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 repor ted to decrease macrophage activity. The present experiment was undertaken to investigate the effects of AMPH and/or diazepam given alone or in combin ation on hamster resistance to Mycobacterium bovis. The effects of these tr eatments on serum cortisol levels were also studied. Adult hamsters were tr eated i.p. with AMPH (group E-1 = 1.0 or 2.0 mg/kg/day), with AMPH (group E -2 = 1.0 Or 2.0 mg/kg/day) plus diazepam (2.0 mg/kg/day), with diazepam (gr oup E-3 = 2.0 mg/kg/day), or with control vehicles (1.0 ml/kg/day) for 40 d ays. Six days after the beginning of the treatments, the animals received i dentical inoculum concentrations of M. bovis. Hamsters treated with AMPH pl us diazepam exhibited: 1) increased weight loss; 2) increased mortality; 3) increased scores of M. bovis colony forming units (CFU) isolated from live r, lung and spleen; 4) increased granuloma areas measured in the liver, lun g 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 alon e or in combination for 20 days increased the serum levels of cortisol in r elation to control hamsters, with the effect being higher in the animals tr eated with both drugs. The present data, which demonstrate an impaired defe nse against M. bovis in hamsters treated with AMPH plus diazepam or with di azepam alone, were tentatively explained on the basis of a direct and/or in direct action of the drugs on macrophage/lymphocyte activity. In the former case, the effects may be related to stimulation of peripheral benzodiazepi ne receptor sites (PBR) present on macrophages/lymphocytes and/or to a dire ct effect of ACTH on immune cells, while in the latter they may be mediated by cortisol via PER and ACTH stimulation of the adrenals.