Kappa Opioid Receptors Regulate Stress-Induced Cocaine Seeking and Synaptic Plasticity

Brown University, Department of Molecular Pharmacology, Physiology and Biotechnology, Providence, RI 02912, USA.
Neuron (Impact Factor: 15.05). 03/2013; 77(5):942-54. DOI: 10.1016/j.neuron.2012.12.034
Source: PubMed


Stress facilitates reinstatement of addictive drug seeking in animals and promotes relapse in humans. Acute stress has marked and long-lasting effects on plasticity at both inhibitory and excitatory synapses on dopamine neurons in the ventral tegmental area (VTA), a key region necessary for drug reinforcement. Stress blocks long-term potentiation at GABAergic synapses on dopamine neurons in the VTA (LTP), potentially removing a normal brake on activity. Here we show that blocking kappa opioid receptors (KORs) prior to forced-swim stress rescues LTP. In contrast, blocking KORs does not prevent stress-induced potentiation of excitatory synapses nor morphine-induced block of LTP. Using a kappa receptor antagonist as a selective tool to test the role of LTP in vivo, we find that blocking KORs within the VTA prior to forced-swim stress prevents reinstatement of cocaine seeking. These results suggest that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse.

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    • "The endogenous KOPr system has been implicated in the reinstatement of cocaine-seeking behaviour as activation of this system reinstates cocaine seeking both in mice and monkeys (Valdez et al. 2007; Redila & Chavkin 2008). Moreover, systemic or intraventral tegmental area administration of ΚOPr antagonists decreased stress-induced reinstatement of cocaine conditioned place preference in rodents (Redila & Chavkin 2008; Graziane et al. 2013) and oral administration of a selective ΚOPr antagonist prevented cocaine-primed reinstatement in mice (Aldrich et al. 2013). "
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    ABSTRACT: The key problem for the treatment of drug addiction is relapse to drug use after abstinence that can be triggered by drug-associated cues, re-exposure to the drug itself and stress. Understanding the neurobiological mechanisms underlying relapse is essential in order to develop effective pharmacotherapies for its prevention. Given the evidence implicating the metabotropic glutamate receptor 5 (mGlu5 R), μ-opioid receptor (MOPr), κ-opioid receptor (ΚOPr) and oxytocin receptor (OTR) systems in cocaine addiction and relapse, our aim was to assess the modulation of these receptors using a mouse model of cue- and priming-induced reinstatement of cocaine seeking. Male mice were trained to self-administer cocaine (1 mg/kg/infusion, i.v.) and were randomized into different groups: (1) cocaine self-administration; (2) cocaine extinction; (3) cocaine-primed (10 mg/kg i.p.); or (4) cue-induced reinstatement of cocaine seeking. Mice undergoing the same protocols but receiving saline instead of cocaine were used as controls. Quantitative autoradiography of mGlu5 R, MOPr, KOPr and OTR showed a persistent cocaine-induced upregulation of the mGlu5 R and OTR in the lateral septum and central amygdala, respectively. Moreover, a downregulation of mGlu5 R and MOPr was observed in the basolateral amygdala and striatum, respectively. Further, we showed that priming- but not cue-induced reinstatement upregulates mGlu5 R and MOPr binding in the nucleus accumbens core and basolateral amygdala, respectively, while cue- but not priming-induced reinstatement downregulates MOPr binding in caudate putamen and nucleus accumbens core. This is the first study to provide direct evidence of reinstatement-induced receptor alterations that are likely to contribute to the neurobiological mechanisms underpinning relapse to cocaine seeking. © 2014 Society for the Study of Addiction.
    Full-text · Article · Dec 2014 · Addiction Biology
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    • "In addition to the classical inhibitor effects on adenylate cyclase activity, KOR also couples to mitogen-activated protein kinase pathways (Bruchas et al., 2010; Al-Hasani and Bruchas, 2011) to mediate various behavioral effects (Bruchas et al., 2011; Potter et al., 2011). It is thought that stress causes dynorphin release activating KOR within monoamine nuclei (ventral tegmental area, dorsal raphe, locus coeruleus) and their projection targets (extended amygdala, nucleus accumbens, etc.; Wise, 2004; Zhang et al., 2005; Carlezon et al., 2006; Gehrke et al., 2008; Land et al., 2008, 2009; Ebner et al., 2010; Bruchas et al., 2011; Al-Hasani et al., 2013; Graziane et al., 2013). The KOR-mediated reduction in dopamine and serotonin activity results in dysphoria-like behavior that drives reinstatement of drug seeking to relieve this negative affective state. "
