Cool Wolf 471554 Here I Am Again ;

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ILAR J. Author manuscript; available in PMC 2013 Jun 7.

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Mediating the Effects of Drug Abuse: The Role of Narp in Synaptic Plasticity

Irving M. Reti, MBBS, Associate professor, Ashley M. Blouin, PhD, Postdoctoral fellow, Paul F. Worley, MD, Professor, Peter C. Holland, PhD, Professor, Alexander W. Johnson, PhD, Research associate, and Jay M. Baraban, MD, PhD, Professor

Irving M. Reti

Psychiatry and Neuroscience Department and Director of the Brain Stimulation Program, both at Johns Hopkins University (JHU) in Baltimore, Maryland

Ashley M. Blouin

Department of Psychiatry and Behavioral Sciences at Johns Hopkins School of Medicine

Paul F. Worley

Solomon Snyder Department of Neuroscience at Johns Hopkins School of Medicine

Peter C. Holland

JHU Department of Psychological and Brain Sciences and the Solomon Snyder Department of Neuroscience

Alexander W. Johnson

JHU Department of Psychological and Brain Sciences

Jay M. Baraban

Solomon Snyder Department of Neuroscience and the Department of Psychiatry and Behavioral Sciences

Abstract

There has been remarkable progress in deciphering the molecular mechanisms that mediate synaptic plasticity. Advances have stimulated interest in determining whether these plasticity mechanisms also mediate the long-lasting behavioral effects induced by drugs of abuse. The observation that drugs of abuse, such as cocaine or morphine, can elicit robust immediate early gene (IEG) responses similar to those induced by long-term potentiation stimulation has provided important support for this hypothesis. Evidence that repeated administration of cocaine produces alterations in expression and trafficking of AMPA receptors, processes that play a central role in synaptic plasticity, has also bolstered this view. Neuronal activity–regulated pentraxin (Narp), an IEG, has emerged as an attractive candidate to mediate long-term effects of drugs of abuse because it encodes a secreted protein that binds to the extracellular surface of AMPA receptors and regulates their trafficking. In this review we provide background information on Narp and closely related proteins, the neuronal pentraxins, and summarize studies of Narp knockout mice demonstrating that this IEG modulates long-term behavioral responses to drugs of abuse.

Keywords: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), drug abuse, immediate early gene (IEG), morphine, Narp, neuronal pentraxin, synaptic plasticity, withdrawal

Introduction

Over the past few decades there has been remark-able progress in deciphering the molecular mechanisms that mediate synaptic plasticity. Advances in these areas have stimulated research that has enhanced understanding of the relevance of these plasticity mechanisms to long-lasting behavioral effects induced by drugs of abuse.

It is now clear that drug addiction induces structural changes in dendritic spines as well as long-term depression (LTD ¹ ) and long-term potentiation (LTP ¹ ) in reward circuits, indicating that plasticity processes are critical contributors to the persistent effects of substance abuse (reviewed in Robinson and Kolb 2004; Russo et al. 2010; Thomas et al. 2008).

There has been considerable interest in determining, at the molecular level, whether similar signaling pathways mediate physiological forms of plasticity and long-lasting changes induced by addiction. Findings that drugs such as cocaine or morphine can elicit robust immediate early gene (IEG ¹ ) responses similar to those induced by LTP stimulation suggest that this is the case (Bhat and Baraban 1993; Graybiel et al. 1990; Harlan and Garcia 1998). And evidence that repeated administration of cocaine alters the expression and trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA ¹ ) receptors (AMPARs ¹ ; Bowers et al. 2010; Wolf 2010), processes that play a central role in synaptic plasticity, bolsters this view.

Because IEGs and AMPARs are prominent in drug-induced plasticity processes, neuronal activity–regulated pentraxin (Narp ¹ ), itself an IEG, has emerged as an attractive candidate to mediate long-term effects of drug abuse, as it encodes a secreted protein that binds to the extracellular surface of AMPARs and regulates their trafficking.

In the following sections, we provide background information on Narp and closely related proteins, the neuronal pentraxins, and then summarize studies, mostly in mice, implicating Narp in mediating behavioral responses to drugs of abuse.

Overview of Narp and Other Neuronal Pentraxins

Identification and Association with AMPA Receptors

Narp was first identified by Hsu and Perin (1995) and subsequently characterized as a neuronal IEG by Worley and coworkers in a screen designed to detect genes induced by seizure activity in the hippocampus (Tsui et al. 1996). Initial characterization revealed that it was also induced in dentate granule cells by brief tetanic stimulation of the perforant pathway, eliciting long-term potentiation of that input. Accordingly, Narp, like other IEGs induced in LTP, has been implicated in mediating enduring forms of synaptic plasticity.

