Prior exposure to a behaviorally sensitizing regimen of d-methamphetamine does not alter the striatal dopaminergic damage induced by a neurotoxic regimen.
Miller-DB; O'Callaghan-JP; Johnson-EA
Addiction Biol 2000 Jul; 5(3):361-367
Repeated exposure to psychostimulant drugs such as d-methamphetamine (d-METH) and cocaine can be associated with extremely long-lived changes in dopamine systems at the behavioral, cellular and molecular level. Sensitization or an enhanced response to drug exposure is one such change. Investigations of these phenomena at the cellular and molecular levels are being conducted in the hope that this will aid in understanding how such adaptations might contribute to drug addition. Repeated exposure to certain amphetamines can also result in damage to dopaminergic pathways. Although some of the same molecular adaptations and mechanisms are suspected to occur or play a role in the neurotoxic sequelae associated with psychostimulant exposure, there has been little attempt to examine the relationship among these phenomena. Here we utilized C57BL/6J female mice to examine whether exposure to a sensitizing regimen of d-METH would impact the degree of neural injury induced by a subsequent exposure to a neurotoxic regimen of the same psychostimulant. Every other day exposure to d-METH (1.0 or 2.0 mg/kg) for 11 days produced a behavioral sensitization, as evidenced by a significant increase in the degree of locomotor activity induced by each subsequent exposure to d-METH. Following a 5-day period of no drug exposure sensitized mice were given a neurotoxic regiment of d-METH (a total of four injections of 10.0 mg/kg, one every 2 hours) and striatal tissue examined 72 hours later. All groups, whether drug-naive or sensitized previously to d-METH, showed exactly the same degree of dopaminergic striatal damage induced by a neurotoxic regimen. This was evidenced by equivalent reductions in dopamine and elevations in GFAP protein, a marker of astrocytic response to injury, GFAP . The inability of a sensitizing regimen to either exacerbate or lessen the neurotoxic actions of the same compound suggests that the molecular and cellular control of these two aspects of psychostimulant exposure may differ.
Neurotoxins; Neurotoxicology; Neurotoxicity; Neurotoxic-effects; Behavioral-disorders; Drug-abuse; Sensitization; Exposure-assessment
Diane B. Miller PhD, Chronic Stress and Neurotoxicology Laboratory, Toxicology and Molecular Biology Branch, CDC/NIOSH-HELD, 1095 Willowdale Road, Morgantown, WV 26505, USA