndecan-1 was removed from the subendothelial surface of peritoneal venules but syndecan-1 deficiency did not affect leukocyte recruitment during S. aureus infection. This study indicates that syndecan-1 in the peritoneum and microcirculation is not a regulator of inflammatory responses but is crucial for providing a barrier to S. aureus infection, which may have important implications for susceptibility to S. aureus infections in PD. / Dissertation / Doctor of Philosophy (Medical Science)

Mycobacterium avium subspecies paratuberculosis (map) is an intracellular pathogen that is known to parasitize macrophages and monocytes. Map infiltrates gastrointestinal tract host tissue where it is the known etiological agent of johne's disease in ruminants and implicated in the etiology of crohn's disease in humans. Map's ability to survive within macrophages enables it to disseminate throughout the rest of the host, possibly infecting other circulating blood leukocytes. In this study, the survival and fate of map strain atcc 43015 (human isolate) following phagocytosis was determined using in vitro murine macrophage cell line j774a.1 and polymorphonuclear cells (pmnc's) from five crohn's disease patients. Pmnc's from three healthy individuals and two ulcerative colitis patients, as well as escherichia coli (atcc 11303) and mycobacterium tuberculosis strain h37ra (atcc 25177), were included as controls (moi 10:1). Maturation of the phagosome was determined by evaluating the presence of stage specific markers on the surface of the phagosomal membrane. The endosomal protein, transferrin receptor, and the lysosomal marker, lamp-1, were then immunostained with cy-5 conjugated secondary antibodies, and colocalization of bacteria with each marker was evaluated separately using confocal scanning laser microscopy (cslm). In both tissue models, colocalization of viable map and m. Tuberculosis with the early endosomal marker, transferrin receptor occurred with an estimated five fold higher frequency than did association with the late lysosomal marker, lamp-1, as compared to live e. Coli, and all dead bacterial species. Using differential live/dead staining and fluorescent microscopy, survival of m. Tuberculosis and map was estimated at 85% and 79%, respectively compared to only 14% for e. Coli. The outcome was similar for both tissue culture and pmncs from all patients tested, suggesting that map and m. Tuberculosis can survive readily in both cell types, and regardless of the disease state of the host or the killing power of the cell. Map's survival appears to mimic m. Tuberculosis', suggesting the ability to resist phagolysosome fusion, by maintaining association with the early endosomes. Overall, the data confirms map virulence in host human blood leukocytes.

The ability to objectively index dopamine (DA) levels in the brain has the potential to revolutionize the field of neuropsychopharmacology, as having a peripheral biomarker of brain DA would enable the objective monitoring of the progression of Parkinson's disease (PD) and other DA-dependent psychiatric states. Of particular relevance to commercialization, it would provide an objective measure of treatment efficacy. We used a DA-depletion approach to determine if peripheral D2Rs are a biomarker for brain DA; mainly, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and PD subjects, which are well-known models of DA depletion in the midbrain of rodents and humans, respectively. Dopamine depletion in the substantia nigra resulted a significant change to DA and norepinephrine (NE) levels in the plasma. Interestingly, these changes could be tracked as a time course from baseline to 15 days after injection with MPTP. Also, the proportion of D2R expressing leukocytes steadily increased (specifically B cells and T cells) during this same time of DA depletion. These results suggest that changes to the dopamine neuron population in the substantia nigra can be tracked with DA and NE level changes and D2R expression on B and T cells, providing a possible biomarker for nigral DA neuron loss to further investigate. In two cohorts of studies comparing subjects with PD vs controls, we found that Parkinson's subjects displayed significantly decreased D2R expression in all populations except for (natural killer) NK cells, CD16+ monocytes, and cytotoxic T cells. We also found that subjects with PD show increased levels in epinephrine (EPI) and DA as compared to control subjects. We did not, however, find any statistically significant correlations between the recorded leukocytic D2R downregulation in PD patients and their elevated DA and EPI plasma levels. Therefore, the results of this study did not provide a clear indication how brain DA levels are being represented in the periphery. Regardless, the modulation of peripheral D2Rs in PD and MPTP seen in this study do show that substantia nigra DA depletion in humans and rodents do manifest in the periphery. Although our study didn't result in a clear narrative of how nigral and peripheral DA system mirror each other, our result provide more evidence D2Rs may be both biomarkers and important substrates for treatment of DA-dependent disorders. Our results give a foundation from which future studies can investigate this connection further.