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Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

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Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking Neuropsychopharmacology (2013) 38, 2657–2665 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking 1 1 1 1 ,1 Xiaohu Xie , Amy A Arguello , Audrey M Wells , Andrew M Reittinger and Rita A Fuchs* 1 Department of Psychology, University of North Carolina, Chapel Hill, NC, USA Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine- seeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaine- seeking behavior. To test this hypothesis, rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 mg/0.5 ml/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 ml/hemisphere), Ro25-6981 (NR2B subunit- containing NMDAR antagonist; 0.2 or 2 mg/0.5 ml/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently impaired drug context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments. Cocaine-seeking behavior during the first 20 min of the test session in the cocaine-paired context was associated with an increase in NR2B subunit activation, and intra-DH PP2 pretreatment disrupted this relationship. Together, these findings suggest that Src-family kinase activation, NMDAR stimulation, and likely Src-family kinase-mediated NR2B subunit-containing NMDAR activation in the DH are necessary for incentive motivational and/or memory processes that promote contextual cocaine-seeking behavior. Neuropsychopharmacology (2013) 38, 2657–2665; doi:10.1038/npp.2013.175; published online 14 August 2013 Keywords: cocaine; context; reinstatement; dorsal hippocampus; Src-family kinases; glutamate INTRODUCTION istration of NMDAR antagonists inhibits the expression of cocaine-conditioned place preference and explicit cue- Exposure to drug-associated environmental stimuli pro- induced instrumental cocaine- or ethanol-seeking behaviors vokes relapse to drug use in cocaine users (Childress et al, (Bachteler et al, 2005; Backstrom and Hyytia, 2006; 1988; Grant et al, 1996; Childress et al, 1999). Paralleling Maldonado et al, 2007). These effects are mediated by these clinical findings, exposure to a previously cocaine- NMDAR populations in multiple brain regions. Consistent paired context induces cocaine-seeking behavior in the with this, NMDAR antagonism in the central amygdala or extinction-reinstatement animal model of drug relapse the nucleus accumbens core attenuates the expression of (Crombag et al, 2008; Fuchs et al, 2008a). Furthermore, morphine-conditioned place preference (Rezayof et al, drug context-induced reinstatement of cocaine-seeking 2007) and explicit cue-induced instrumental cocaine-seek- behavior depends on glutamatergic neurotransmission, in ing behavior (Backstrom and Hyytia, 2007), respectively. part via the stimulation of metabotropic glutamate receptor NMDAR antagonism in the DH also disrupts the expression subtype 1 (mGluR1), within the dorsal hippocampus (DH) of amphetamine-induced conditioned place preference (Xie et al, 2010). (Sakurai et al, 2007); however, it has yet to be investigated Similar to mGluR1s, N-methyl-D-aspartate glutamate whether the stimulation of NMDAR populations in the DH (NMDA) receptors (NMDARs) critically regulate environ- is necessary for drug context-induced reinstatement of mentally induced drug-seeking behaviors. Systemic admin- instrumental drug-seeking behavior. NMDAR function is critically regulated by the Src family of tyrosine kinases (Groveman et al, 2012; Salter and Kalia, *Correspondence: Dr RA Fuchs, Department of Psychology, University of North Carolina at Chapel Hill, CB no. 3270, Davie Hall, Room 121, 2004). Five members of the family have been identified in Chapel Hill, NC 27599-3270, USA, Tel: (919) 843 9112, Fax: the mammalian brain, including Src, Fyn, Lyn, Yes, and Lck (919) 962 2537, E-mail: [email protected] (Salter and Kalia, 2004). In cultured hippocampal neurons Received 21 March 2013; revised 11 July 2013; accepted 12 July 2013; or brain slices, activation of Src-family kinases increases the accepted article preview online 22 July 2013 phosphorylation of NR2B NMDAR subunits (Lu et al, 1999a; Src and contextual cocaine seeking X Xie et al 2658 Stramiello and Wagner, 2008), which is required for The operant conditioning chambers were configured to one NR2B subunit surface expression and NMDAR