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Background: Oxytocin reduces cued reinstatement of cocaine seeking in male and female rats, but the underlying neurobiology has not been uncovered. The majority of effort on this task has focused on oxytocin and dopamine interactions in the nucleus accumbens core. The nucleus accumbens core is a key neural substrate in relapse, and oxytocin administration in the nucleus accumbens core reduces reinstatement to methamphetamine cues. Further, the nucleus accumbens core has strong glutamatergic innervation from numerous regions including the prefrontal cortex. Thus, we hypothesize that oxytocin regulates presynaptic glutamate terminals in the nucleus accumbens core, thereby affecting reinstatement. Methods: To begin to evaluate this hypothesis, we examined the effects of intra-nucleus accumbens core oxytocin on extracellular glutamate levels in this region. We next determined if direct infusion of oxytocin into the nucleus accumbens core could attenuate cued reinstatement of cocaine seeking in a manner dependent on metabotropic glutamate 2/3 receptors. Finally, we tested if site-specific application of oxytocin in the prefrontal cortex reduced cued reinstatement of cocaine seeking. Results: We found an increase in nucleus accumbens core extracellular glutamate for several minutes following reverse dialysis of oxytocin. In male and female rats with a history of cocaine self-administration, site-specific application of oxytocin in the nucleus accumbens core and prefrontal cortex had opposing effects, decreasing and increasing cued reinstatement, respectively. The mGlu2/3 antagonist LY-341495 reversed oxytocin’s ability to attenuate cued reinstatement. Conclusions: While the precise mechanism by which oxytocin increases nucleus accumbens core glutamate is yet to be determined, the present results clearly support oxytocin mediation of glutamate neurotransmission in the nucleus accumbens core that impacts cued cocaine seeking. Keywords: neuroactive peptides, substance abuse, relapse, reinstatement, glutamate, prefrontal cortex Introduction Oxytocin is a well-characterized neuroendocrine hormone of areas involved in addiction, including the limbic regions produced within the paraventricular nucleus and supraoptic and ventral striatum (Knobloch and Grinevich, 2014). Oxytocin nucleus of the hypothalamus. Oxytocin cells project to a number receptors are ubiquitous throughout the brain, are Gq-coupled, Received: January 29, 2018; Revised: February 16, 2018; Accepted: March 13, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 677 provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ijnp/article-abstract/21/7/677/4939245 by Ed 'DeepDyve' Gillespie user on 03 July 2018 678 | International Journal of Neuropsychopharmacology, 2018 Significance Statement In animal models, oxytocin consistently decreases relapse to cues that are associated with the physiological effects of the drug, but very little is known about the neural mechanisms driving this ability. We uncovered bi-directionality of oxytocin’s effect on reinstatement of cocaine seeking with increased and decreased responding following site-specific application of the neuropep- tide in the PFC or the NAcc, respectively. This study indicates the PFC and NAcc are critical structures involved in the interaction between oxytocin and glutamatergic signaling in males and females and provides critical insight that will aid in the develop- ment of oxytocin-based therapies. and activate transduction pathways which include IP3 receptor localization of mGlu receptors are believed to drive these effects activation and the release of intracellular calcium stores (Gimpl (Kalivas, 2009; Moussawi et al., 2009; Wang et al., 2013). and Fahrenholz, 2001). Recently, oxytocin has received increased Recently, we have shown that site-specific application of oxyto- interest as a treatment for many neuropsychiatric disorders, cin into the NAcc decreases cued reinstatement of methamphet- including addiction. amine-seeking and, importantly, blockade of mGlu2/3 receptors Addiction remains a persistent problem that affects both prevents this effect (Bernheim et al., 2017). This finding is note- men and women and treatments aimed at preventing relapse worthy, because it suggests that NAcc oxytocin interacts with are needed. Oxytocin shows promise to fill this identified need. glutamate via a presynaptic mechanism. In the NAcc, oxytocin In humans, oxytocin administration alleviates stress-induced receptors have been detected on astrocytes, 5HT-2a-expressing marijuana craving (McRae-Clark et al., 2013) and reduces some neurons, and on parvalbumin-positive interneurons (Di Scala- symptoms of alcohol withdrawal (Pedersen et al., 2013). Similarly, Guenot and Strosser, 1992Di Scala-Guenot et ; al., 1994 Dölen et ; al., in rodents, oxytocin reduces ethanol self-administration and con- 2013). Oxytocin receptor mRNA is found in glutamate neurons in sumption in mice (MacFadyen et al., 2016; King et al., 2017); reduces the ventral tegmental area (Peris et al., 2017) and PFC (Tan et al., morphine tolerance and withdrawal effects (Sarnyai and Kovács, 2017), regions that send glutamate projections to the NAcc. 2014), blocks methamphetamine-conditioned behaviors (Qi et al., To begin to understand oxytocin’s actions within the PFC-NAcc 2009), and reduces