Kappa Opioid Receptors Regulate
Stress-Induced Cocaine Seeking
and Synaptic Plasticity
Nicholas M. Graziane,1,3Abigail M. Polter,1Lisa A. Briand,2R. Christopher Pierce,2and 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
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 rein-
forcement. Stress blocks long-term potentiation at
GABAergic synapses on dopamine neurons in the
VTA (LTPGABA), potentially removing a normal brake
on activity. Here we show that blocking kappa
opioid receptors (KORs) prior to forced-swim stress
rescues LTPGABA. In contrast, blocking KORs does
not prevent stress-induced potentiation of excitatory
synapses nor morphine-induced block of LTPGABA.
Using a kappa receptor antagonist as a selective
tool to test the role of LTPGABAin 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.
Despite the health risks associated with drug abuse, addicted
individuals have difficulty abstaining, and relapse rates remain
high. Exposure to stress is associated with drug addiction in
humans and can induce relapse and craving (Brown et al.,
1995; Doherty et al., 1995; Sinha et al., 1999; Sinha, 2001; Sinha
and Li, 2007). Similarly, a variety of stressful stimuli can reinstate
drug seeking in animal models (Erb et al., 1996; Ahmed and
Koob, 1997; Shaham et al., 2000; Sorge and Stewart, 2005),
even when stressors are separated both in time and in context
from the drug-taking environment (Conrad et al., 2010). This
behavior relies on the mesolimbic reward system, but the
mechanisms that underlie stress-induced reinstatement remain
unclear. By understanding the influence of stress on the
mesolimbic reward system, it may be possible to develop valid
treatments addressing stress-related drug craving, a major
contributor to relapse.
Acute and sustained exposure to drugs of abuse alters
synaptic plasticity in vulnerable brain areas (Wolf, 2002; Kauer
and Malenka, 2007; Lu ¨scher and Malenka, 2011). Ventral teg-
mental area (VTA) dopamine neurons are part of the circuit
contributing to the reinforcing effects of addictive drugs (Wise,
2004; Everitt and Robbins, 2005). Furthermore, acute exposure
to either addictive drugs or stress causes parallel changes in
plasticity at excitatory and inhibitory synapses on VTA dopamine
neurons. At glutamatergic inputs, a single exposure to psychos-
timulants, morphine, nicotine, ethanol, or to acute stress in-
creases the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid receptor/N-methyl d-aspartate receptor (AMPAR/NMDAR)
ratio, a measure of long-term potentiation (LTP) (Ungless et al.,
2001; Saal et al., 2003; Kauer and Malenka, 2007). The potenti-
ation of excitatory VTA synapses following cocaine or acute
stress is blocked by NMDAR antagonists and requires insertion
of GluA1 receptors (Saal et al., 2003; Dong et al., 2004). Stress
activates the hypothalamic-pituitary-adrenal (HPA) axis leading
to an increase in circulating glucocorticoid hormone, thus
activating glucocorticoid receptors and initiating transcription.
The potentiation of VTA excitatory synapses by stress is pre-
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
synapses on VTA dopamine neurons, one injection of morphine,
nicotine, cocaine, ethanol, or a single exposure to acute stress
blocks long-term potentiation (LTPGABA) at GABAA receptor
synapses on dopamine neurons (Nugent et al., 2007, 2009;
Guan and Ye, 2010; Niehaus et al., 2010). Glucocorticoid re-
ceptor activation is required for stress to block LTPGABA, but in
general much less is known about the mechanisms controlling
plasticity of inhibitory synapses in the VTA (Niehaus et al., 2010).
