Elsevier

Brain Research Bulletin

Volume 152, October 2019, Pages 257-264
Brain Research Bulletin

A glutamatergic insular-striatal projection regulates the reinstatement of cue-associated morphine-seeking behavior in mice

https://doi.org/10.1016/j.brainresbull.2019.07.023Get rights and content

Highlights

  • IC and NAc core were activated following cue-induced morphine-seeking behavior.

  • Inhibition of IC→NAc core input blocked the reinstatement of expressed CPP.

  • Inhibition of glutamatergic IC→NAc core input suppressed CPP reinstatement.

  • Reinstatement of cue-associated drug-seeking require glutamatergic IC→NAc core input.

Abstract

Recently, the insular cortex (IC) was identified as part of the neuronal circuit responsible for the reward expectations in cue-triggered behaviours. Moreover, there are evidences that connections between the IC and the ventral striatum, particularly with the nucleus accumbens (NAc), may mediate the retrieval and performance of actions based on incentive memory. However, the precise role of the IC-NAc connections in cue-related drug-seeking behaviour remains unclear. We used the morphine-induced conditioned place preference (CPP) paradigm to assess the formation and relapse of cue-related drug-seeking. cFos immunostaining was used to determine the activation of the brain regions. Chemogenetic and optogenetic methods were used to manipulate the activity of IC-to-NAc projection neurons. The result showed that neurons in IC and NAc core but not NAc shell were activated following cue-induced morphine-seeking behaviour. Negligible effect of inhibition of IC-to-NAc core projection (IC→NAc core) on morphine CPP expression, whereas chemogenetic inactivation of this projection potently blocked the reinstatement of expressed morphine CPP. Furthermore, optogenetic inhibition of glutamatergic IC→NAc core inputs significant suppressed the CPP reinstatement without significant effect on CPP expression. We demonstrated here, for the first time, that IC→NAc core glutamatergic projection is required for the reinstatement of cue-associated drug seeking behaviour in mice. The present study provide insights into modulations of relapse of cue-associated drug-seeking behaviour following repeated overexposure to opioids in humans.

Introduction

The ability to use environmental information to predict the availability of rewards is a fundamental cognitive process for individuals (Kusumoto-Yoshida et al., 2015). Repeated pairings of a neutral cue with reward availability leads to the formation of conditioned associations that drive motivation for reward-seeking behavior. In drug addiction, drug-related cues contribute to relapse by triggering craving even after sustained periods of abstinence or extinction (Sinha and Li, 2007; Zironi et al., 2006).

The insular cortex (IC) has been proposed to be responsible for interoceptive information and emotional and motivational integration of visceral information (Allen et al., 1991). Recent evidence suggests that the IC also plays a role in processing cues associated with the delivery of addictive drugs. In humans, brain imaging studies have demonstrated that patients with cocaine dependence exhibit reduced cortical thickness in the IC (Makris et al., 2008). Patients with methamphetamine dependence exhibit activation in the IC (Paulus et al., 2008). In animal studies, the anterior IC is critical for the retrieval of instrumental outcome values (Balleine and Dickinson, 2000). Moreover, a number of studies have investigated the role of the IC in cue-related drug seeking behavior. For example, pharmacological inactivation of the IC attenuated context-induced reinstatement of cocaine-seeking behavior (Arguello et al., 2017). Moreover, IC was also found regulates self-administration of drugs of abuse, such as alcohol (Pushparaj and Le Foll, 2015), nicotine (Pushparaj et al., 2015), and cocaine (Cosme et al., 2015), and was involved in cue-induced reinstatement of nicotine seeking. However, it remains open to question how the information coded in the IC contacts other reward circuits to drive performance.

The nucleus accumbens (NAc) has long been known as essential for reinforcing the effects of a variety of addictive drugs (Volkow and Morales, 2015). It is divided into two main functional areas: the NAc shell and the NAc core. Both areas contain broad connections to the cortical and limbic areas. In particular, the glutamatergic projections to the NAc mainly control drug-taking behavior and relapse after drug extinction through the cortico-accumbens circuitry (Kalivas and Volkow, 2011). It is already known that the NAc receives innervation from the IC (Wright and Groenewegen, 1996). Considerable evidence has implicated the NAc and IC in a part of the network responsible for conscious pleasure from drugs (Burton et al., 2015; Laurent et al., 2012; Naqvi and Bechara, 2010). Based on previous work, it seems reasonable to propose that the IC-NAc connections may mediate cue-associated drug seeking and the relapse of this behavior after abstinence. To test this hypothesis, we first confirmed the activation of the IC, NAc core and NAc shell during the expression and reinstatement of a morphine conditioned place preference (CPP) test. Then, we used the designer receptors exclusively activated by designer drugs (DREADDs) to test whether inhibition of the IC suppresses morphine CPP and whether the IC to NAc projection affects CPP expression and reinstatement. Next, we tested the contribution of the glutamatergic IC to NAc neuron projections to the cue-induced morphine-seeking behavior in vGluT2-cre transgenic mice.