reinstatement of methamphetamine seeking circuit in a model of cocaine relapse, we first determined if oxy- (Carson et al., 2010a; Cox et al., 2013; Baracz and Cornish, 2016). tocin had an effect on NAcc glutamate levels and then used the Additionally, oxytocin decreases methamphetamine responding cocaine self-administration, extinction, and reinstatement model on a progressive ratio schedule of reinforcement in female but to assess reinstated responding to cocaine associated cues using not male rats (Cox et al., 2013). In humans, cocaine use decreases site-specific application of oxytocin into the PFC and NAcc. We plasma oxytocin levels (Light et al., 2004) and our laboratory has also tested whether blockade of mGluR2/3 receptors in the NAcc shown that systemic oxytocin decreases active lever presses would block oxytocin’s effects and determined whether oxyto- for cocaine, cocaine intake during self-administration, and cue- cin administration increased NAcc glutamate release. Finally, we induced reinstatement of cocaine seeking following extinction in tested whether systemic administration of oxytocin and mGluR male and female rats (Zhou et al., 2014Leong et ; al., 2016, 2017). In receptor antagonists would also decrease cued reinstatement of spite of this strong evidence indicating the potential of oxytocin cocaine seeking since oxytocin treatment regimens are delivered as a treatment for cocaine addiction, very little is known about through systemic circulation in cocaine addicts. the specific mechanisms behind oxytocin’s behavioral effects and whether those mechanisms are sexually dimorphic. Methods The prefrontal cortex (PFC) exerts top-down control over the nucleus accumbens core (NAcc). A recent report phenotyped Subjects oxytocin receptor expressing neurons in mouse PFC and found Experiment 1 used 12 male Sprague-Dawley rats (Charles River that 46% and 33% of oxytocin-expressing neurons in the PFC are glutamatergic and GABAergic, respectively. The glutamater - Laboratories). Experiments 2 to 4 used a total of 45 male and 45 female Sprague-Dawley rats (Harlan). All rats weighed 250 to 300 g gic oxytocin receptor expressing neurons project to the NAcc (Tan et al., 2017). Maladaptive changes in glutamatergic regu- (male) and 225 to 250 g (female) at the time of arrival. Rats were single-housed on a reversed 12-hour-light/-dark cycle (lights off at lation occur in the PFC-NAcc pathway following cocaine expos- ure (Scofield et al., 2016). Briefly, 2 to 3 weeks following cocaine 6:00 am) in a temperature- and humidity-controlled vivarium. All experimental procedures were conducted during the dark cycle. self-administration, basal extracellular glutamate levels are decreased in the NAcc and the PFC-NAcc glutamate projection is Rats received water ad libitum and were kept on a stable intake diet 20 to 40 g of standard rat chow daily throughout the study. necessary for the reinstatement of cocaine seeking (Baker et al., 2003; McFarland et al., 2003). Compounds such as ceftriaxone Procedures were conducted in accordance with the “Guide for the Care and Use of Laboratory Rats” (Institute of Laboratory Animal and N-acetylcysteine increase NAcc basal extracellular glutam- ate and attenuate both cocaine- and cue-primed reinstatement Resources on Life Sciences, National Research Council, 2011) and approved by the IACUC of the University of Florida (Experiment of cocaine seeking while attenuating glutamate release in the NAcc (Baker et al., 2003; Knackstedt et al., 2010; Trantham- 1) and the Medical University of South Carolina (Experiments 2–4). Davidson et al., 2012). The ability of N-acetylcysteine to attenu- ate the reinstatement of cocaine seeking is prevented by both Experiment 1: Microdialysis and High Performance systemic and intra-NAcc infusion of the mGlu2/3 antagonist Liquid Chromatography (HPLC) for Quantification of LY341495 (Moran et al., 2005; Moussawi et al., 2011). Conversely, Glutamate activation of NAcc mGlu2/3 receptors decreases cued cocaine seeking but also reduces consumption of chow (Baptista et al., Surgery to implant intracranial guide cannulas occurred in a stereotaxic frame (Stoelting). Stainless-steel guide cannulas 2004; Peters et al., 2008). Presynaptic rather than postsynaptic Downloaded from https://academic.oup.com/ijnp/article-abstract/21/7/677/4939245 by Ed 'DeepDyve' Gillespie user on 03 July 2018 Weber et al. | 679 (22 gauge; Synaptech) were bilaterally aimed 2 mm above the i.p., Sigma) was given before surgery as an analgesic. Surgical NAcc according to the following coordinates anterior-poste- procedures were conducted using aseptic techniques. One end rior (AP) + 1.2 mm, medial-lateral (ML) ± 1.6 mm, dorsal-ventral of a silastic catheter was implanted into the external right (DV) −5.5 mm; (Paxinos and Watson, 2007) and were secured to jugular vein. The other end ran subcutaneously, exited from a the skull with stainless-steel skull screws and dental acrylic small incision on the back, and attached to an infusion can- (Co-Oral-Ite Dental MFG. Co.). The analgesic ketorolac (2 mg/kg, nula (PlasticsOne Inc.). Cephazolin (10 mg/0.1 mL) was given i.p.) was administered for 3 days following surgery. One week post-surgery (0.1 mL i.v.) and during recovery along with after surgery, a microdialysis probe was implanted unilaterally. 