Sequence analysis of the Narp transcript revealed homology to other members of the pentraxin family, including two other neuronal pentraxins, NP1 and neuronal pentraxin receptor (NPR ¹ ) (Figure 1; Dodds et al. 1997; Garlanda et al. 2005; Schlimgen et al. 1995). However, NP1 and NPR are not IEGs (their expression is not induced in the hippocampus by seizure stimulation).

The pentraxin family (adapted from figure 1 in Garlanda et al. 2005). The carboxy (C)-terminal of pentraxins contains a conserved pentraxin domain (~200 amino acids [aa] long) including an 8 aa sequence, HxCxS/TWxS, shared by all family members and called the pentraxin signature. Sequence homology among all family members is relatively high in the pentraxin domain, but not in the N-terminal domain. For example, among humans the N-terminal sequence of long pentraxin 3 (PTX3) has only 10% identity with the NP1 N-terminal domain sequence, whereas identity in the N-terminal domain among the neuronal pentraxins (Narp, NP1, and NPR) is higher, between 28% and 38%. The neuronal pentraxins function in the nervous system, and the nonneuronal pentraxins (CRP, SAP, PTX3, and PTX4) function in the immune system (Garlanda et al. 2005). The color image is available in the online posting of this article at www.ilarjournal.com. CRP, C-reactive protein; NPR, neuronal pentraxin receptor; PTX4, long pentraxin 4; SAP, serum amyloid protein; TM, transmembrane domain

Pentraxins form pentameric structures that aggregate into larger complexes. NP1 and Narp coprecipitate from brain extracts, confirming that endogenous neuronal pentraxins form stable aggregates as well (Xu et al. 2003). Furthermore, in several neuronal populations Narp and NP1 are coexpressed in the same cells (e.g., dentate granule cells), although this is not always the case (for example, immunostaining studies have detected Narp, but not NP1, in the orexin neurons of the hypothalamus; Reti et al. 2002a). Coexpression of pairs of neuronal pentraxin family members indicates that they are able to form heteromeric assemblies (Kirkpatrick et al. 2000). Narp and NP1 are secreted proteins, whereas NPR possesses an amino terminal transmembrane domain and is therefore tethered to the membrane (Dodds et al. 1997). On the extracellular surface, Narp, NP1, and NPR form large, organized heteromeric complexes that are stabilized by disulfide bonds (Xu et al. 2003).

Neuronal pentraxins localize to excitatory synapses where their conserved, carboxy-terminal pentraxin domains can interact with the N-terminal extracellular domain of AMPARs (O'Brien et al. 1999; Sia et al. 2007; Xu et al. 2003), suggesting that they may be integral to synapse formation or stabilization. Consistent with this view, overexpression of recombinant Narp in vitro increases the number of excitatory but not inhibitory synapses.

Moreover, in transfected hEK293T cells Narp interacts with itself, forming large surface clusters that coaggregate with AMPAR subunits, and Narp-expressing hEK293T cells induce clustering of neuronal AMPARs (O'Brien et al. 1999). These findings prompted the suggestion that Narp may have agrinlike properties at central synapses (Fong and Craig 1999).

Heterogeneous Expression of Narp in the Brain

Immunohistochemical localization of Narp in brain sections has enabled identification of several important features of Narp expression in the nervous system. First, even though it was identified as an IEG induced by neuronal activation, Narp also displays prominent constitutive expression in many brain pathways. Second, it is expressed in a remarkably heterogeneous fashion—rather than being expressed at all excitatory synapses, it regulates AMPAR trafficking in selected pathways. Third, Narp is targeted to axons where it appears to be released from presynaptic terminals. The following examples illustrate these points.

A survey of Narp expression in the nervous system revealed that, in the hypothalamus, orexin neurons stain strongly for Narp whereas adjacent areas are blank (Reti et al. 2002a). Interestingly, melanin-concentrating hormone (MCH) neurons, which cluster next to orexin cells, stain strongly for NP1 but not Narp.

In the hippocampus, Narp is expressed primarily in dentate granule cells. Under basal conditions, only scattered Narp-positive cell bodies are present. However, there is prominent staining in the mossy fiber pathway, which contains axons of dentate granule cells that project to the cornu ammonis region 3 (CA3; see Figure 2; Reti et al. 2002b). After seizure stimulation, Narp staining is dramatically induced in granule cell bodies but then appears to be trafficked rapidly into the mossy fiber projection.

