A glutamatergic insular-striatal projection regulates the reinstatement of cue-associated morphine-seeking behavior in mice
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)
- et al.
From ventral-medial to dorsal-lateral striatum: neural correlates of reward-guided decision-making
Neurobiol. Learn. Mem.
(2015) - et al.
A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior
Neuroscience
(1999) - et al.
Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior
Neuropsychopharmacology
(2001) - et al.
Modulatory effects of Ampicillin/Sulbactam on glial glutamate transporters and metabotropic glutamate receptor 1 as well as reinstatement to cocaine-seeking behavior
Behav. Brain Res.
(2017) - et al.
Functional role for cortical-striatal circuitry in modulating alcohol self-administration
Neuropharmacology
(2018) - et al.
Silencing the insular-striatal circuit decreases alcohol self-administration and increases sensitivity to alcohol
Behav. Brain Res.
(2018) - et al.
Cortical thickness abnormalities in cocaine addiction--a reflection of both drug use and a pre-existing disposition to drug abuse?
Neuron
(2008) - et al.
The hidden island of addiction: the insula
Trends Neurosci.
(2009) - et al.
Reduced behavioral and neural activation in stimulant users to different error rates during decision making
Biol. Psychiatry
(2008) - et al.
Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit
Neurobiol. Learn. Mem.
(2017)
Involvement of the rostral agranular insular cortex in nicotine self-administration in rats
Behav. Brain Res.
Involvement of the caudal granular insular cortex in alcohol self-administration in rats
Behav. Brain Res.
Histone acetylation in drug addiction
Semin. Cell Dev. Biol.
The orbital cortex in rats topographically projects to central parts of the caudate-putamen complex
Neurosci. Lett.
Is an epigenetic switch the key to persistent extinction?
Neurobiol. Learn. Mem.
The brain on drugs: from reward to addiction
Cell
Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons
Neuron
Patterns of overlap and segregation between insular cortical, intermediodorsal thalamic and basal amygdaloid afferents in the nucleus accumbens of the rat
Neuroscience
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.
Context is a trigger for relapse to alcohol
Behav. Brain Res.
Organization of visceral and limbic connections in the insular cortex of the rat
J. Comp. Neurol.
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
Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats
Psychopharmacology (Berl)
The effect of lesions of the insular cortex on instrumental conditioning: evidence for a role in incentive memory
J. Neurosci.
Cited by (13)
Distinct reward processing by subregions of the nucleus accumbens
2023, Cell ReportsBrain recovery of the NAc fibers and prediction of craving changes in person with heroin addiction: A longitudinal study
2023, Drug and Alcohol DependenceCitation Excerpt :Besides, insula acts as a receiver for interoceptive signals and reduced interceptive signaling may be lead to the loss of control over drug intake, craving and the propensity to return to using drugs (Droutman et al., 2015; Joshi et al., 2020). The association between insula and NAc may mediate the retrieval and performance of actions based on incentive memory in morphine seeking behavior in mice (Zhang et al., 2019). White-matter tract connecting insula and NAc was demonstrated in a gambling research (Leong et al., 2016).
Insula lesions reduce stimulus-driven control of behavior during odor-guided decision-making and autoshaping
2022, Brain ResearchCitation Excerpt :This wide-ranging but somewhat nebulous definition comes from insula’s vast connectivity throughout the brain, making this region relevant for the brain’s emotional, motivational, and sensorimotor control (Gogolla, 2017). Recently, a significant body of research has emerged to demonstrate an equally vast role for insula in reward-learning and decision-making (Droutman et al., 2015a); across humans and rodents, insula has been proven necessary for cue and context-induced responding (Arguello et al., 2017; Cosme et al., 2015; Ho et al., 2018; Naqvi and Bechara, 2009; Pelchat et al., 2004; Zhang et al., 2019), anticipation and craving (Garavan, 2010; Kusumoto-Yoshida et al., 2015; Samuelsen et al., 2013; Wang et al., 1999), and expression of goal and habit-directed behavior (Kesner and Gilbert, 2007; Naqvi and Bechara, 2010; Contreras et al., 2012). This work, while impressive, leaves the outstanding question of how insula is involved in more complex decision-making tasks that vary expected rewards across multiple dimensions, use different stimulus–response rules to guide behavior, and alter reward contingencies repeatedly within a given behavioral session.
Cannabidiol attenuated the maintenance and reinstatement of extinguished methylphenidate-induced conditioned place preference in rats
2021, Brain Research BulletinCitation Excerpt :Subsequently, both priming dose of MPH (0.25 or 0.5 mg/kg; i.p.) reinstated the CPP induced in rats after the extinction phase which is consistent with our previous research (Kashefi et al., 2019). Several studies have shown that dopamine (Guerrero-Bautista et al., 2019; Kim et al., 2016; Sadeghzadeh et al., 2017; Yazdani et al., 2019) and other neurotransmitters such as acetylcholine (Zannone et al., 2018), (Daza-Losada et al., 2007; Vidal-Infer et al., 2012), glutamate (Chesworth et al., 2013; Leão et al., 2010; Siahposht-Khachaki et al., 2017; Zhang et al., 2019) and orexin (Edalat et al., 2018; Qi et al., 2013; Tung et al., 2016) play an essential role in reinstatement. The mesolimbic dopaminergic system appears to be the major neuroanatomical substrate of behavioral sensitization and release of DA from neurons that reinforces behavior (De Vries et al., 1998).