0.05 mL of Taurolidine-Citrate Catheter Solution (TCS; Access Probes were constructed of a 2-mm cuprophane membrane Technologies). Experiment 2 and 3 required the use of chronic, (20 kDa cut-off weight, outer diameter 0.36 mm; Synaptech). indwelling intracranial cannula. In this case, intracranial guide Subjects were placed into a plexiglass box (45 cm × 45 cm) and cannulas (Plastics One) directed at the NAcc or PFC, in separ - perfused with artificial cerebral spinal fluid (aCSF: 125 mM NaCl, ate groups of rats, were stereotaxically implanted after the 2.5 mM KCl, 1 mM MgCl26H2O, 5 mM D-glucose, 1.2 mM CaCl2H20, catheter surgery, under the same plane of anesthesia. The rat 0.75 mL 10 x phosphate buffered saline). Liquid switches (CMA was placed in the stereotactic apparatus, and the skin overly- Harvard Apparatus Company) were utilized to minimize pres- ing the skull was excised. The skull was cleared, and bregma sure changes when changing perfusion solutions. Following 4 and lambda were positioned at the same DV coordinate. NAcc hours of equilibration to aCSF perfusion (2 μL/min), six 10-min coordinates were measured from bregma at the skull surface as baseline samples were collected. Following baseline sample col- follows: AP +1.5 mm, ML ± 2.8 mm, DV -7.1mm, at a 10º angle. We lections, reverse dialysis of oxytocin (36 µM/side in aCSF), with or targeted the prelimbic (PL) area of PFC using the following coor - without the voltage-gated sodium channel blocker tetrodotoxin dinates: AP +2.8 mm, ML ± 0.6 mm, and DV -2.7 mm measured (TTX; 1 μM) occurred for 5 min, followed by aCSF for 60 minutes. from bregma. Jeweler’s screws were used to anchor the cannula This concentration of oxytocin was chosen to approximate the to the skull and were cemented in place. Dummy wires were concentration infused in Experiments 2 to 3, accounting for loss inserted through the cannula to prevent obstruction by debris due to dialysis membrane permeability. This concentration of and were the same length as the cannula. Rats recovered 5to TTX was chosen because it does not reduce basal extracellular 10 days before initiating cocaine self-administration. glutamate in the NAcc of drug-naïve animals (Baker et al., 2002; Pati et al., 2016) but does prevent synaptic glutamate release in Experiments 2–4: Self-Administration, Extinction, this brain region (McFarland et al., 2003). Furthermore, this con- and Reinstatement centration suppresses action potentials in the striatum in vitro (Jiang and North, 1991). During oxytocin/TTX perfusion and for Self-administration procedures (see Figure 2 timeline) were the subsequent 60 minutes, dialysate samples were collected based on recent self-administration studies in males and once/5 min. The hemisphere of probe insertion was counterbal- females (Cox et al., 2013; Leong et al., 2016, 2017). All self- anced, and probing separated by at least 2 days. Twelve rats were administration experiments were conducted during the rats’ used in this experiment. Five of the 12 rats were probed bilat- dark cycle in standard Plexiglas self-administration chambers erally, while 4 were only probed unilaterally, yielding a total of 9 (30 x 20 x 20 cm) that were enclosed in sound attenuating cubi- rats (14 hemispheres: oxytocin= 8, oxytocin+ TTX = 6) that were cles with a ventilation fan (Med Associates) and linked to a com- used for the data presented in Figure 1. Three rats that received puterized data collection program (MED PC, Med Associates). surgeries were eliminated due to illness prior to probing (n = 1), Each chamber was equipped with 2 retractable levers with a improper cannulae placement (n= 1), and head cap loss (n= 1). white stimulus light above each lever, a house light, and a tone generator. For cocaine self-administration, infusion tubing was enclosed in steel spring leashes (Plastics One Inc) and con- Experiments 2 to 4: Surgery nected to the infusion cannula and a weighted swivel apparatus Rats were anesthetized with i.p. injections of ketamine (66 mg/ (Instech) that was suspended above the box to allow for free kg, i.p., Vedco Inc.) mixed with xylazine (1.3 mg/kg, i.p., Lloyd movement within the chamber. Laboratories), and equithesin (0.5 mL/kg). Ketorolac (2.0 mg/kg, Cocaine hydrochloride (provided by the National Institute on Drug Abuse) was dissolved in 0.9% sterile saline and admin- istered at a dose of 0.5 mg/kg/infusion. Self-administration sessions were conducted 6 d/week for 2 h/d. The house light remained on throughout the sessions, and the appropriate num- ber of responses on the active lever resulted in activation of the infusion pump and delivery of a 2-sec i.v. cocaine infusion and a 5-sec presentation of a cue complex (illumination of the white stimulus light over the active lever and activation of tone gen- erator; 78 dB, 4.5 kHz), followed by a 20-second time-out period. During the time-out period, responses on the active and inactive levers were recorded but had no scheduled consequences. Rats initially self-administered cocaine on a fixed ratio 1 (FR1) sched- ule of reinforcement (1 lever press resulted in a drug infusion) until they reached the criterion of a minimum of 5 days with >10 infusions. Rats then moved to a FR3 schedule for a minimum of Figure 1. Oxytocin (36 µM/side) increases glutamate levels in the nucleus 3 days, followed by a FR5 schedule for the remainder of the self- accumbens core (NAcc) of drug naïve rats