Narp expression in the hippocampus (reprinted from Reti et al. 2002b). (A) An immunoblot. Lanes 1 and 2 demonstrate that Narp antibody reliably detects a single band migrating very slowly on SDS-PAGE. Lane 3 shows that preincubation with the glutathione S-transferase (GST)-Narp fusion protein blocks detection of the band by the Narp antibody. Each lane was loaded with 35 mg protein from hippocampus. (B) Narp hippocampal immunostaining. There is prominent Narp mossy fiber (mf) staining in the hippocampus extending to cornu ammonis region (CA) 3, but only scattered cell body staining in the dentate gyrus (DG). In CA1, the cell body staining is more uniform but less intense. The color image is available in the online posting of this article at www.ilarjournal.com.

Another example of selective Narp expression is in dorsal root ganglia. Prominent staining occurs in a high percentage of small nociceptive neurons but only rarely in large neurons. Again, in these cells Narp is trafficked down axons into terminals in the spinal cord, where it is expressed in external laminae of the dorsal horn (our unpublished data).

Evidence for Narp Secretion

It has been difficult to determine how Narp secretion is regulated by using conventional neuronal culture preparations. Typically, changes in protein secretion can be monitored by assaying the media. But Narp complexes appear to remain associated with cellular membranes or the extracellular matrix after secretion, suggesting a need for alternate approaches.

After noticing very strong Narp staining in the posterior pituitary, we wondered whether Narp might be secreted into the bloodstream (Reti et al. 2008a). We confirmed that it is prominently expressed in hypothalamic vasopressin neurons, which send axons to the posterior pituitary. Using affinity purification methods, we found that Narp is present in serum and that serum Narp levels are elevated in response to the same panel of stressors that trigger vasopressin secretion. We also confirmed that hypophysectomy greatly reduces Narp levels in the serum, indicating that serum Narp originates from the posterior pituitary.

These studies demonstrate that Narp is secreted from axon terminals in an activity-dependent fashion in parallel with vasopressin. To determine whether Narp and vasopressin are released from the same or different vesicles, we performed double-label electron microscopy immunostaining studies, which showed that they are present in the same vesicle population and that Narp may be coreleased with neuropeptides.

Our findings support our working model of the action of Narp and other neuronal pentraxins at synapses: they are secreted from presynaptic terminals in an activity-dependent fashion and form large aggregates that bind to postsynaptic AMPARs to regulate their trafficking. These findings also imply that Narp and other neuronal pentraxins are well positioned to play a key role in synaptic plasticity.

Link to Synaptic Plasticity

Direct evidence supporting the participation of neuronal pentraxins in regulating AMPAR trafficking is available from studies demonstrating that axonally derived NP1 and NPR are crucial for the recruitment of AMPARs to both artificial and native synapses (Sia et al. 2007). NPR is also essential in metabotropic glutamate receptor (mGluR ¹ )-LTD in a process that involves activation of the extracellular metalloprotease TACE (tumor necrosis factor [TNF]-α-converting enzyme), cleavage of NPR near the transmembrane domain, and rapid endocytosis of NPR and AMPAR (Cho et al. 2008).

In the visual system, neuronal pentraxins are important for the activity-dependent segregation and refinement of eye-specific retinal ganglion cell projections to the dorsal lateral geniculate nucleus (Bjartmar et al. 2006). And Chang and colleagues (2010) have recently shown that in the hippocampus Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons.

These findings support the view that neuronal pentraxins are involved in synaptic plasticity and that Narp is an attractive candidate to mediate long-lasting behavioral changes induced by drugs of abuse.

Role of Narp in Aversive Conditioning

Based on previous observations that administration of cocaine induces IEG expression in the striatum (Bhat and Baraban 1993), we initially anticipated that Narp would follow a similar pattern of activation. Unexpectedly, extensive attempts to trigger Narp expression in rat striatum and ventral tegmental area (VTA) with acute and chronic psychostimulants or morphine were unsuccessful (Reti et al. 2002b). However, very high doses of amphetamine, which have been associated with dysphoric effects, induced Narp expression in neurons in the central nucleus of the amygdala. As this region is thought to coordinate responses to aversive stimuli (for example, it appears to encode conditioned place aversion induced by opiate withdrawal; Heinrichs et al. 1995; Stinus et al. 1990), we considered the possibility that Narp might be involved in modulating such responses. ² Thus, induction of Narp by opiate withdrawal might mediate changes in synaptic plasticity that underlie this long-lasting behavioral response.

