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

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron Article Kappa Opioid Receptors Regulate Stress-Induced Cocaine Seeking and Synaptic Plasticity Nicholas M. Graziane,1,3 Abigail M. Polter,1 Lisa A. Briand,2 R. Christopher Pierce,2 and Julie A. Kauer1,* 1Brown University, Department of Molecular Pharmacology, Physiology and Biotechnology, Providence, RI 02912, USA 2Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA 3Present address: University of Pittsburgh, 900 South Trenton Avenue, Apt. 1, Pittsburgh, PA 15221, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2012.12.034 SUMMARY mesolimbic reward system, it may be possible to develop valid treatments addressing stress-related drug craving, a major Stress facilitates reinstatement of addictive drug contributor to relapse. seeking in animals and promotes relapse in humans. Acute and sustained exposure to drugs of abuse alters Acute stress has marked and long-lasting effects on synaptic plasticity in vulnerable brain areas (Wolf, 2002; Kauer plasticity at both inhibitory and excitatory synapses and Malenka, 2007; Lu¨ scher and Malenka, 2011). Ventral teg- on dopamine neurons in the ventral tegmental mental area (VTA) dopamine neurons are part of the circuit area (VTA), a key region necessary for drug rein- contributing to the reinforcing effects of addictive drugs (Wise, 2004; Everitt and Robbins, 2005). Furthermore, acute exposure forcement. Stress blocks long-term potentiation at to either addictive drugs or stress causes parallel changes in GABAergic synapses on dopamine neurons in the plasticity at excitatory and inhibitory synapses on VTA dopamine VTA (LTPGABA), potentially removing a normal brake neurons. At glutamatergic inputs, a single exposure to psychos- on activity. Here we show that blocking kappa timulants, morphine, nicotine, ethanol, or to acute stress in- opioid receptors (KORs) prior to forced-swim stress creases the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic rescues LTPGABA. In contrast, blocking KORs does acid receptor/N-methyl d-aspartate receptor (AMPAR/NMDAR) not prevent stress-induced potentiation of excitatory ratio, a measure of long-term potentiation (LTP) (Ungless et al., synapses nor morphine-induced block of LTPGABA. 2001; Saal et al., 2003; Kauer and Malenka, 2007). The potenti- Using a kappa receptor antagonist as a selective ation of excitatory VTA synapses following cocaine or acute stress is blocked by NMDAR antagonists and requires insertion tool to test the role of LTPGABA in vivo, we find that blocking KORs within the VTA prior to forced-swim of GluA1 receptors (Saal et al., 2003; Dong et al., 2004). Stress activates the hypothalamic-pituitary-adrenal (HPA) axis leading stress prevents reinstatement of cocaine seeking. to an increase in circulating glucocorticoid hormone, thus These results suggest that KORs may represent activating glucocorticoid receptors and initiating transcription. a useful therapeutic target for treatment of stress- The potentiation of VTA excitatory synapses by stress is pre- triggered relapse in substance abuse. vented when glucocorticoid receptors are blocked and can be mimicked by direct activation of glucocorticoid receptors in VTA slices (Saal et al., 2003; Daftary et al., 2009). At inhibitory INTRODUCTION synapses on VTA dopamine neurons, one injection of morphine, nicotine, cocaine, ethanol, or a single exposure to acute stress Despite the health risks associated with drug abuse, addicted blocks long-term potentiation (LTPGABA) at GABAA receptor individuals have difficulty abstaining, and relapse rates remain synapses on dopamine neurons (Nugent et al., 2007, 2009; high. Exposure to stress is associated with drug addiction in Guan and Ye, 2010; Niehaus et al., 2010). Glucocorticoid re- humans and can induce relapse and craving (Brown et al., ceptor activation is required for stress to block LTPGABA, but in 1995; Doherty et al., 1995; Sinha et al., 1999; Sinha, 2001; Sinha general much less is known about the mechanisms controlling and Li, 2007). Similarly, a variety of stressful stimuli can reinstate plasticity of inhibitory synapses in the VTA (Niehaus et al., 2010). drug seeking in animal models (Erb et al., 1996; Ahmed and Previous studies suggested that opioid receptor activation Koob, 1997; Shaham et al., 2000; Sorge and Stewart, 2005), blocks LTP at GABAergic synapses (Nugent et al., 2007; Guan even when stressors are separated both in time and in context and Ye, 2010). Here we have tested the idea that stress may from the drug-taking environment (Conrad et al., 2010). This block LTP through release of endogenous opioids and activation behavior relies on the mesolimbic reward