Hypofunction of the dorsal hippocampal NMDA receptors impairs retrieval of memory to partially presented foreground context in a single-trial fear conditioning in rats

Melik, Enver; Babar, Emine; Ozen, Elif; Özgünen, Tuncay

doi:10.1016/j.euroneuro.2005.07.008

Cited by 20 publications

(15 citation statements)

References 42 publications

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“…Reciprocal positive feedback interactions occur between mGlu5 and NMDA receptors in that activation of NMDA receptors can activate mGluR5-mediated neural responses and vice versa (Doherty et al, 1997;Alagarsamy et al, 1999). Although the role of mGlu5 receptors in memory retrieval is not fully understood, NMDA receptors have been implicated in memory retrieval in animal models of fear conditioning (Melik et al, 2006;Matus-Amat et al, 2007) and spatial working memory (Yoshihara and Ichitani, 2004). Thus, functional blockade of mGluR5 may have impeded NMDA receptor-mediated effects on the retrieval of rewardrelated memory, thereby resulting in the observed decrease produced by MTEP of conditioned reinstatement induced by both the cocaine and SCM S ϩ .…”

Section: Discussionmentioning

confidence: 99%

Dissociation of the Effects of MTEP [3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on Conditioned Reinstatement and Reinforcement: Comparison between Cocaine and a Conventional Reinforcer

Martin‐Fardon¹,

Baptista²,

Dayas³

et al. 2009

J Pharmacol Exp Ther

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To advance understanding of the potential of metabotropic glutamate receptor (mGluR) 5 as treatment targets for cocaine addiction, the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]piperidine] (a selective mGluR5 antagonist) on conditioned reinstatement of cocaine seeking were examined. To test whether modification of conditioned reinstatement by MTEP is selective for drug-directed behavior or reflects general actions on motivated behavior, effects of MTEP on reinstatement induced by a stimulus conditioned to palatable conventional reward, sweetened condensed milk (SCM), were also evaluated. Previous data suggest that mGluR manipulations preferentially interfere with conditioned reinstatement compared with cocaine self-administration. Therefore, the effects of MTEP on cocaine self-administration were compared with MTEP's effects on SCM-reinforced behavior using the same cocaine doses and SCM concentrations employed for establishing conditioned reinstatement. Male Wistar rats were trained to associate a discriminative stimulus (S D ) with response-contingent availability of cocaine or SCM and subjected to reinstatement tests after extinction of cocaine or SCM-reinforced behavior. MTEP (0.3-10 mg/kg i.p.) dose-dependently attenuated the response-reinstating effects of both the cocaine S D and SCM S D . MTEP also decreased cocaine self-administration without a clear graded dose-response profile and did not modify SCM-reinforced responding. The findings implicate mGluR5-regulated glutamate transmission in appetitive behavior controlled by reward-related stimuli but without selectivity for cocaine seeking. However, the data suggest a differential role for mGluR5 in the acute reinforcing effects of cocaine versus conventional reward. These observations identify mGluR5 as potential treatment targets for cocaine relapse prevention, although the profile of action of mGluR5 antagonists remains to be more closely examined for potential anhedonic effects.

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Section: Discussionmentioning

confidence: 99%

Dissociation of the Effects of MTEP [3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on Conditioned Reinstatement and Reinforcement: Comparison between Cocaine and a Conventional Reinforcer

Martin‐Fardon¹,

Baptista²,

Dayas³

et al. 2009

J Pharmacol Exp Ther

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“…For instance, NMDAR stimulation is necessary for the retrieval or expression of spatial, inhibitory avoidance, and trace fear memory (Corcoran et al, 2011;Matus-Amat et al, 2007;Melik et al, 2006;Quinn et al, 2005;Rodrigues et al, 2001), but not contextual fear memory (Fellini et Pound sign represents significant difference relative to all other time points (ANOVA time simple main effect, Tukey test, po0.05). Yoshihara and Ichitani, 2004).…”

Section: Discussionmentioning

confidence: 99%

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

Xie

Arguello

Wells

et al. 2013

Neuropsychopharmacol

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Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaineseeking 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 cocaineseeking 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 subunitcontaining 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.

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“…Among the subunits, NR2A and NR2B subunits are predominantly expressed in excitatory neurons in adult forebrain regions including hippocampus and cortex, which are believed to play essential roles in learning and memory (Furukawa et al, 2005;Monyer et al, 1994). NMDARs hypofunction was found to cause memory defects (Melik et al, 2006;Rompala et al, 2013), while genetic overexpression of NR2B subunit in the forebrain of mice and rats enhanced memory functions such as object recognition memory, fear memory, fear extinction memory, hippocampus-dependent spatial memory, and prefrontal cortex-dependent spatial working memory (Cui et al, 2011;Tang et al, 1999;Wang et al, 2009). Although NMDARs, especially the NR2B-containing NMDARs are supposed to be crucially involved in the processes underlying memory formation Shimizu et al, 2000;Tang et al, 1999;Tsien et al, 1996;Zhao et al, 2005), it has also been found that excessive activation of NMDARs mediates the excitotoxicity in the pathogenesis of numerous neuropsychiatric and neurological disorders.…”

Section: Introductionmentioning

confidence: 98%

NR2B overexpression leads to the enhancement of specific protein phosphorylation in the brain

Zhang

et al. 2014

Brain Research

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Hypofunction of the dorsal hippocampal NMDA receptors impairs retrieval of memory to partially presented foreground context in a single-trial fear conditioning in rats

Cited by 20 publications

References 42 publications

Dissociation of the Effects of MTEP [3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on Conditioned Reinstatement and Reinforcement: Comparison between Cocaine and a Conventional Reinforcer

Dissociation of the Effects of MTEP [3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on Conditioned Reinstatement and Reinforcement: Comparison between Cocaine and a Conventional Reinforcer

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

NR2B overexpression leads to the enhancement of specific protein phosphorylation in the brain

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