A role for nicotine in neuroprotection against disorders associated with monoaminergic and cognitive dysfunction

The aim of this dissertation was to investigate potential mechanisms whereby nicotine (NIC) is neuroprotective to the dopamine (DA), serotonin (5- HT), and memory systems. As early as 1939, clinical studies have indicated that tremors, or Parkinson's disease (PD), are less likely to occur among tobacco smokers. More recent epidemiological studies have found an inverse correlation between tobacco smoking and PD risk. PD is the second most common neurodegenerative disorder characterized by death of DA and 5-HT neurons in the nigrostriatal pathway and is associated with motor and memory dysfunction. Extensive preclinical studies have since demonstrated that NIC is neuroprotective in models of PD. The mechanism by which NIC is neuroprotective is of particular interest in the field of neurodegeneration to understand disease risk and to develop better prevention and treatment strategies. Noteworthy, the abuse of methamphetamine (METH), a potent psychostimulant, causes long-term neurotoxic effects resembling some aspects of PD, including deficits to the DA, 5-HT and memory systems. The data presented in this dissertation indicate that long-term (56 d) oral NIC administration to rats starting in adolescence attenuates both the dopaminergic and memory deficits, but not the serotonergic deficits, caused by a high-dose METH regimen. The dopamine transporter (DAT) function and density in the iv striatum and nucleus accumbens core were used as markers of dopaminergic integrity, and the novel object recognition (NOR) test was used as marker of memory function. NIC is also neuroprotective when given short-term (21 d) beginning in adolescence, but not when it is initiated during adulthood. However, neuroprotection occurs when the duration of NIC administration is extended to 39 d beginning in adulthood. NIC pretreatment alone is sufficient for neuroprotection against METH-induced DAT deficits as well as NOR deficits. Furthermore, NIC ameliorates the NOR deficits caused by METH when given as posttreatment, suggesting that NIC has cognitive protection and cognitive enhancement properties. Lastly, the densities of α4β2 and α6β2 nicotinic acetylcholine receptors are upregulated and downregulated, respectively, after administration of NIC in combination with METH. These data suggest an involvement of these receptors in neuroprotection against METH-induced dopaminergic and memory deficits.