Methamphetamine preconditioning: differential protective effects on monoaminergic systems in the rat brain

Abstract

Pretreatment with methamphetamine (METH) can attenuate toxicity due to acute METH challenges. The majority of previous reports have focused mainly on the effects of the drug on the striatal dopaminergic system. In the present study, we used a regimen that involves gradual increases in METH administration to rats in order to mimic progressively larger doses of the drug used by some human METH addicts. We found that this METH preconditioning was associated with complete protection against dopamine depletion caused by a METH challenge (5 mg/kg x 6 injections given 1 h apart) in the striatum and cortex. In contrast, there was no preconditioning-mediated protection against METH-induced serotonin depletion in the striatum and hippocampus, with some protection being observed in the cortex. There was also no protection against METH-induced norepinephrine (NE) depletion in the hippocampus. These results indicate that, in contrast to the present dogmas, there might be differences in the mechanisms involved in METH toxicity on monoaminergic systems in the rodent brain. Thus, chronic injections of METH might activate programs that protect against dopamine toxicity without influencing drug-induced pathological changes in serotoninergic systems. Further studies will need to evaluate the cellular and molecular bases for these differential responses.

Figure 1

Effects of METH pretreatment and challenge on markers of striatal DA (A) and 5-HT (B) terminals. Values were normalized to SAL/SAL controls and expressed as percentages of controls ± SEM. N = 8–10 animals per group. Key to statistics: * p <0.05 in comparison to SAL/SAL group, # p <0.05 in comparison to SAL/METH group.

Figure 2

Levels of DA, DOPAC and HVA (A) and of 5-HT and 5-HIAA (B) in the nucleus accumbens following METH pretreatment and challenge. Values were normalized to SAL/SAL controls and expressed as percentages of controls ± SEM. N = 8–10 animals per group. Key to statistics: * p <0.05 in comparison to SAL/SAL group.

Figure 3

Effects of METH pretreatment and challenge on markers of cortical DA (A) and 5-HT (B) terminals. Values were normalized to SAL/SAL controls and expressed as percentages of controls ± SEM. N = 8–10 animals per group. Key to statistics: * p <0.05 in comparison to SAL/SAL group, # p <0.05 in comparison to SAL/METH group.

Figure 4

Levels of NE, 5-HT, 5-HIAA in the hippocampus following METH pretreatment and challenge. Values were normalized to SAL/SAL controls and expressed as percentages of controls ± SEM. N = 8–10 animals per group. Key to statistics: ** p <0.01, *** p<0.001 in comparison to SAL/SAL group.