Effects of treatment with amphetamine and diazepam on Mycobacterium bovis-induced infection in hamsters

Tuberculosis is an example of an infection with an intracellular bacterium in which sensitivity is determined mainly by the host response. Macrophages are the architectural and functional units of the granulomas described in tuberculosis. Treatment with amphetamine (AMPH) and diazepam has been reported to decrease macrophage activity. The present experiment was undertaken to investigate the effects of AMPH and/or diazepam given alone or in combination on hamster resistance to Mycobacterium bovis. The effects of these treatments on serum cortisol levels were also studied. Adult hamsters were treated i.p. with AMPH (group E1 = 1.0 or 2.0 mg/kg/day), with AMPH (group E2 = 1.0 or 2.0 mg/kg/day) plus diazepam (2.0 mg/kg/day), with diazepam (group E3 = 2.0 mg/kg/day), or with control vehicles (1.0 ml/kg/day) for 40 days. Six days after the beginning of the treatments, the animals received identical inoculum concentrations of M. bovis. Hamsters treated with AMPH plus diazepam exhibited: 1) increased weight loss; 2) increased mortality; 3) increased scores of M. bovis colony forming units (CFU) isolated from liver, lung and spleen; 4) increased granuloma areas measured in the liver, lung and spleen. These effects were not induced by AMPH (1.0 or 2.0 mg/kg/day) given alone and were produced by diazepam (2.0 mg/kg/day) treatment per se. Furthermore, AMPH (2.0 mg/kg/day) and diazepam (2.0 mg/kg/day) given alone or in combination for 20 days increased the serum levels of cortisol in relation to control hamsters, with the effect being higher in the animals treated with both drugs. The present data, which demonstrate an impaired defense against M. bovis in hamsters treated with AMPH plus diazepam or with diazepam alone, were tentatively explained on the basis of a direct and/or indirect action of the drugs on macrophage/lymphocyte activity. In the former case, the effects may be related to stimulation of peripheral benzodiazepine receptor sites (PBR) present on macrophages/lymphocytes and/or to a direct effect of ACTH on immune cells, while in the latter they may be mediated by cortisol via PBR and ACTH stimulation of the adrenals.