Methamphetamine preconditioning responses to methamphetamine-induced injury in the rat ventral midbrain

Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Following habituation, rats were injected intraperitoneally with either (+-)-METH-hydrochloride (NIDA, Baltimore, MD) or an equivalent volume of 0.9% saline for a period of three weeks as described in Table S1 in supplemental data. The saline- or METH-pretreated animals received either saline or METH (5 mg/kg x 8 at 1 h intervals) challenges 72 hours after the preconditioning period. Similar doses of METH are known to cause significant decreases in the levels of monoamines in the rat striatum (Graham et al., J. Neurochem. 2008; 105:1873-1885, Cadet et al, Neurotox. Res. 2009; 15:252-259) which received dopaminergic terminals from midbrain dopaminergic cell bodies located in the substantia nigra (SN) and ventral tegmental area (VTA) (Lindvall and Björklund, Biochem Psychopharmacol 1978; 19:1-23, Domesick, Ann N Y Acad Sci. 1988; 537:10-26). Thus, the four groups of animals were: saline/saline (SS), saline/METH (SM), METH/saline (MS), and METH/METH (MM). The various groups were compared to the saline control group (SS group).