function of two distinctly different contexts (Contexts 1 and 2, (Ali and Salter, 2001; Groveman et al, 2012; Lu et al, 1999a; described in Supplementary Materials and Methods). Active Salter and Kalia, 2004; Stramiello and Wagner, 2008). lever presses resulted in cocaine reinforcement (cocaine Conversely, pharmacological inhibition of Src-family hydrochloride; 0.15 mg/0.05 ml per infusion, i.v.; NIDA, kinases in the dorsomedial striatum decreases the phos- Research Triangle Park, NC) under a FR-1/20 s-time-out phorylation of NR2B subunits and the expression of drug- schedule (Fuchs et al, 2007). Responses on the other primed alcohol-seeking behavior (Wang et al, 2010). (inactive) lever were recorded but had no scheduled However, the putative contributions of Src-family kinases consequences. Rats that did not reach a minimum of 10 in the DH to context-induced motivated behaviors, and sessions with X10 cocaine infusions/session were elimi- specifically to drug context-induced cocaine-seeking beha- nated from the experiment. The remaining rats received vior, have not been explored. daily 2-h extinction-training sessions in an alternate context The present study evaluated the hypothesis that NMDARs (1 or 2). During extinction training, lever responses were and Src-family kinases within the DH critically regulate recorded but had no scheduled consequences. Before the drug context-induced cocaine-seeking behavior. In experi- fourth extinction-training session, rats were adapted to the ments 1 and 2, we investigated the dose-dependent effects intracranial microinfusion procedure, as described pre- of the NMDAR antagonist, AP5, and the Src-family kinase viously (Fuchs et al, 2007). As active lever responses during inhibitor, PP2, in the DH on drug context-induced cocaine- cocaine self-administration training averaged between 50 seeking behavior and the possible rate-altering effects and 75/session (see Supplementary Table S1), extinction of these manipulations on food-reinforced instrumental training continued until a criterion of p25 active lever responding and general locomotor activity. In experiment 3, responses/session on at least two consecutive days was we examined the effects of the behaviorally effective dose reached. Rats that reached this criterion were used for of PP2 on NR2B subunit activation in the DH in relation subsequent reinstatement testing. to drug context-induced cocaine-seeking behavior. Finally, in experiment 4, we examined the dose-dependent effects of intra-DH administration of the selective NR2B subunit- Reinstatement Testing containing NMDAR antagonist, Ro25-6981, on drug con- Cocaine-seeking behavior was assessed in the cocaine-paired text-induced cocaine-seeking behavior, food-reinforced and extinction contexts during four test sessions, using a instrumental responding, and locomotor activity. counterbalanced experimental design, as described pre- viously (Xie et al, 2010) and in the Supplementary Materials MATERIALS AND METHODS and Methods. Rats received bilateral vehicle or AP5 (0.25 or 2.5 mg/0.5 ml/hemisphere; N ¼ 7, experiment 1), PP2 (6.25 or Animals 62.5 ng/0.5 ml/hemisphere; N ¼ 8, experiment 2), or Ro25- 6981 (0.2 or 2 mg/0.5 ml/hemisphere; N ¼ 8, experiment 4) Male Sprague–Dawley rats (Charles-River, N ¼ 64; 250– microinfusions into the DH immediately before testing. 275 g) were individually housed in a temperature- and In experiment 3, rats received bilateral vehicle or PP2 humidity-controlled vivarium on a reversed light/dark (62.5 ng/0.5 ml/hemisphere; N ¼ 6–9) microinfusions into the cycle. Rats were maintained on 20–25 g of rat chow per DH and either a 1-h test session in the cocaine-paired context day and ad libitum water. The housing and treatment of the or exposure to the home cage, followed by euthanasia. rats followed the guidelines of the ‘Guide for the Care and Use of Laboratory Rats’ (Institute of Laboratory Animal Resources, Commission on Life Sciences 2011) and were app- Locomotor Activity and Food-Reinforced Instrumental roved by the Institutional Animal Care and Use Committee of Behavior the University of North Carolina at Chapel Hill. Pharmacological manipulations may produce motor side effects that alter the expression of motivated behavior. Food Training and Surgery Hence, in experiments 1, 2, and 4, at least 72 h after the last To expedite
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