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The striatum can be divided into the DLS (dorsolateral striatum) and the VMS (ventromedial striatum), which includes NAcC (nucleus accumbens core) and NAcS (nucleus accumbens shell). Here, we examined differences in electrophysiological properties of MSSNs (medium-sized spiny neurons) based on their location, expression of DA (dopamine) D1/D2 receptors and responses to the μ-opioid receptor agonist, DAMGO {[D-Ala2-MePhe4-Gly(ol)5]enkephalin}. The main differences in morphological and biophysical membrane properties occurred among striatal sub-regions. MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances) compared with cells in the VMS. RMPs (resting membrane potentials) were similar among regions except for D2 cells in the NAcC, which displayed a significantly more depolarized RMP. In contrast, differences in frequency of spontaneous excitatory synaptic inputs were more prominent between cell types, with D2 cells receiving significantly more excitatory inputs than D1 cells, particularly in the VMS. Inhibitory inputs were not different between D1 and D2 cells. However, MSSNs in the VMS received more inhibitory inputs than those in the DLS. Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount. DAMGO also increased cellular excitability in the VMS, as shown by reduced threshold for evoking APs (action potentials). Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.

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Environmental enrichment (EE) has long been postulated as a behavioral treatment for drug addiction based on its preventive effects in animal models: rodents experiencing prior EE exhibit increased resistance to establishing drug taking and seeking. However, the therapeutic effects of EE, namely, the effects of EE when applied after drug exposure, are often marginal and transient. Using incubation of cue-induced cocaine craving, a rat relapse model depicting progressive intensification of cocaine seeking after withdrawal from cocaine self-administration, our present study reveals that after cocaine withdrawal, in vivo circuit-specific long-term depression (LTD) unmasks the therapeutic power of EE to achieve long-lasting anti-relapse effects. Specifically, our previous results show that cocaine self-administration generates AMPA receptor (AMPAR)-silent excitatory synapses within the basolateral amygdala (BLA) to nucleus accumbens (NAc) projection, and maturation of these silent synapses via recruiting calcium-permeable (CP) AMPARs contributes to incubation of cocaine craving. Here, we show that after cocaine withdrawal and maturation of silent synapses, the BLA-to-NAc projection became highly resistant to EE. However, optogenetic LTD applied to this projection in vivo transiently re-silenced these silent synapses by removing CP-AMPARs. During this transient window, application of EE resulted in the insertion of nonCPAMPARs, thereby remodeling the "incubated" BLA-to-NAc projection. Consequently, incubation of cocaine craving was decreased persistently. These results reveal a mechanistic basis through which the persistent anti-relapse effects of EE can be unleashed after drug withdrawal.nvironmental enrichment (EE) promotes neurocircuit development and improves brain recovery from disease conditions and has long been hypothesized as a behavioral therapy for drug addiction (1-4). Whereas animal studies demonstrate clear preventive effects of EE [i.e., animals experiencing prior EE exhibit increased resistance to establishing drug taking and seeking (5-7)], the therapeutic effects of EE, namely, the effects of EE when applied after drug exposure, are less consistent. For example, in the incubation of cue-induced cocaine-craving model in rats, where cocaine seeking progressively intensifies during prolonged withdrawal from cocaine self-administration (8, 9), EE applied after cocaine self-administration only marginally reduces incubation of cocaine craving, and any anti-incubation effect observed disappears upon termination of EE treatment (10-13). These results raise both opportunities and challenges for EE-based treatment of drug addiction.Incubation of cocaine craving is partially mediated by synaptic accumulation of calcium permeable (CP) AMPA receptors (AMPARs) in the nucleus accumbens (NAc) (14,15). A portion of these CP-AMPARs move into cocaine-generated silent excitatory synapses within the projection from the basolateral amygdala (BLA) pyramidal neurons to NAc medium spiny neurons (MSNs) (16), a critical proje...