Morphine Differentially Alters the Synaptic and Intrinsic Properties of D1R- and D2R-Expressing Medium Spiny Neurons in the Nucleus Accumbens

Abstract

Exposure to opioids reshapes future reward and motivated behaviors partially by altering the functional output of medium spiny neurons (MSNs) in the nucleus accumbens shell. Here, we investigated how morphine, a highly addictive opioid, alters synaptic transmission and intrinsic excitability on dopamine D1-receptor (D1R) expressing and dopamine D2-receptor (D2R) expressing MSNs, the two main output neurons in the nucleus accumbens shell. Using whole-cell electrophysiology recordings, we show, that 24 h abstinence following repeated non-contingent administration of morphine (10 mg/kg, i.p.) in mice reduces the miniature excitatory postsynaptic current (mEPSC) frequency and miniature inhibitory postsynaptic current (mIPSC) frequency on D2R-MSNs, with concomitant increases in D2R-MSN intrinsic membrane excitability. We did not observe any changes in synaptic or intrinsic changes on D1R-MSNs. Last, in an attempt to determine the integrated effect of the synaptic and intrinsic alterations on the overall functional output of D2R-MSNs, we measured the input-output efficacy by measuring synaptically-driven action potential firing. We found that both D1R-MSN and D2R-MSN output was unchanged following morphine treatment.

One Is Not Enough: Understanding and Modeling Polysubstance Use

“…Data from Bonci and Williams (1996), Kang et al (1996Kang et al ( , 1998, Robinson and Kolb (1997), Robinson and Kolb (2004), Badiani et al (1999), Mansvelder and McGehee (2000), Dahchour and De Witte (2000), Uslaner et al (2001), Brown and Kolb (2001), Robinson et al (2002), Saal et al (2003), Amantea et al (2004), Hamilton and Kolb (2005), Nasif et al (2005), Kolb et al (2006), Kolb et al (2018), Huang et al (2007), Zhou et al (2007) McDevitt et al, 2019) and induces silent synapses on iMSNs via AMPA internalization (Graziane et al, 2016). Moreover, during withdrawal, opioid-generated silent synapses on iMSNs are eliminated (Graziane et al, 2016), and the intrinsic excitability of iMSNs is weakened (McDevitt et al, 2019). Given that MSNs create a dense network of lateral inhibition within the NAc, with ∼30% of iMSNs synapsing onto other iMSNs or dMSNs (Taverna et al, 2008), it is possible that opioidinduced disruptions in iMSN signaling could disrupt local NAc microcircuitry and facilitate aberrant C-BG-T network dynamics.…”

Cocaine-induced projection-specific and cell type-specific adaptations in the nucleus accumbens

“…These changes often exhibit projection and cell-type specificity, are mediated by different AMPAR subtypes, may organize into different functional ensembles, and differentially regulate cocaine-elicited behaviors. Beyond cocaine, projection and cell-type specificities of NAc circuits have also been observed in seeking behaviors induced by other drugs of abuse as well as natural rewards, with similar and yet differential cellular and circuit features in each case 55 , 120 , 209 – 211 . It is important for future studies to define both the uniqueness and common ground underlying the ensemble, circuit, and behavioral correlates induced by these drug/reward experiences.…”

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum

“…Our results show that, although morphine can induce an overall structural plasticity in the MSNs of the CPu, it is unable to modify their passive membrane properties and intrinsic excitability. Interestingly, previous studies have demonstrated that repeated morphine exposure specifically alters the activity of the NAc MSNs which expressed the dopamine D2 receptors (D 2 R) [ 56 , 57 ]. Thus, as in our analysis we did not identify striatal MSNs subpopulations—e.g., direct- and indirect-pathway projection neurons—it remains to be investigated in future works whether morphine specifically mediates changes in one of them.…”