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 wholecell electrophysiology recordings, we show, that 24 h abstinence following repeated noncontingent administration of morphine (10 mg/kg, i.p.) in mice reduces 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 on synaptic or intrinsic changes on D1R-MSNs. Lastly, 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. 42 4 much lesser degree (Bertran-Gonzalez et al., 2008). Mice were singly-housed and maintained on 43 a regular 12 hour light/dark cycle (lights on 07:00, lights off 19:00) with ad libitum food and 44 water. 45 2.2. Drugs 46 (−)-morphine sulfate pentahydrate was provided by the National Institute on Drug Abuse Drug 47 Supply Program. NBQX and AP5 were purchased from Tocris Biosciences. Picrotoxin was 48 purchased from Sigma Aldrich. Tetrodotoxin (TTX) was purchased from Enzo. 49 2.3. Repeated systemic injections of saline or morphine 50 Before drug administration, mice were allowed to acclimate to their home cages for >5d. For 51 drug treatment, we used a 5d repeated drug administration procedure (Huang et al., 52 2009;Graziane et al., 2016). In all electrophysiological experiments, once per d for 5d, mice were 53 taken out of the home cages for an intraperitoneal (i.p.) injection of either (−)-morphine sulfate 54 pentahydrate (10mg/kg in 0.9% saline) or the same volume of 0.9% saline, and then placed back 55 to the home cage at ~Zeitgeber time (ZT) 2 (ZT0=lights on, ZT12=lights off). Animals were 56 randomly selected for each drug treatment. Morphine-or saline-treated animals were then used 57 for electrophysiological recordings ~24h following the last injection.58 2.4. Acute Brain Slice Preparation 59 At ~ZT time 2, mice were deeply anesthetized with isoflurane and cardiac perfused with an ice-60 cold NMDG-based cutting solution containing (in mM): 135 N-methyl-d-glutamine, 1 KCl, 1.2 61 KH2PO4, 0.5 CaCl2, 1.5 MgCl2, 20 choline-HCO3, and 11 glucose, saturated with 62 95%O2/5%CO2, adjusted to a pH of 7.4 with HCl, osmolality adjusted to 305 mmol/kg. 63Following perfusion, mice were decapitated and brains were rapidly removed. 250 m coronal 64 brain slices containing the nucleus accumbens shell were prepared ...

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.