Repeated
methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of
Parkinson's disease. Many METH abusers
smoke cigarettes and thus self-administer
nicotine; yet few studies have investigated the effects of
nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that
nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2
nicotinic acetylcholine receptors (nAChRs). This study revealed that oral
nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to
nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose
nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose
nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of
nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that
nicotine increased striatal α4β2 expression, as assessed using [(125)I]
epibatidine. Both METH and
nicotine decreased striatal α6β2 expression, as assessed using [(125)I]α-
conotoxin MII. These findings indicate that
nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of
nicotine exposure affect this protection.