Role of NMDA Receptors in Dopamine Neurons for Plasticity and Addictive Behaviors

Abstract

Summary A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.

Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior

“…A unifying interpretation of these results is that bursts of DA neuron activity in response to important events provide generalized salience signals that facilitate learning associations of environmental cues with these events, whereas increased tonic DA, such as those measured by microdialysis, is independent of burst firing, and provides sufficient DA to engage most behaviors. Lack of NMDARs in DA neurons not only impairs burst firing, but also precludes LTP of synaptic AMPARs (21,22). AMPAR currents are transiently potentiated in DA neurons after exposure to cocaine, stress, or during learning paradigms (21,22,(45)(46)(47).…”

“…To assess whether disruption of phasic DA leads to generalized behavioral impairment, we performed an extensive analysis of DAdependent behaviors (summarized in Table 1). Lack of NMDAR in DA neurons does not affect 24-hour locomotor activity during light or dark phase, the locomotor response in a novel environment, or acute responses to cocaine, amphetamine, morphine, or D1R agonists (22). Because DA neurons are directly and indirectly modulated by hormones that regulate feeding behavior (31), we monitored daily ad libitum food consumption and the latency of calorie-restricted (85% body weight) control and KO mice to eat freely available food pellets.…”

“…Genetic inactivation of the essential NR1 subunit (Grin1) of the NMDAR selectively in neurons expressing the dopamine transporter gene (Slc6a3) is sufficient to inactivate NMDAR currents in these cells (21,22). To determine whether burst firing depends on functional NMDAR signaling, we monitored DA neuron activity in freely moving control (Slc6a3 ϩ/Cre ;Grin1 ϩ/lox ) and knockout (KO, Slc6a3 ϩ/Cre ;Grin1 ⌬/lox ) mice, chronically implanted with recording electrodes in the ventral tegmental area/substantia nigra pars compacta.…”

“…Drug seeking behavior, as monitored by acquisition of cocaine CPP, is impaired in these KO mice during the first 3 days of training (22), but an association can eventually be formed after 8 context-reward presentations (21). To assess whether phasic DA facilitates reinforcement learning for natural rewards, we monitored the acquisition of food CPP.…”

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

“…Cocaine enhances DA neurotransmission by inhibiting transporters that remove DA from the extracellular space, allowing levels of DA to rise in downstream targets of DA neurons (Di Chiara and Imperato, 1988). Elevated DA signaling triggered by cocaine is implicated in behavioral effects, including locomotor stimulation and sensitization, and conditioned place preference (CPP; Pierce and Kalivas, 1997;Zweifel et al, 2008).…”