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Reversal of Cocaine-Associated Synaptic Plasticity in Medial Prefrontal Cortex Parallels Elimination of Memory Retrieval

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Reversal of Cocaine-Associated Synaptic Plasticity in Medial Prefrontal Cortex Parallels Elimination of Memory Retrieval Neuropsychopharmacology (2017) 42, 2000–2010 © 2017 American College of Neuropsychopharmacology. All rights reserved 0893-133X/17 www.neuropsychopharmacology.org Reversal of Cocaine-Associated Synaptic Plasticity in Medial Prefrontal Cortex Parallels Elimination of Memory Retrieval 1,2 *,1,3 James M Otis and Devin Mueller 1Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA; 2Department of Psychiatry, University of North Carolina- 3 Chapel Hill, Chapel Hill, NC, USA; Department of Basic Sciences, Neuroscience Division, Ponce Health Sciences University-School of Medicine, Ponce Research Institute, Ponce, Puerto Rico Addiction is characterized by abnormalities in prefrontal cortex that are thought to allow drug-associated cues to drive compulsive drug seeking and taking. Identification and reversal of these pathologic neuroadaptations are therefore critical for treatment of addiction. Previous studies using rodents reveal that drugs of abuse cause dendritic spine plasticity in prelimbic medial prefrontal cortex (PL-mPFC) pyramidal neurons, a phenomenon that correlates with the strength of drug-associated memories in vivo. Thus, we hypothesized that cocaine-evoked plasticity in PL-mPFC may underlie cocaine-associated memory retrieval, and therefore disruption of this plasticity would prevent retrieval. Indeed, using patch clamp electrophysiology we find that cocaine place conditioning increases excitatory presynaptic and postsynaptic transmission in rat PL-mPFC pyramidal neurons. This was accounted for by increases in excitatory presynaptic release, paired- pulse facilitation, and increased AMPA receptor transmission. Noradrenergic signaling is known to maintain glutamatergic plasticity upon reactivation of modified circuits, and we therefore next determined whether inhibition of noradrenergic signaling during memory reactivation would reverse the cocaine-evoked plasticity and/or disrupt the cocaine-associated memory. We find that administration of the β -adrenergic receptor antagonist propranolol before memory retrieval, but not after (during memory reconsolidation), reverses the cocaine-evoked presynaptic and postsynaptic modifications in PL-mPFC and causes long-lasting memory impairments. Taken together, these data reveal that cocaine-evoked synaptic plasticity in PL-mPFC is reversible in vivo, and suggest a novel strategy that would allow normalization of prefrontal circuitry in addiction. Neuropsychopharmacology (2017) 42, 2000–2010; doi:10.1038/npp.2017.90; published online 24 May 2017 INTRODUCTION Kolb, 2004,1999), an effect that parallels the formation of drug-associated memories in vivo (Muñoz-Cuevas et al, Presentation of contextual cues associated with previous 2013). Thus, addiction is associated with adaptations in PFC, drug use drives compulsive drug seeking and taking which may underlie drug-associated memories, but whether (Childress et al, 1986; Heather et al, 1991), creating a these adaptations could be reversed in vivo is unknown. significant obstacle in recovery from addiction. Disruption of Previously, we found that inhibition of β-adrenergic the associative memories that allow cues to trigger drug receptor (β-AR) signaling can persistently impair the seeking would alleviate this compulsion, although the expression of drug-associated memories (Otis and Mueller, neuroadaptations that underlie and maintain drug- 2011; Otis et al, 2013,2014a). Specifically, we observed that associated memories remain unclear. Previous studies show systemic administration of β-AR antagonists before a single that abnormalities in prefrontal cortex (PFC) are associated cocaine-conditioned place preference (CPP) memory retrie- with addiction. For example, drug-associated cues are val test prevents CPP expression during that test and during particularly capable of activating the PFC in addicts, and subsequent treatment-free tests. This impairment is long the level of PFC activation correlates with reported drug lasting, and provides protection against cocaine-induced cravings (Grant et al, 1996; Grüsser et al, 2004; Kilts et al, reinstatement. In addition, CPP behavioral deficits are not 2001). Furthermore, in rodent studies, drug exposure causes due to β-AR antagonism in the peripheral nervous system dendritic spine gain in pyramidal neurons of the prelimbic (Otis and Mueller, 2011), but can be replicated through local medial PFC (PL-mPFC; Robinson et al, 2001; Robinson and infusions of β-AR antagonists into the PL-mPFC (Otis et al, 2013). Importantly, systemic or intra-PL-mPFC injections of *Correspondence: Dr D Mueller, Department of Basic Sciences, β-AR