system, but the of opioid receptors. Stress is often accompanied by release of mechanisms that underlie stress-induced reinstatement remain the endogenous opioid peptide, dynorphin, and subsequent unclear. By understanding the influence of stress on the activation of its receptor, the kappa opioid receptor (KOR) 942 Neuron 77, 942–954, March 6, 2013 ª2013 Elsevier Inc. Neuron Inhibitory VTA Plasticity and Reinstatement (Nabeshima et al., 1992). There is strong evidence indicating We next wanted to identify the mechanisms by which stress that the kappa opioid system regulates neuronal activity in the blocked LTPGABA. The lack of LTPGABA could reflect a stress- VTA. KORs are functionally expressed in the VTA (Speciale induced loss of the synapse’s ability to potentiate. Alternatively, et al., 1993; Arvidsson et al., 1995; Mansour et al., 1996), and if GABAergic synapses were maximally potentiated following the multiple dynorphin expressing regions innervate the VTA (Fallon stressful experience, no further potentiation would be possible et al., 1985; Meredith, 1999; Dong and Swanson, 2003; Chartoff in vitro (occlusion). We carried out three experiments to et al., 2009; Poulin et al., 2009). Pharmacological activation of determine whether acute stress blocks or occludes LTPGABA. kappa opioid receptors in the VTA causes a subset of dopamine We bath applied the adenylate cyclase activator, forskolin, to neurons to hyperpolarize and decrease their firing rate (Margolis slices from animals stressed 24 hr earlier. Forskolin potentiates et al., 2003, 2006a, 2008). KOR activation also reduces the GABAergic synapses on VTA dopamine neurons via cAMP/ somatodendritic release of dopamine in the VTA (Ford et al., PKA signaling, and this pathway intersects the NO\cGMP- 2007). induced potentiation of GABAA synapses as the effects of The dynorphin-kappa opioid receptor system is also strongly SNAP and forskolin are not additive (Nugent et al., 2009). We implicated in stress-related behaviors (Bals-Kubik et al., 1993; found that in slices from both naive animals and animals exposed Beardsley et al., 2005, 2010; Valdez et al., 2007; Land et al., to forced swim, forskolin potentiated GABAergic synapses. 2009; Bruchas et al., 2010). Conditioned aversion, elicited These data indicate that acute stress does not itself induce when a place or an odor is paired with stress, is absent in mice LTP, but instead blocks the ability of GABAergic synapses to lacking dynorphin and in animals treated with kappa antagonists potentiate; forskolin can overcome this block (Figures 1D–1F) (Land et al., 2008), suggesting that KOR activation is a necessary (IPSC amplitudes: naive animal, 131 ± 7% of pre-forskolin step in the development of aversion to stressful experiences. values, n = 9; stressed animal, 136 ± 5% of pre-forskolin values, Kappa opioid receptors are also involved in behaviors at the n = 5). We also recorded miniature IPSCs (mIPSCs) in dopamine nexus between stress and drug seeking (McLaughlin et al., neurons from stressed animals. Because GABAergic synapses 2003, 2006; Beardsley et al., 2005; Carey et al., 2007; Redila on VTA dopamine neurons are potentiated via increased presyn- and Chavkin, 2008; Beardsley et al., 2010; Sperling et al., aptic GABA release (Nugent et al., 2007), we examined paired 2010). These findings suggest that the kappa opioid system pulse ratios and mIPSC frequency in animals after stress. could modulate the compulsion to seek cocaine (or other drugs Because LTPGABA is associated with a decrease in the paired- of abuse) after stress (Bruchas et al., 2010). pulse ratio (PPR), a lower PPR in stressed animals versus We tested the hypothesis that kappa opioid receptor activa- controls would indicate that LTPGABA was occluded by stress. tion blocks LTPGABA in VTA dopaminergic neurons following Instead, paired-pulse ratios in dopamine neurons from stressed acute cold water swim stress. A similar stressor has recently animals were not significantly different from those in slices from been shown to induce reinstatement to drug seeking in rats, an naive animals (PPR: nonstressed animals, 0.61 ± 0.04, n = 28; effect that lasts for several days after stress (Conrad et al., stressed animals, 0.65 ± 0.06, n = 21, p > 0.05, Student’s 2010). We report here that a KOR antagonist given prior to acute t test). Similarly, if potentiation at GABAergic synapses were stress rescues LTPGABA. We also find that delivery of the same maximally induced by stress in vivo, we would expect an antagonist directly into the VTA prevents stress-induced rein- increased mIPSC frequency. Instead, there was no significant statement of cocaine-seeking behavior in

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