Nicotine, Methamphetamine‐Induced Dopaminergic Deficits, and the Impact on α4β2 and α6β2 Nicotinic Receptors

Abstract

Methamphetamine (METH) abuse can cause persistent dopaminergic deficits that likely contribute to an increased risk for developing Parkinson's disease. Most METH abusers begin smoking cigarettes in adolescence, and thus are exposed to nicotine (NIC) prior to METH exposure. Our preclinical studies demonstrate that NIC exposure via drinking water beginning at post-natal day (PND) 40 through PND 96 (i.e., from adolescence through adulthood) attenuates the persistent dopaminergic deficits and alterations in α4β2 and α6β2 nicotinic receptors (nAChR) expression, consequent to a high-dose METH exposure. Current studies aimed to investigate whether NIC neuroprotection remains when NIC is removed 2 h or 24 h prior to METH or if the presence of NIC during and after METH is necessary for neuroprotection. Results revealed that oral NIC exposure from PND 40 – 88/89 attenuated METH-induced decreases in striatal dopamine transporter (DAT) expression/function and α4β2 nAChR expression, as assessed in rats that received a high-dose METH treatment on PND 89 and were evaluated at PND 96. NIC pre-treatment did not attenuate the persistent METH-induced deficits in α6β2 nAChR expression. However, NIC per se downregulated α6β2 nAChR suggesting that the reduction in α6β2 nAChR in METH-treated rats reflects a downregulation caused by NIC as opposed to lack of neuroprotection to these receptors. In summary, these data suggest that NIC pre-treatment protects against METH-induced dopaminergic deficits, particularly those involving α4β2-expressing dopaminergic terminals.