when measured using reverse dialysis administration sessions. To verify catheter patency when rats for up to 20 minutes past application time. The effect was blocked in the pres- were not administering cocaine, a 0.10- to 0.12-mL i.v. infusion ence of tetrodotoxin (TTX). * Significant increase from baseline (-10 relative to 5 and 10 minutes) (P < .05). of methohexital sodium (Eli Lilly), a short-acting barbiturate Downloaded from https://academic.oup.com/ijnp/article-abstract/21/7/677/4939245 by Ed 'DeepDyve' Gillespie user on 03 July 2018 680 | International Journal of Neuropsychopharmacology, 2018 Figure 2. Experimental timeline of self-administration experiments is depicted at the top of the figure. (A) Active lever responding increased as FR values increased and inactive lever responding decreased over time. Females responded more on both levers relative to males on the first day of self-administration. *Significant differ - ence between males and females (P < .05). (B) Females received more infusions relative to males (P < .05). (C) All animals diminished responding on the active lever over the extinction days. Females responded more than males on the inactive lever on day 1 of extinction. *Significant difference between male and female rats (P < .05). # Significant difference from day 1 of extinction (P < .05). that produces a rapid loss of muscle tone when administered directly into the NAcc. For intracranial administration, oxytocin i.v. After each self-administration session, rats’ catheters were was infused at a concentration of 0.6 nmol/0.25L/side ( µ Baracz flushed with 0.05 mL TCS. et al., 2012; Cox et al., 2017; Bernheim et al., 2017). LY341495 was Following self-administration, rats underwent 2-hour daily infused at a concentration of 1.3 nmol/0.25L/side based on a µ extinction sessions for a minimum of 10 days, where responses range of 2 efficient doses (Kim et al, 2015; Richard and Berridge, on both the active and inactive levers were recorded but had no 2011; Bernheim et al., 2017). The microinjector extended 1 mm scheduled consequences. Extinction criterion consisted of <25 (PFC) or 1.5 mm (NAcc) beyond the cannula. The PFC infusion active lever presses for 3 consecutive days (Leong et al., 2017; took place over 1 minute and the NAcc infusion occurred over 2 Cox et al., 2013; Bernheim et al., 2017). Upon reaching extinc- minute; injectors were left in place an additional minute to allow tion criteria, rats underwent cued reinstatement tests for 2 diffusion of the drug. Five minutes after the final microinfusion, hours. Responses on the active lever resulted in presentation of animals were placed into the chamber for reinstatement testing. only the light + tone stimulus complex (described above) that At the end of the experiment, rats were decapitated and brains previously accompanied i.v. cocaine using an FR1 schedule of were collected for histological assessment of cannula placement. reinforcement. No cocaine was administered during this test. In brief, rats were deeply anesthetized with Equithesin and then Responses on the inactive lever were also recorded. Each rat was transcardially perfused with 150 to 200 mL cold 0.9% saline fol- tested twice with at least 2 extinction sessions (2 h/d) between lowed by 400 to 500 mL of 4% paraformaldehyde. Brains were tests. Test conditions and test order were randomly assigned removed and postfixed in 4% paraformaldehyde for 24 hours, without replacement until groups were full. Specific experimen- submerged in 20% sucrose for 48 hours, and then sectioned on tal methods are detailed below for intracranial microinfusions a vibratome. Sections were mounted on microscope slides and and drug administration. cannula placement was verified within the NAcc or PFC. Experiments 2 to 3: Intracranial Microinfusions Experiment 4: Systemic Oxytocin and LY-341495 Administration Animals received a microinfusion of either oxytocin (0.6 nmol/0.2 5µL/side; Cell Sciences) or saline (0.25 µL/side) in the PFC or NAcc. Rats received a systemic injection of LY-341495 (1 mg/kg) or Some animals received a microinfusion of either LY-341495 vehicle (i.p.) followed by oxytocin (1 mg/kg) or saline (i.p.) 5 min- (1.3 nmol/0.25 µL/side; Tocris Bioscience) or saline (0.25 µL/side) utes later. For systemic injections oxytocin was administered at before oxytocin (0.6 nmol/0.25µL/side) or saline (0.25µL/side) 1 mg/kg (Cox et al., 2013, Zhou et al., 2015; Leong et al., 2016) and Downloaded from https://academic.oup.com/ijnp/article-abstract/21/7/677/4939245 by Ed 'DeepDyve' Gillespie user on 03 July 2018 Weber et al. | 681 LY341495 was injected at 1 mg/kg (Scofield et al., 2015; Bernheim Figure 2B represents the number of infusions received by et al., 2017). After the second injection, animals waited 30 min- males and females during self-administration. Females received utes before being placed into the operant chamber for reinstate- a greater number of cocaine infusions than males as indicated ment testing to allow the locomotor-suppressing effects of by a main effect of sex [F(12,87) = 10.96, P = .0014]. There was also systemic oxytocin to diminish before testing. a significant main effect of day [F(12,1044) = 13.7, P < .0001] as the number of infusions increased over time. The sex by day inter- action was not significant. Data Analysis Figure 2C depicts active and inactive lever