We assessed the role of NMDAR on striatal neurons in cue reactivity, an element of cocaine addiction, in the place conditioning paradigm. Our results show that mice deficient in NMDAR on striatal neurons failed to show cocaine CPP.
In the conditional KO mice, the excision of NMDAR was restricted by RGS9-dependent Cre expression (13
). RGS9 mRNA is expressed in striatal cholinergic interneurons, the striatal indirect pathway projecting to the external segment of the pallidum, and the striatal direct pathway to the internal segment of the pallidum and the midbrain (14
). RGS9-depenedent Cre expression reduced the amount of NMDAR produced in cell bodies of striatal neurons and expressed in their dendrites and terminals (13
). By contrast, NMDAR expressed on terminals of corticostriatal projection neurons and striatal glial cells were not significantly affected (13
). Thus, the effects of NMDAR deletion on behavior in our conditional mouse model is potentially attributable to NMDAR expressed on terminals of striatal neurons in the globus pallidus/ventral pallidum and the midbrain, as well as the dendrites and cell bodies of striatal neurons within the striatum.
Although RGS9 is highly enriched in striatal neurons, low levels of RGS9 exist elsewhere (17
). It is possible that NMDAR may be reduced in neurons other than striatal neurons. However, in our conditional NMDAR KO mouse, RGS9-cre activity is confined to striatal neurons and is not found in the cortex, cerebellum or midbrain (13
). NMDAR reduction outside the striatum is likely to be minimal. Our mouse model complements other conditional NMDAR deletion mouse lines whose NMDAR levels are reduced in dopaminergic neurons (8
The place conditioning paradigm does not simply evaluate the rewarding effects of addictive substances. Rather, the CPP evaluates the detection of sensory cues and the approach-inducing, incentive effects of cocaine. The CPP also examines the acquisition of an association between the representations of the two events, the retrieval and expression of such an association, and the expression of an approach behavior. A defect in any of these processes would disrupt a CPP.
The general ability to detect sensory stimuli and guide behavior through classical conditioning does not seem to be impaired in conditional NMDAR KO mice. Passive avoidance is normal in these mice (13
). Moreover, the motor ability to express a conditioned behavior is apparently normal, since conditional KO mice exhibit normal motor activity in an open field (13
). Although our experiment was not designed to identify the exact process through which a basal NMDAR tone influences CPP, indirect evidence suggests that NMDAR might be required for some acquisition, but not for expression processes. When infused into the accumbens, a subregion of the striatum, during acquisition, the NMDAR antagonist AP-5 prevents the establishment of conditioned approach to cues associated with food. However, AP-5 did not impair expression of the once-acquired approach behavior (19
). Thus, a basal, constitutive NMDAR tone is likely to alter the susceptibility to cocaine cue reactivity through its impact on the incentive effects of cocaine, their association with sensory cues, or both.
Within the striatum, NMDAR levels in the nucleus accumbens are likely to be a determinant of cocaine CPP. In this subregion of the striatum, repeated cocaine injections cause alterations in NMDAR-dependent long-term depression (LTD) in mice (20
). Consistent with this finding, our conditional KO mice show impairments in LTD in the nucleus accumbens (13
). It is unclear whether reduced LTD in the nucleus accumbens plays a functional role in cocaine CPP. Therefore, a future challenge is to determine a causal association between altered synaptic plasticity in the accumbens and elements of cocaine addiction.
Pre-existing traits accentuate or reduce susceptibility to addiction (5
). The capacity to form cue reactivity may be associated with pre-existing traits. Basal, constitutive NMDAR tone may contribute to addiction susceptibility through its effects on cue reactivity. Our conditional KO mouse provides a novel means to explore the role of striatal NMDAR in this aspect of addiction to other substances.