Infection of immunodeficient horses with Sarcocystis neurona does not result in neurologic disease.

Equine protozoal myeloencephalitis is a progressive neurologic disease of horses most commonly caused by infection with the apicomplexan parasite Sarcocystis neurona. Factors affecting neuroinvasion and neurovirulence have not been determined. We investigated the pathogenesis of infection with S. neurona in horses with severe combined immune deficiency (SCID). Two immunocompetent (IC) Arabian horses and two Arabian horses with SCID were infected orally with 5 x 10(5) sporocysts of S. neurona. Four IC horses and one SCID horse were infected intravenously (i.v.) with 5 x 10(8) merozoites of the WSU-1 isolate of S. neurona. Despite prolonged parasitemia and persistent infection of visceral tissues (skeletal muscle, cardiac muscle, lung, liver, and spleen) as demonstrated by PCR and culture, SCID horses did not develop neurologic signs after oral or i.v. infection. S. neurona was undetectable in the neuronal tissues of SCID horses by either PCR, immunohistochemistry, or culture. In contrast, although parasitemia was undetectable in orally infected IC horses and of only short duration in i.v. infected IC horses, four of six IC horses developed neurologic signs. S. neurona was detectable by PCR and/or culture of neural tissue but not visceral tissue of IC horses with neurologic disease. Infected SCID horses are unable to clear S. neurona from visceral tissues, but the infection does not result in neurologic signs; in contrast, IC horses rapidly control parasitemia and infection of visceral tissues but frequently experience neuroinvasion and exhibit clinical signs of neurologic disease.

Depletion of natural killer cells does not result in neurologic disease due to Sarcocystis neurona in mice with severe combined immunodeficiency.

Sarcocystis neurona is an apicomplexan parasite that is the primary etiologic agent of equine protozoal myeloencephalitis in horses. Protective immune responses in horses have not been determined, but interferon-gamma (IFN-gamma) is considered critical for protection from neurologic disease in mice. The role of adaptive and innate immune responses in control of parasites was explored by infecting BALB/c, IFN-gamma knockout (GKO), and severe combined immune deficient (SCID) mice with S. neurona (10(4) sporocysts/mouse). Immune competent BALB/c mice eliminated parasites within 30 days, with no sign of neurologic disease, whereas GKO mice developed fulminant neurologic disease. In contrast, SCID mice remained healthy throughout the experimental period despite the persistence of parasite at low levels in some mice. Treatment with anti-IFN-gamma antibody resulted in neurologic disease in infected SCID mice. Although SCID mice lack adaptive immune responses, they have natural killer (NK) cells capable of producing significant quantities of IFN-gamma. Therefore, SCID mice were infected with sporocysts of S. neurona and treated with anti-asialo GM1. Depletion of NK cells, confirmed by flow cytometry, did not result in neurologic disease in SCID mice. These results indicate that IFN-gamma mediates protection from neurologic disease in SCID mice. Protective levels of IFN-gamma may originate from a low number of nondepleted NK cells or from a non-T cell, non-NK cell population.

Repeated cocaine decreases the avoidance response to a novel aversive stimulus in rats.

RATIONALE: Stress interacts with cocaine to produce enhanced neurochemical and behavioral responding to cocaine; however, few studies have examined unconditioned behavioral responses to aversive stimuli after repeated cocaine. OBJECTIVES. Studies were conducted to measure the approach/avoidance response to an aversive stimulus after repeated cocaine treatment in male and female rats. METHODS: An unconditioned approach/avoidance task was used in which rats were placed into a box with a novel, aversive stimulus (formaldehyde; Form), and place aversion was assessed. RESULTS: Initial studies established a dose-response curve using different concentrations of Form, and also determined that avoidance of Form was abolished by pretreatment with an anxiolytic dose of chlordiazepoxide. To examine the effects of prior cocaine treatment, intact or gonadectomized male and female rats were pretreated with daily saline or cocaine (15 mg/kg, IPx5 days), and their approach/avoidance response to Form was tested 4-7 days later. In intact males, cocaine decreased the avoidance of Form, and previous gonadectomy completely abolished this response. Decreased avoidance behavior did not appear to be linked to behavioral sensitization to cocaine, since gonadectomized males demonstrated locomotor sensitization when given subsequent cocaine challenge. In females, avoidance of Form was not altered by either cocaine or gonadectomy. Three experiments further characterized the approach/avoidance response to Form in males. In the first experiment, daily footshock stress did not significantly alter the avoidance of Form. In a second study, rats that displayed high and low locomotor responses to a novel cage showed no differences between groups in their avoidance of Form. In the third experiment, intra-nucleus accumbens microinjection of fluphenazine (5 micro g/side) attenuated the daily cocaine-induced decrease in avoidance of Form. CONCLUSIONS: These studies demonstrate that gonadal hormones may mediate cocaine-induced alterations in approach/avoidance to an aversive stimulus in males, and suggest that testosterone may act centrally to modulate dopamine responsiveness in the nucleus accumbens.