responding dur - Glutamate levels were normalized to the average base- ing extinction in males and females. On the active lever there a line glutamate value for each subject and group differences significant main effect of day [F(9,513) = 125.8, P < .0001] as lever (TTX+oxytocin vs oxytocin) over time were examined using presses decreased over time, specifically day 2 to 10 were signifi- repeated measures (RM) ANOVA with RM conducted on the cantly lower than extinction day one. The interaction between time variable. The number of lever responses and infusions sex and extinction day and the main effect of sex were not sig- were the primary dependent variables during drug self-admin- nificant. On the inactive lever there was a significant interaction istration and they were analyzed using ANOVA with day (within between sex and extinction day [F(9,513) = 3.71, P = .0002] with subjects) and sex (between subjects) as independent variables. females responding more on day one of extinction relative to For reinstatement testing, lever responses were analyzed using males (Holm-Sidak’s, P < .05). There was also a significant main a 2-way ANOVA with sex and treatment as between subject effect of day [F(9,513) = 24.7, P < .0001] as lever presses decreased factors. Posthoc comparisons were conducted using a Holm- over time. The main effect of sex was not significant. Sidak’s correction for family wise error when appropriate, with the alpha set at 0.05. All analyses were conducted with Experiment 2: Intra-Accumbal Oxytocin Reduced Prism Software versions 6 and 7. All data are expressed as the Cued Reinstatement of Cocaine Seeking and mean ± SEM. mGlu2/3 Receptor Antagonism Blocked this Effect in Males and Females Results Figure 3A depicts findings for intra-accumbal effects of oxytocin and blockade with LY-341495 in male (n= 16) and female (n = 16) Experiment 1: Oxytocin-Induced Glutamate Release rats. NAcc oxytocin decreased lever responding in response to in the NAcc Was Blocked by Administration of TTX cues and LY341495 reversed this effect. There was a main effect Figure 1 illustrates that oxytocin reverse dialyzed in the NAcc of drug treatment [F(3,53) = 8.12, P < .002], but no significant main increased extracellular glutamate, which was blocked by co- effect of sex and no significant interaction between sex and administration of TTX. There was a significant time x treatment drug treatment. Posthoc comparisons on the main effect of drug interaction, [F(7,84) = 2.16, P < .03]. Follow-up comparisons show treatment showed that Veh/Sal, LY/Sal, and LY/Oxy groups had that oxytocin increased glutamate at 5 and 10 min relative to greater lever responding vs the Veh/Oxy group (Holm-Sidak’s, baseline assessed at -10 (Holm-Sidak’s multiple comparisons, P < .05). Figure 3B depicts the data for male and female rats sep- P < .05), while TTX blocked oxytocin induced glutamate release arately to visualize the lack of a sex difference on reinstatement at all time points. testing. Two males and two females were excluded from the study following histological analyses. Figure 3C depicts the ter - minal point of the injectors used to infuse the test compounds Experiments 2 to 4: Self-Administration and into the NAcc. Extinction Self-administration and extinction data were consolidated Experiment 3: Oxytocin in the PFC Increases between experiments, because they did not differ and were Reinstatement to Cocaine-Associated Cues conducted under identical conditions. Figure 2A depicts the active and inactive lever presses throughout the self-adminis- Figure 3D illustrates that oxytocin microinfusions in the pre- tration period for all the male (n = 45) and female (n = 45) rats frontal cortex of male (n = 13) and female (n = 13) rats increased that were used in the reinstatement testing in Experiments 2 cued reinstatement of cocaine seeking. There was a main to 4. The timeline in Figure 2 depicts the breakdown of these effect of drug treatment [F(1,24)= 5.69, P < .002], with oxyto- animals for each experiment. For active lever presses, there cin increasing active lever presses. However, the main effect was a significant interaction between sex and self-adminis- of sex and interaction between sex and drug treatment were tration day [F(12,1032) = 1.88, P = .03] with females respond- not significant. Figure 3E depicts the data for male and female ing more on day one of self-administration relative to males rats separately to visualize the lack of a sex difference on (Holm-Sidak’s, P < .05). There was also a main effect of sex reinstatement testing. F igure 3F depicts the terminal point of [F(1,86) = 5.63, P = .02] with females pressing the active lever the injectors used to infuse the test compounds into the PL more than males. There was also a significant main effect area of the PFC. of day [F(12,1032) = 91.6, P < .0001] as lever presses increased over time and as the FR increased. On the inactive lever Experiment 4: Systemic Oxytocin Decreased Cued there was also a significant interaction between sex and self- Reinstatement of Cocaine seeking and mGlu2/3 administration day [F(12,1032) = 2.33, P = .0006] with females Receptor Antagonism Blocked this Effect in Males responding more on day one of self-administration relative and Females to males (Holm-Sidak’s, P < .05). The main effect of sex was not significant, but there was a significant