Drugs of abuse, such as the psychostimulant methamphetamine (METH), are frequently used by the population at risk for HIV infection. Studies in experimental animals indicates that METH has the potential to produce selective toxic effects on dopaminergic and serotoninergic neurons in the CNS. The mechanisms of METH-induced damage remains the subject of active investigation. The effects of energy metabolism, endogenous neurotransmitters, temperature, and free radical-induced toxicity have all been proposed to be important in the mechanisms mediating the effects of METH. Many of these mechanisms and sites of damage converge with those in HIV- induced CNS damage. Interactions of METH and HIV, which both affect an increasing population, is unknown. Using SIV-infected rhesus monkeys we have been able to derive a neurovirulent strain of virus that can induce both histopathological and functional abnormalities in the CNS. Nonhuman primates are also appropriate models for the effects of METH on the CNS of humans. Here we propose to examine the interactions of SIV and METH in CNS infection and injury. Our working hypothesis is that the CNS is infected by virus early after SIV inoculation, and can be continuously infected by circulating SIV or SIV-infected cells. The toxicity to the CNS is related to the number and activation state of the brain microglia and macrophages, both of which increase following CNS virus infection. METH may increase this toxicity by a number of nonexclusive mechanisms; specifically we will examine the possibility that functional measures of physiology (temperature and movement), neuronal circuitry (evoked potentials), behavior (bimanual motor skills), viral load (quantitative SIV RNA analysis), histopathological indicators (macrophage and lymphocyte infiltration) are altered by the interaction of METH and SIV.
| Persidsky, Yuri; Fox, Howard (2007) Battle of animal models. J Neuroimmune Pharmacol 2:171-7 |
| Madden, Lisa J; Flynn, Claudia T; Zandonatti, Michelle A et al. (2005) Modeling human methamphetamine exposure in nonhuman primates: chronic dosing in the rhesus macaque leads to behavioral and physiological abnormalities. Neuropsychopharmacology 30:350-9 |
