In vitro, acute treatment of mouse striatal neurons with nicotine has different effects on PKA activity depending on the nicotine dose. Acute, low doses of nicotine decrease PKA-mediated DARPP-32 phosphorylation, primarily by activating dopamine D2 receptors.84 High doses of nicotine increase PKA-mediated DARPP-32 phosphorylation, mainly by activating D1 receptors.84 In rats treated with nicotine for 14 days, PKA activity is decreased in whole brain homogenates,85 suggesting that chronic nicotine exposure decreases PKA activity in the brain. However, postmortem studies have shown that smokers and former smokers have higher PKA activity and PKA catalytic subunit protein levels in the NAc and ventral midbrain than do nonsmokers.86 These results indicate that prolonged smoking in humans, similar to chronic cocaine treatment in monkeys,83 may upregulate PKA activity in some brain regions that are important for addiction.