main effect of day Figure 4A illustrates that oxytocin reduced cued reinstate- [F(12,1032) = 4.3, P < .0001] as inactive lever presses decreased ment of cocaine seeking and prevention of this effect by over time. LY341395 in males (n = 16) and females (n = 16). There was a Downloaded from https://academic.oup.com/ijnp/article-abstract/21/7/677/4939245 by Ed 'DeepDyve' Gillespie user on 03 July 2018 682 | International Journal of Neuropsychopharmacology, 2018 Figure 3. (A-B) Oxytocin (0.6 nmol/0.25 µL/side) infused into the NAcc decreased cued reinstatement of cocaine seeking. LY-341495 (1.3 nmol/0.25 µL/side) blocked oxy- tocin’s effect but was without impact when given alone. *Significant difference from VEH/OXY (P < .05). (C) Anatomical depiction of the terminal point of the injectors used to infuse compounds. Numbers depict AP difference from bregma in mm. (D-E) Oxytocin (0.6 nmol/0.25 µL/side) infused into the prefrontal cortex (PFC) increased lever responding during reinstatement of cocaine seeking compared with vehicle in both males and females. *Significant difference from oxytocin (P < .05). (F) Depiction of the terminal point of the injectors used to infuse compounds. Inset depicts the number of rats that tested in the specific condition. Black and gray symbols depict males and females, respectively. Numbers depict AP difference from bregma in mm. main effect of drug treatment [F(3,53)= 8.12, P < .0002], but Discussion no significant main effect of sex or significant interaction Here we report several potentially important findings regard- between sex and drug treatment. Posthoc comparisons ing regionally specific effects of oxytocin on reinstatement of showed that Veh/Sal, LY/Sal, and LY/Oxy groups had greater cocaine seeking. First, we demonstrate that oxytocin applied lever responding than the Veh/Oxy group (Holm-Sidak’s, directly into the NAcc increased extracellular glutamate levels P < .05). Figure 4B depicts the data for male and female in drug-naïve animals in a TTX-dependent manner. Second, rats separately to visualize the lack of a sex difference on oxytocin delivered directly into the PFC increased reinstated reinstatement testing. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/7/677/4939245 by Ed 'DeepDyve' Gillespie user on 03 July 2018 Weber et al. | 683 Figure 4. (A-B) Oxytocin (1 mg/kg, i.p.) reduced active presses in both sexes during cued reinstatement. LY-341495 (1 mg/kg, i.p.) blocked oxytocin’s effect but was with- out impact when given alone in males and females. Inset depicts the number of rats that tested in the specific condition. *Significant difference from VEH/OXY (P < .05). responding on the active lever, while oxytocin into the NAcc (Zhou et al., 2014) and increases the insertion of GluA2-lacking caused a decrease in cued reinstatement. This opposing pat- calcium-permeable AMPA receptors (Qi et al., 2012). This neural tern of reinstatement is the first to demonstrate regionally spe- adaptation is typically found in the NAcc (Conrad et al., 2008), cific effects of oxytocin on reinstatement of drug seeking. Third, and we recently discovered a similar change in the mPFC after using an mGlu2/3 receptor antagonist before oxytocin prevented prolonged cocaine abstinence (Pena-Bravo et al., 2017). This inter - the oxytocin induced decrease in cued reinstatement. These play between glutamate and oxytocin may explain the potenti- results raise questions regarding oxytocin as a therapeutic ated reinstatement we found following oxytocin infusion into option for cocaine addiction and stress the important need to the mPFC. Oxytocin-induced excitatory input from the PL-PFC elucidate oxytocin’s mechanism. may modulate glutamatergic signaling in downstream pathways The NAcc is one of the major neural substrates involved in such as the NAcc. It should be noted that intra-NAcc and intra- reward and motivation (Ito et al., 2004 Bjorklund et ; al., 2008), and PFC vehicle infusions resulted in different levels of active lever glutamate physiology is disrupted in this area following drug self- pressing during the test, which may contribute to the interpreta- administration (Cornish and Kalivas, 2000Kali ; vas and Volkow, tions of the ability of intra-PFC oxytocin to increase reinstate- 2011). We show that oxytocin increased extracellular glutamate ment. However, the mean active lever presses fall within the in the NAcc. Although the source of the extracellular glutamate published range of cued reinstatement for animals with cannula is beyond this report, the rise in glutamate levels was prevented in the medial mPFC (James et al., 2018; McLaughlin and See 2003; by co-infusion of TTX. TTX is a sodium channel blocker that Fuchs et al., 2004a). Likewise, reinstatement responding follow- inhibits the firing of action potentials in neurons. This finding is ing vehicle infusions into the NAcc were within range of previous critical to oxytocin’s action in the NAcc, because TTX blockade studies that had cannula or viral infusions into the NAcc (Fuchs of glutamate typically indicates a neuronal source. This find- et al., 2004b; Scofield et al., 2015; Reissner et al. 2015). We believe ing is surprising, because oxytocin receptors in the NAcc have that the different values for vehicle-infused rats occurred, been detected on astrocytes, parvalbumin positive interneurons, because these experiments