Date Published: January 7, 2010
Publisher: Public Library of Science
Author(s): Lei Phillip Wang, Fei Li, Xiaoming Shen, Joe Z. Tsien, Warren H. Meck. http://doi.org/10.1371/journal.pone.0008616
Abstract: Nicotine from smoking tobacco produces one of the most common forms of addictive behavior and has major societal and health consequences. It is known that nicotine triggers tobacco addiction by activating nicotine acetylcholine receptors (nAChRs) in the midbrain dopaminergic reward system, primarily via the ventral tegmental area. Heterogeneity of cell populations in the region has made it difficult for pharmacology-based analyses to precisely assess the functional significance of glutamatergic inputs to dopamine neurons in nicotine addiction. By generating dopamine neuron-specific NR1 knockout mice using cre/loxP-mediated method, we demonstrate that genetic inactivation of the NMDA receptors in ventral tegmental area dopamine neurons selectively prevents nicotine-conditioned place preference. Interestingly, the mutant mice exhibit normal performances in the conditioned place aversion induced by aversive air puffs. Therefore, this selective effect on addictive drug-induced reinforcement behavior suggests that NMDA receptors in the dopamine neurons are critical for the development of nicotine addiction.
Partial Text: Nicotine from smoking tobacco produces one of the most common forms of addictive behavior. It is well established that systemic nicotine stimulates nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA), consequently enhancing the phasic firing of VTA dopamine neurons and the release of dopamine to targets including the nucleus accumbens. At a concentration close to those experienced by a cigarette smoker nicotine can modulate DA neuron firing by acting on both postsynaptic and presynaptic neuronal nAChRs. Activation of the postsynaptic nAChRs which locate on the DA neurons and are mainly β2 subunits containing,  depolarizes the DA neurons and in the mean time quickly leads to desensitization of the activated nAChRs. The presynaptic nAChRs which locate on the excitatory glutamatergic terminals that project onto the DA neurons and are mainly α7 subunits containing and highly permeable to calcium. Activation of the presynaptic α7 containing nAChRs increases calcium in glutamatergic presynaptic terminals and facilitates glutamate release and subsequent synaptic excitation of DA neurons. This presynaptic mechanism, when paired with post-synaptic depolarization, can induce long-term potentiation (LTP)  which greatly outlasts the activation of nAChRs. Similar to that seen in hippocampal Schaffer collateral pathway, induction of this LTP depends on functional NMDA receptors. Recruiting changes in a long-lasting glutamatergic signaling has been postulated to be crucial for explaining the time scale discrepancy between fast desensitization (within a few seconds) of nAChR after nicotine binding and the often observed long-lasting (more than hours) reward/reinforcement effects of nicotine on addictive behavior. Additionally, injection of NMDA receptor antagonists into the VTA blocks nicotine-induced burst firing of VTA dopamine neurons as well as prolonged dopamine release in the nucleus accumbens .
Using conditioned place preference as the behavioral readout, we studied nicotine induced associate learning in a genetically modified mouse model where NMDA receptor function is selectively blocked in the dompaminergic neurons. Comparing with their littermates, the mutant DA-NR1-KO mice, displayed clear deficits in developing nicotine conditioned place preference. In contrast, these mutant mice displayed normal learning and memory in air puff induced place aversion, a paradigm that shares some similar contextual memory components but differs in the nature of enforcement. These results therefore suggest that lack of nicotine mediated conditioning is likely due to reward-reinforcement components than context associative memory process. Because of the nature of the genetic lesion, a DA neuron selective deletion of NMDAR1, our data strongly suggest NMDAR1 mediated signals in DA neuron be an essential element for developing nicotine induced associative learning.