Consistent with this hypothesis, we found that Narp is selectively induced by morphine withdrawal in the rat central nucleus of the amygdala as well as in other parts of the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses (Reti and Baraban 2003). Activation of these nuclei by drug withdrawal is thought to contribute to continued drug use, especially in the context of stimuli associated with withdrawal. In the presence of these cues, the drive to avoid the dysphoric effects of withdrawal may contribute to drug craving (Goldberg et al. 1969; Hutcheson et al. 2001; Koob and Le Moal 2005). In another set of studies, we found that Narp is induced in the extended amygdala by withdrawal from other addictive drugs (nicotine and the cannabinoid Δ⁹-tetrahydrocannabinol), indicating that it is a common component of the transcriptional response triggered by drug withdrawal (Reti et al. 2009).

Based on these immunohistochemical findings, we hypothesized that Narp knockout (KO ¹ ) mice would be deficient in long-term aversive effects of morphine withdrawal (acute physical signs of morphine withdrawal are unaffected by Narp deletion; Reti et al. 2008b). To test this hypothesis we used a conditioned place aversion task that involved placing morphine-dependent mice on one of two floors after administration of either saline or the morphine receptor antagonist naltrexone, which triggered morphine withdrawal. After several training sessions, we placed the mice in a chamber with both floor types and assessed the time they spent on each. Surprisingly, the Narp KO mice acquired and sustained stronger aversive responses to the environment conditioned with morphine withdrawal compared to the controls. Paradoxically, the Narp KO mice exhibited accelerated extinction of this heightened aversive response.

Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and therefore may regulate plasticity processes that underlie drug addiction. Accordingly, individual differences in the expression or release of Narp may affect the intensity or duration of withdrawal symptoms and thus contribute to susceptibility to continued drug use.

Role of Narp in Appetitive Conditioning

To determine whether Narp deletion might also affect behavioral responses elicited by morphine administration, as opposed to those elicited by withdrawal, we evaluated Narp KO mice on locomotor sensitization to morphine. Both wild-type (WT ¹ ) and KO mice showed robust and comparable sensitization to the psychomotor activating effects of morphine (Crombag et al. 2008).

We next assessed the impact of Narp deletion on the ability of morphine treatments, when paired with a distinct set of environmental cues, to establish conditioned place preference (CPP ¹ ). In this paradigm, naïve mice of both groups were placed on one of two floors after either morphine or saline administration. After several training sessions, the mice were placed in a chamber with both floor types and the time spent on each floor was recorded. Both the WT and Narp KO mice developed place preference for the morphine-paired environmental stimulus (floor type) and the magnitude of the preference was comparable in both groups.

We found large differences, however, between the WT and KO mice in their rates of extinction (i.e., repeatedly testing mice in the absence of morphine injections; Figure 3). The WT mice exhibited a progressive return to preconditioning levels within the first half of the extinction phase, consistent with the expectation that repeated exposure to the positive or negative conditioned stimulus in the absence of morphine resulted in extinction. In contrast, the Narp KO mice failed to show any evidence of extinction.

Effect of Narp deletion on extinction of morphine-conditioned place preference. Average time spent on previously morphine-paired and saline-paired floor types for wild-type (WT) (top panel) and Narp knockout (KO) mice (bottom panel) across 23 (nonreinforced) extinction sessions (30 mins each). Error bars indicate ± SEM. Reprinted from Crombag et al. (2008).

Neuronal pentraxins also modulate behavioral responses elicited by cocaine. Pacchioni and Kalivas (Pacchioni et al. 2009) found that deletion of either Narp or NP1 promotes cocaine-induced place preference, whereas NPR deletion does not affect this response. In addition, Narp and NP1 KO mice show blunted locomotor responses to AMPA microinjection into the nucleus accumbens (NAc ¹ ) when tested 3 weeks after the discontinuation of repeated cocaine injections, whereas the AMPA response is augmented in NPR KO mice.

Consistent with the lower AMPA responsiveness after chronic cocaine in Narp KO mice, GluR1 levels were lower in the postsynaptic density (PSD) fraction of Narp KO mice withdrawn from cocaine. Thus, Narp and NP1 KO mice displayed similar results in these studies, in contrast to the effects observed in NPR KO mice.