were conducted separately by differ - and serotonergic 5HTa receptor-expressing neurons, but not ent personnel during different time periods. on medium spiny neurons, cholinergic interneurons, or nitric We have not entirely ruled out astrocyte regulation of glutam- oxide synthase 1 expressing interneurons (Di Scala-Guenot and ate release as a mechanism by which oxytocin decreases cued Strosser, 1992; Di Scala-Guenot et al., 1994; Dolen et al., 2013). reinstatement within the NAcc. Wang and colleagues (Wang As such, the neuronal source of glutamate is unclear, but it is et al., 2017) recently reported that astrocytes in the supra optic possible that oxytocin receptors may be localized on presynaptic nucleus of the hypothalamus express oxytocin receptors and glutamate terminals to modulate glutamate release. Since oxyto- oxytocin depolarized astrocyte membrane potentials while cin receptors are predominately Gq-coupled, binding by oxytocin reducing GFAP expression. Importantly, these effects of oxytocin would likely stimulate glutamate release. Although this localiza-on GFAP plasticity were modulated by PKA and pERK1/2. In the tion has not been demonstrated in the NAcc, oxytocin receptor NAcc, Scofield and colleagues (2015) demonstrated that specific mRNA is found in glutamate neurons in the ventral tegmental activation of astrocytes (via Gq-coupled DREADDs) decreased area (Peris et al., 2017) and PFC (Tan et al., 2017) and both of these cued reinstatement of cocaine seeking through an mGluR2/3- neuronal populations likely send projections to NAcc. dependent mechanism. Here, we speculate that the localization Surprisingly, oxytocin infused into the PFC increased of astroglial oxytocin receptors in the NAcc reduces relapse via responding for cocaine cues. The medial (m) PFC glutamatergic Gq signaling in the cell that can activate transduction pathways innervation of the NAcc is a central pathway involved in relapse including IP3 receptors and the release of intracellular calcium (for review, see Koob and Volkow, 2016). Pharmacological inacti- stores resulting in astrocytic glutamate transmitter release (Di vation of the PL area of the mPFC or optogenetic inhibition of cor - Scala-Guenot and Strosser, 1992Di Scala-Guenot et ; al., 1994; tical projection neurons to the NAcc prevents reinstated cocaine Hamilton and Attwell, 2010). Extrasynaptic glutamate can thereby seeking (McLaughlin, 2003; Di Pietro et al., 2006; Stefanik et al., activate mGluR2/3 receptors located presynaptically on cortical 2013). Recently, oxytocin receptors have been identified on glu- glutamatergic axons, inhibiting synaptic release of glutamate, tamate (46%) neurons in the PFC that project to the NAcc (Tan thus restoring glutamatergic tone (Moussawi and Kalivas, 2010). et al., 2017). Importantly, oxytocin also increases expression of We have recently reported that mGlu2/3 receptor antagon- GluA1 receptors in the PFC of cocaine experienced male rats ism reversed the ability of oxytocin to reduce reinstatement to Downloaded from https://academic.oup.com/ijnp/article-abstract/21/7/677/4939245 by Ed 'DeepDyve' Gillespie user on 03 July 2018 684 | International Journal of Neuropsychopharmacology, 2018 methamphetamine (but not sucrose) cues (Bernheim et al., 2017), evidence of oxytocin penetration of the blood brain barrier by and this current report extends this finding to cocaine. Both of showing that systemic oxytocin results in changes in Fos+ oxy- these consistent outcomes are in line with Scofield et al., (2015) tocin neurons (Carson et al., 2010b) and normalizes drug and showing that mGluR2/3 antagonism can block reinstatement to drug-cued increases in Fos expression (Carson et al., 2010b; Cox cocaine and methamphetamine (unpublished data) cues initi- et al., 2017; Leong et al., 2017). Direct evidence of oxytocin pene- ated by astrocytic GqDREADD stimulation. Other compounds that trance of the blood brain barrier has also been described in both restore cocaine-induced changes in neuroplasticity also restore rodents and primates (Neumann et al., 2013; Freeman et al., 2016). tone on mGlu2/3 receptors. For example, the cysteine-glutamate As described above, numerous studies are in agreement that per - exchanger and glutamate transporters are downregulated follow- ipherally administered oxytocin is able to decrease intake of ing cocaine self-administration (Moran et al., 2005 Kali ; vas, 2009). addictive substances implying a central mechanism of action Treatments with ceftriaxone and n-acetylcysteine repair these (reviewed in Bowen and Neumann, 2017). However, there is no neural adaptations, thereby restoring glutamate tone on mGlu2/3 reason to expect that peripherally administered oxytocin, once it receptors (Knackstedt and Kalivas, 2009). Whether oxytocin has crossed the blood brain barrier, would preferentially act in NAcc long-term changes that restore glutamate physiology or whether to inhibit addictive behaviors in contrast to the PFC where oxyto- this neuropeptide is an acute modulator of this system is beyond cin increased reinstatement to cocaine seeking. Thus, one might the scope of this study. We also know that oxytocin acts on local expect that peripheral administration of oxytocin would not be neurons in the NAcc to mediate its effects. Previously, our group as effective in decreasing reinstatement of cocaine seeking due