antagonists do not influence locomotion, do not induce Neuroscience Division, Ponce Health Sciences University-School of Medicine, Ponce Research Institute, P.O. Box 7004, Ponce 00732-7004, an affective state capable of inducing a CPP or aversion, and Puerto Rico, Tel: +1 787 840 2575 Ext. 2588, Fax: +1 787 844 1980, have no effect on memory when administered after, rather E-mail: [email protected] than before, a single CPP retrieval test (Otis and Mueller, Received 21 December 2016; revised 26 April 2017; accepted 27 April 2011; Otis et al, 2013). Taken together, β-AR blockade during 2017; accepted article preview online 3 May 2017 memory retrieval eliminates the expression of a cocaine- Prelimbic plasticity and cocaine-associated memory retrieval JM Otis and D Mueller 2001 associated memory. However, whether β-AR blockade also of pretest propranolol injections on time spent in the center eliminates neuroadaptations associated with cocaine expo- chamber during the first and second CPP test (saline-treated sure and learning is unknown. rats, n = 8; propranolol-treated rats, n = 7; ANOVA, effect of = = Here we combine in vivo neuropharmacology with ex vivo group: F1,13 0.25, p 0.63). Thus, to simplify data analysis patch-clamp electrophysiology, and find that cocaine place and illustration, place conditioning data were analyzed using conditioning increases both presynaptic release and post- CPP scores, as quantified by time spent in the previously synaptic efficacy at glutamatergic synapses of PL-mPFC cocaine paired chamber minus time in the saline-paired pyramidal neurons. Furthermore, we find that inhibition of chamber, subtracted from preconditioning test scores. β-AR signaling before memory retrieval, but not after Differences in CPP scores were analyzed using two-way (during memory reconsolidation), reverses the cocaine- ANOVAs (group × test), and planned comparison post hoc evoked neuroadaptations in PL-mPFC and causes long- analyses were performed to compare differences in CPP lasting disruption of the cocaine-associated memory. Taken scores between the two groups for each test. together, these data reveal that cocaine-evoked synaptic plasticity in PL-mPFC is reversible in vivo, and suggest a Electrophysiology novel strategy that would allow normalization of prefrontal circuitry in addiction. Rats were anesthetized with pentobarbital (50 mg/kg, i.p.) and brains were rapidly extracted and sectioned (350 μm) in – ice-cold (0 2 °C) oxygenated (20 : 1 ratio of O2 :CO2) MATERIALS AND METHODS artificial cerebral spinal fluid (aCSF; in mM: 124 NaCl, 2.8 Subjects KCl, 1.25 NaH2PO4, 2 MgSO4, 2 CaCl2, 26 NaHCO3, and 20 glucose) using a vibrating blade (Leica, VT1200). Slices All behavioral protocols were approved by the Institutional recovered in warm aCSF (32 °C) for a minimum of 30 min Animal Care and Use Committee at the University of before recordings. During recordings, slices were continu- Wisconsin-Milwaukee. Male Long–Evans rats (3–5 months) ously perfused with aCSF (2 ml/min), in the presence of were housed individually in clear plastic cages with water picrotoxin (100 μM) for blockade of GABA-mediated and rat chow (Harlan Laboratories) available ad libitum. Rats currents. PL-mPFC pyramidal neurons were visualized using were maintained on a 14-h light/dark schedule (lights on at differential interference contrast through a liquid-immersion 0700 hours), and all behavioral protocols were completed lens mounted on an upright light microscope (Nikon during the light cycle. Instruments). Layer V/VI PL-mPFC pyramidal neurons were identified based on morphology and electrophysiologi- Drugs cal characteristics, as described previously (Otis et al, 2013,2014b). Whole-cell recordings were obtained using Cocaine HCl (National Institute on Drug Abuse) was low-resistance borosilicate pipettes (2–5MΩ) containing a dissolved in sterile saline (0.9% NaCl) and administered at potassium gluconate-based internal solution (in mM: 110 K- β a dose of 10 mg/kg (i.p.). The -AR antagonist propranolol gluconate, 20 KCl, 10 HEPES, 2 MgCl2, 2 ATP, 0.3 GTP, 10 (Sigma-Aldrich) was dissolved in sterile saline (0.9%) and phosphocreatine, 0.2% biocytin; pH 7.3, and mOsm 280). administered at a dose of 10 mg/kg (i.p.). Current-clamp and voltage-clamp recordings were made using a signal amplifier (MultiClamp 700B, Molecular Conditioning and Testing Devices) and digitizer (Digidata 1440A, Molecular Devices). Throughout all recordings, the liquid–liquid junction poten- Place conditioning and testing were performed as described tial of 13 mV was compensated through voltage subtraction. previously in detail (Otis and Mueller, 2011). Briefly, the Current-clamp recordings were used for characterization conditioning apparatus was composed of two distinguishable of intrinsic neuronal excitability. Rheobase was first eval- conditioning chambers separated by a smaller center uated by
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