The reduction in AMPA responsiveness in Narp and NP1 KO mice aligns with in vitro studies indicating that Narp and NP1 enhance glutamate signaling by clustering AMPA receptors. NPR, on the other hand, mediates endocytosis of surface AMPARs during mGluR1-dependent LTD (Cho et al. 2008), consistent with the increased AMPA responses observed in NPR KO mice. These studies support the hypothesis that neuronal pentraxin family members mediate changes in AMPAR responsiveness thought to underlie long-term behavioral responses induced by cocaine.

We also examined whether Narp deletion affects performance on tasks used to assess motivational consequences of food-rewarded learning (Johnson et al. 2007). We noted that Narp KO mice were unimpaired both in learning simple Pavlovian discriminations and instrumental lever pressing and in the acquisition of at least two aspects of Pavlovian incentive learning, conditioned reinforcement and instrumental transfer.

In contrast, Narp deletion resulted in a substantial deficit in the ability to use specific outcome expectancies to modulate performance in a devaluation task. Mice acquired instrumental lever pressing for two rewards, one to be devalued later and one not. Both mutant and WT mice readily acquired instrumental responding for both rewards. After training, mice were prefed with one of the two rewards, devaluing it. Responding on both levers was then assessed in extinction (i.e., the mice received no food reward). In WT mice, pre-feeding of one reward resulted in preferential responding on the lever that had produced the other, nondevalued, reward in training.

The results indicated that WT mice could use the devaluation experience to update a representation of the value of the prefed reward and use that information to direct subsequent instrumental performance. The Narp KO mice, on the other hand, responded equivalently on both levers, suggesting that they were unable to process the altered reward information and modify their performance accordingly.

Role of Glutamate Receptors in Extinction Learning

The basolateral nucleus of the amygdala (BLA) and medial prefrontal cortex (mPFC ¹ ) both project to the NAc, which appears to be important in appetitive extinction learning.

Sutton and colleagues (2003) detected changes in the levels of AMPAR (GluR1 and GluR2) subunits in the NAc after extinction of instrumental cocaine self-administration. They also reported that virus-mediated overexpression of GluR1 and -2 facilitates extinction of cocaine self-administration. Self and colleagues (2004) subsequently found that after extinction of cocaine self-administration Narp levels increase in the NAc, consistent with the hypothesis that Narp stabilizes AMPA receptors. More recently, Knackstedt and colleagues (2010) reported that extinction training after cocaine self-administration was associated with elevated Narp levels in the PSD of the NAc core, whereas there was no alteration in Narp levels in rats that had not undergone extinction. As Narp regulates AMPAR trafficking, our behavioral findings combined with these biochemical results suggest that Narp expression in one or both of these inputs to the NAc plays a critical role in mediating extinction of behavioral responses conditioned to drug administration.

To address this hypothesis, we conducted retrograde tracing studies to determine whether Narp is expressed in afferents from the BLA and mPFC to the NAc (Johnson et al. 2010). Under basal conditions, we found that there is prominent constitutive expression of Narp in both regions. (In contrast to the BLA, the adjacent central nucleus shows low levels of basal expression except after drug withdrawal, as described above.) To ascertain whether the Narp-positive neurons in the BLA project to the accumbens, we injected cholera toxin b (CTb), a retrograde tracer, into the NAc and then double stained sections for CTb and Narp.

Remarkably, our studies demonstrated that virtually all of the neurons labeled in the BLA after CTb injection are Narp-positive, as are a high percentage of CTb-positive neurons in the mPFC (unpublished data). Thus, even though we have not detected Narp-positive neuronal cell bodies in the striatum or NAc, our findings indicate that this key nucleus of the reward system is innervated by multiple Narp-positive afferents.

To assess the function of these afferent pathways in mediating the effects of Narp deletion on behavioral responses, we used localized injections of a dominant negative viral construct into the mPFC to study the effects in the Narp-positive neurons of selective Narp inactivation. This construct encodes a truncated version of Narp that binds to and inhibits axonal transport of endogenous Narp, effectively blocking its release from presynaptic terminals. We found that selective blockade of Narp in the mPFC mimics the loss of food reward devaluation described above (Johnson et al. 2010). ³

We anticipate that the approach we have described will be useful in identifying the Narp afferents to the NAc that play a critical role in mediating extinction of morphine-induced conditioned place preference.

Looking Ahead: Implications for Addiction Research

Studies of Narp in the limbic system have yielded two major findings—anatomical and behavioral—that are directly relevant to drug addiction research.