has shown that systemic oxytocin reduces motivation and seek- to the additive effects of the opposing actions in NAcc and PFC. ing of methamphetamine and that this reduction is blocked by There are likely more sites of action of oxytocin in addition to administration of an oxytocin receptor antagonist in the NAcc the NAcc and PFC that can impact reward circuitry in a way to (Cox et al., 2017). Combined, these data suggest that oxytocin reg- decrease drug-seeking. A likely possibility is oxytocin receptor ulates relapse through multiple independent or interdependent localization on cell bodies in the VTA, which when activated by mechanisms that are yet to be defined. direct oxytocin administration (Melis et al., 2007 Tang ; et al., 2014; We report a sex difference in drug intake with females earn- Xiao et al., 2017), exert primarily excitatory actions on neuro- ing more cocaine infusions relative to males during self-adminis- transmission in the NAcc to increase dopamine and/or glutamate tration. However, this difference did not occur on reinstatement release in NAcc, precluding the need for further reward seeking. tests in response to cocaine conditioned cues, in agreement In summary, we reveal several important issues regarding with our recent publications (Bechard et al., 2017; Leong et al., oxytocin’s mechanism. First, we found that oxytocin increases 2017). This pattern of findings is consistent with the notion glutamate in the NAcc. Second, to our knowledge, this is the that sex differences in addiction are more robust during drug first study to uncover bi-directionality of oxytocin’s effect on self-administration, and sex differences are relatively minor reinstatement of cocaine seeking with increased and decreased once compulsive drug taking has set in (Becker and Koob, 2016). responding following site specific application of the neuropep- Females have been reported to show greater cocaine-primed tide in the PL-PFC or the NAcc, respectively. Third, we also uncov- reinstatement than males (Lynch and Carroll, 2000 Kippin ; et al., ered that mGluR2/3 receptors can mediate oxytocin-induced 2005; Anker and Carroll, 2011), but cue-induced reinstatement is attenuation of reinstatement to cocaine seeking. Combined, this relatively similar between sexes (Fuchs et al., 2005 F; eltenstein study indicates that the PFC and NAcc are critical structures et al., 2011a; Cox et al., 2017). Previously, we (Bechard et al., 2017; involved in the interaction between oxytocin and glutamatergic Leong et al., 2017) and others (Feltenstein et al., 2011b) found no signaling in males and females. sex differences in cocaine-cued reinstatement, as well as similar reinstatement across all estrous cycle phases. This report is con- Acknowledgments sistent with our previous work showing males and females lever We thank Shannon Ghee, Carole Berini, and Angela Kearns for press equally to cocaine-associated cues and oxytocin decreases technical assistance. Cocaine was supplied by National Institute cued reinstatement to cocaine seeking to the same extent in on Drug Addiction. male and female rats (Leong et al., 2016, 2017). For therapeutic purposes, oxytocin has been administered Conflict of Interest via intranasal administration in which the peptide enters the blood stream via the nasal passage. In Experiments 2 and 3, we The authors do not have any competing financial interests in tested site-specific administration of oxytocin, rather than sys- relation to this work. The data collected for this manuscript were temic administration. The final experiment demonstrates that supported by the National Institute of Health, National Institute a more translationally relevant administration route results in of Drug Addiction grants: P50 DA016511 (C.M.R.), R01 DA033049 the same pattern of responding as intra-accumbal microinfu- (C.M.R.), R01 DA033436 (L.K.), and T32 DA728823 (K.C.L. and R.W.). sions. Oxytocin (i.p.) decreased reinstatement to cocaine seek- All authors discussed the experimental design, results, and impli- ing, and this was reversed by the mGluR2/3 antagonist similar cations at length. R.A.W., K.C.L., and C.L. oversaw and conducted to what was seen when oxytocin was infused directly into the the experiments including surgery, behavior, and microinfusions. NAcc. The i.p. delivery of oxytocin results in activation of periph- C.L. conducted the HPLC study. R.A.W., C.L., and K.C.L. contrib- eral oxytocin receptors and can produce a decrease in locomotor uted to writing the initial version of the manuscript. C.R.M. con- activity in male and female rats (Zhou et al., 2014 2015 , ; Leong ducted the statistical analysis and wrote the final version of the et al., 2016). As such, a peripheral mechanism of action for the manuscript. L.K. and J.P. edited the final manuscript version. behavioral effects of oxytocin cannot be ruled out using a sys- temic delivery route. Statement of Interest Relatively small amounts of oxytocin cross the blood brain barrier after systemic administration (Landgraf et al., 1979; The authors declare there are no conflicts of interest to disclose. All authors contributed in a significant way to the manuscript Ermisch et al., 1985). 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International Journal of Neuropsychopharmacology – Oxford University Press
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