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    ABSTRACT: Stress increases the risk of drug abuse, causes relapse to drug seeking, and potentiates the rewarding properties of both nicotine and cocaine. Understanding the mechanisms by which stress regulates the rewarding properties of drugs of abuse provides valuable insight into potential treatments for drug abuse. Prior reports have demonstrated that stress causes dynorphin release, activating kappa opioid receptors (KOR) in monoamine circuits resulting in both potentiation and reinstatement of cocaine and nicotine conditioned place preference. Here we report that kappa opioid-dependent reinstatement of cocaine and nicotine place preference is reduced when the mice are exposed to a randomized chronic mild stress (CMS) regime prior to training in a conditioned place preference-reinstatement paradigm. The CMS schedule involves seven different stressors (removal of nesting for 24 h, 5 min forced swim stress at 15°C, 8 h food and water deprivation, damp bedding overnight, white noise, cage tilt, and disrupted home cage lighting) rotated over a 3-week period. This response is KOR-selective, as CMS does not protect against cocaine or nicotine drug-primed reinstatement. This protection from reinstatement is also observed following sub-chronic social defeat stress, where each mouse is placed in an aggressor mouse home cage for a period of 20 min over 5 days. In contrast, a single acute stressor resulted in a potentiation of KOR-induced reinstatement, as previously reported. Prior studies have shown that stress alters sensitivity to opioids and prior stress can influence the pharmacodynamics of the opioid receptor system. Together, these findings suggest that exposure to different forms of stress may cause a dysregulation of kappa opioid circuitry and that changes resulting from mild stress can have protective and adaptive effects against drug relapse.
    Full-text · Article · Aug 2013 · Frontiers in Pharmacology
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    • "DA signalling within the VTA also plays an important role in induction of GABAergic plasticity (Pan et al. 2008a; Dacher & Nugent, 2011; Dacher et al. 2013), so it is likely that selective activation of DA neurons by such in vivo manipulations produce parallel drug-induced GABAergic plasticity as appeared after exposures to morphine and cocaine (Liu et al. 2005; Dacher & Nugent, 2011). Because of the importance of GABAergic transmission and plasticity in VTA DA cell firing and the shaping of reward-and drug-related learning (Parker et al. 2011; Tan et al. 2012; van Zessen et al. 2012; Tolu et al. 2013; Graziane et al. 2013 "
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    ABSTRACT: Persistent changes in excitatory and inhibitory synaptic strengths to the ventral tegmental area (VTA) dopamine (DA) neurons in response to addictive drugs may underlie the transition from casual to compulsive drug use. While enormous amount of work has been done in the area of glutamatergic plasticity of the VTA, little is known regarding the learning rules governing GABAergic plasticity in the VTA. Spike-timing-dependent plasticity, STDP, has attracted considerable attention primarily due to its potential roles in processing and storage of information in the brain and there is emerging evidence for the existence of STDP at inhibitory synapses. We therefore used whole-cell recordings in rat midbrain slices to investigate whether near coincident pre- and postsynaptic firing induces a lasting change in synaptic efficacy of VTA GABAergic synapses. We found that a Hebbian form of STDP including LTP and LTD can be induced at GABAergic synapses onto VTA DA neurons and relies on the precise temporal order of pre-and postsynaptic spiking. Importantly, GABAergic STDP is heterosynaptic (NMDR-dependent): triggered by correlated activities of the presynaptic glutamatergic input and postsynaptic DA cells. GABAergic STDP is postsynaptic and has an associative component since pre- or postsynaptic spiking per se did not induce STDP. STDP of GABAergic synapses in the VTA provides physiologically relevant forms of inhibitory plasticity that may underlie natural reinforcement of reward-related behaviors. Moreover, this form of inhibitory plasticity may mediate some of the reinforcing, aversive and addictive properties of drugs of abuse.
    Full-text · Article · Jul 2013 · The Journal of Physiology
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