From an anatomical perspective, the selective expression of Narp in many of the major afferent pathways to the NAc suggests that Narp regulates plasticity in these pathways, which are active in guiding motivated behavior. However, two prominent NAc inputs that do not express Narp serve as interesting counterexamples. One is the dopamine input from the VTA, which does not express Narp or other neuronal pentraxins. Conceivably, as this input is thought to encode deviations from anticipated reward, it may be desirable to have this type of information remain consistent over time. The other input comes from the MCH neurons of the hypothalamus. However, as mentioned above, these neurons express another neuronal pentraxin, NP1. Further studies are necessary to determine how Narp and NP1 differentially affect synaptic plasticity in these inputs.

From a behavioral perspective, Narp KO mice reveal a selective defect in extinction of CPP (they display normal performance in a wide variety of other learning paradigms) and may thus be useful in research on mechanisms of extinction from drug craving. Their persistent preference for cues associated with morphine despite extensive extinction training indicates that this behavior is not subject to stimulus-response control, a hallmark of addiction. Furthermore, these findings leave open the possibility of identifying which accumbal afferents contribute critically to this Narp phenotype and hence regulate extinction of drug craving. Narp KO mice may also be effective models in preclinical tests of treatments to enhance extinction of drug craving and perhaps reduce the risk of reinstatement.

In summary, our studies indicate that Narp regulates the lability or stability of synaptic plasticity afferents to the NAc. In the CPP paradigm the absence of Narp leads to loss of extinction, suggesting that the plasticity changes that mediate the association of morphine with environmental cues are abnormally stable. Similarly, Narp KO mice do not alter their behavior after devaluation of food reward, again suggesting that they are unable to recalibrate the appetitive value of this stimulus. Assuming that this devaluation is mediated by a change in synaptic efficacy, it could be attributed to the loss of plasticity resulting from the absence of Narp.

While these two examples indicate that the absence of Narp renders synapses less susceptible to modification (or remodification) in response to experience, our earlier studies of aversive conditioning suggest that Narp may play a different role in circuits underlying that behavior. Narp KO mice reach extinction faster, consistent with the possibility of reduced stability of the synapses that encode the fear response. Accordingly, the impact of Narp and related neuronal pentraxins on plasticity and behavior may vary depending on which specific family members are expressed (or coexpressed) in these inputs and whether the underlying event involves removal or insertion of AMPA receptors.

It will be important in future studies to determine how Narp and other neuronal pentraxin family members regulate the stability of diverse forms of synaptic plasticity that mediate rapid and long-lasting changes in behavior.

Acknowledgments

This review was supported by grants from the National Institutes of Health (NIH) National Institute on Drug Abuse⁴ (RO1 DA016303, Reti; R25 DA021630-04, Blouin; P50 DA-0266, Baraban) and National Institute of Neurological Disorders and Stroke (RO1 NS039156, Worley).

Footnotes

¹Abbreviations that appear ≥3x throughout this article: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPAR, AMPA receptor; CPP, conditioned place preference; IEG, immediate early gene; KO, knockout; LTD, long-term depression; LTP, long-term potentiation; mGluR, metabotropic glutamate receptor; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; Narp, neuronal activity–regulated pentraxin; NPR, neuronal pentraxin receptor; WT, wild-type

²Narp is also induced in the central nucleus of the amygdala by long-term stress such as restraint, but not by short-term stressors such as footshock (Reti et al. 2009).

³Narp deficiency has been linked to synapse development in the visual system (Bjartmar et al. 2006), so our findings indicate that the effect of Narp deletion on food reward devaluation in the KO mouse is due to the absence of presynaptic release of Narp rather than to a developmental abnormality in Narp-containing pathways.

Contributor Information

Irving M. Reti, Psychiatry and Neuroscience Department and Director of the Brain Stimulation Program, both at Johns Hopkins University (JHU) in Baltimore, Maryland.

Ashley M. Blouin, Department of Psychiatry and Behavioral Sciences at Johns Hopkins School of Medicine.

Paul F. Worley, Solomon Snyder Department of Neuroscience at Johns Hopkins School of Medicine.

Peter C. Holland, JHU Department of Psychological and Brain Sciences and the Solomon Snyder Department of Neuroscience.

Alexander W. Johnson, JHU Department of Psychological and Brain Sciences.

Jay M. Baraban, Solomon Snyder Department of Neuroscience and the Department of Psychiatry and Behavioral Sciences.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676422/

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