Section snippets

Animals

Animal care and experimental protocols for this study were approved by the Institutional Animal Care and Use Committee at the Xi’an Jiaotong University, and all procedures were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. C57BL/6J mice (RRID:IMSR_JAX:000664) and Vglut2-ires-Cre knock-in mice (RRID:IMSR_JAX:028863) (Vong et al., 2011) were ordered from the Jackson Laboratory (Bar Harbor, Maine, USA). As the Vglut2-ires-Cre

Results

First, we tested whether the IC, NAc core and NAc shell are activated during the expression and reinstatement of morphine CPP. The timeline is shown in Fig. 1A. Fig. 1B shows the CPP score during different CPP stages. After 4 sessions of CPP conditioning, the morphine-paired mice expressed significant CPP compared with the saline group (n = 16/group; ANOVA, F(2,45) = 215.3, P <  0.0001; post-hoc, P <  0.0001). Then, the animals were trained and tested with the extinction procedure. After

Discussion

The present study provides novel evidence that a functional connection between the IC and the NAc core is required for the relapse of cue-associated drug-seeking behavior after abstinence. We first showed that the IC and NAc core were both activated in contextual cue-induced CPP expression and morphine-priming CPP reinstatement. The CPP paradigm is a classical model for addiction memory and drug-seeking behavior. By pairing the drug with a specific environmental context, the reward properties

Conclusions

Given that different and overlapping brain areas contribute to relapse of drug-seeking for different drugs, the effects of glutamatergic projections on reinstatement that have been identified primarily in the NAc may generalize to other key structures. We demonstrated here, for the first time, that the IC→NAc core glutamatergic projection is required for the reinstatement of cue-associated drug seeking behavior in mice. We believe that our findings provide some insights into modulations of

Author contribution

Study concept and design: ZR, JW, WH, TQ.

Acquisition of data: ZR, JW, ZY, LF, LB.

Analysis and interpretation of data: ZY, ZR.

Drafting of the manuscript: ZR, WY, WH.

Funding

This work was supported by the Science and Technology Project of Xi’an [2017118SF/YX012(2)]; and the Key Science and Technology Project of Shaanxi Province [2018SF-120].

Declaration of Competing Interest

The authors declare no conflict of interest.

References (48)

  • A. Pushparaj et al.

    Involvement of the rostral agranular insular cortex in nicotine self-administration in rats

    Behav. Brain Res.

    (2015)
  • A. Pushparaj et al.

    Involvement of the caudal granular insular cortex in alcohol self-administration in rats

    Behav. Brain Res.

    (2015)
  • W. Renthal et al.

    Histone acetylation in drug addiction

    Semin. Cell Dev. Biol.

    (2009)
  • E.A. Schilman et al.

    The orbital cortex in rats topographically projects to central parts of the caudate-putamen complex

    Neurosci. Lett.

    (2008)
  • J.M. Stafford et al.

    Is an epigenetic switch the key to persistent extinction?

    Neurobiol. Learn. Mem.

    (2011)
  • N.D. Volkow et al.

    The brain on drugs: from reward to addiction

    Cell

    (2015)
  • L. Vong et al.

    Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons

    Neuron

    (2011)
  • C.I. Wright et al.

    Patterns of overlap and segregation between insular cortical, intermediodorsal thalamic and basal amygdaloid afferents in the nucleus accumbens of the rat

    Neuroscience

    (1996)
  • J. Zhang et al.

    Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus

    Neurosci. Lett.

    (2016)
  • I. Zironi et al.

    Context is a trigger for relapse to alcohol

    Behav. Brain Res.

    (2006)
  • G.V. Allen et al.

    Organization of visceral and limbic connections in the insular cortex of the rat

    J. Comp. Neurol.

    (1991)
  • S. Arai et al.

    Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen

    Neuropsychopharmacology

    (2008)
  • A.A. Arguello et al.

    Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats

    Psychopharmacology (Berl)

    (2017)
  • B.W. Balleine et al.

    The effect of lesions of the insular cortex on instrumental conditioning: evidence for a role in incentive memory

    J. Neurosci.

    (2000)
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