Previous studies suggested that opioid receptor activation
blocks LTP at GABAergic synapses (Nugent et al., 2007; Guan
and Ye, 2010). Here we have tested the idea that stress may
block LTP through release of endogenous opioids and activation
of opioid receptors. Stress is often accompanied by release of
the endogenous opioid peptide, dynorphin, and subsequent
activation of its receptor, the kappa opioid receptor (KOR)
942 Neuron 77, 942–954, March 6, 2013 ª2013 Elsevier Inc.
(Nabeshima et al., 1992). There is strong evidence indicating
that the kappa opioid system regulates neuronal activity in the
VTA. KORs are functionally expressed in the VTA (Speciale
et al., 1993; Arvidsson et al., 1995; Mansour et al., 1996), and
multiple dynorphin expressing regions innervate the VTA (Fallon
et al., 1985; Meredith, 1999; Dong and Swanson, 2003; Chartoff
et al., 2009; Poulin et al., 2009). Pharmacological activation of
kappa opioid receptors in the VTA causes a subset of dopamine
neurons to hyperpolarize and decrease their firing rate (Margolis
et al., 2003, 2006a, 2008). KOR activation also reduces the
somatodendritic release of dopamine in the VTA (Ford et al.,
The dynorphin-kappa opioid receptor system is also strongly
implicated in stress-related behaviors (Bals-Kubik et al., 1993;
Beardsley et al., 2005, 2010; Valdez et al., 2007; Land et al.,
2009; Bruchas et al., 2010). Conditioned aversion, elicited
when a place or an odor is paired with stress, is absent in mice
lacking dynorphin and in animals treated with kappa antagonists
step in the development of aversion to stressful experiences.
Kappa opioid receptors are also involved in behaviors at the
nexus between stress and drug seeking (McLaughlin et al.,
2003, 2006; Beardsley et al., 2005; Carey et al., 2007; Redila
and Chavkin, 2008; Beardsley et al., 2010; Sperling et al.,
2010). These findings suggest that the kappa opioid system
could modulate the compulsion to seek cocaine (or other drugs
of abuse) after stress (Bruchas et al., 2010).
We tested the hypothesis that kappa opioid receptor activa-
tion blocks LTPGABA in VTA dopaminergic neurons following
acute cold water swim stress. A similar stressor has recently
been shown to induce reinstatement to drug seeking in rats, an
effect that lasts for several days after stress (Conrad et al.,
2010). We report here that a KOR antagonist given prior to acute
stress rescues LTPGABA. We also find that delivery of the same
antagonist directly into the VTA prevents stress-induced rein-
statement of cocaine-seeking behavior in a self-administration
paradigm. Together our results suggest a link between the
GABAergic control of VTA neurons and cocaine seeking after
exposure to stress, and provide a rationale for the use of KOR
antagonists in therapeutic treatment of stress-induced relapse.
Stress Blocks LTPGABA
GABAergic synapses on dopamine neurons are persistently
potentiated by anincrease in postsynaptic Ca2+, which activates
nitric oxide (NO) synthase in turn generating NO. NO then travels
retrogradely to potentiate GABA release from nearby presyn-
aptic GABAergic nerve terminals through a cGMP-dependent
signaling cascade (Nugent et al., 2007), thus inducing LTPGABA
(Figure 7). Our previous work demonstrated that brief exposure
to stress blocks LTPGABAat these synapses 24 hr later (Niehaus
et al., 2010). Confirming our earlier results, after a 5 min cold
water forced swim stress (FSS), when midbrain slices were
prepared 24 hr later, LTPGABAwas blocked in VTA dopamine
neurons. In contrast, SNAP triggered robust LTPGABAin slices
from control animals that did not experience forced-swim stress
We next wanted to identify the mechanisms by which stress
blocked LTPGABA. The lack of LTPGABAcould reflect a stress-
induced loss of the synapse’s ability to potentiate. Alternatively,
if GABAergic synapses were maximally potentiated following the
stressful experience, no further potentiation would be possible
in vitro (occlusion). We carried out three experiments to
determine whether acute stress blocks or occludes LTPGABA.
We bath applied the adenylate cyclase activator, forskolin, to
slices from animals stressed 24 hr earlier. Forskolin potentiates
GABAergic synapses on VTA dopamine neurons via cAMP/
PKA signaling, and this pathway intersects the NO\cGMP-
induced potentiation of GABAA synapses as the effects of
SNAP and forskolin are not additive (Nugent et al., 2009). We
to forced swim, forskolin potentiated GABAergic synapses.
These data indicate that acute stress does not itself induce
LTP, but instead blocks the ability of GABAergic synapses to
potentiate; forskolin can overcome this block (Figures 1D–1F)
(IPSC amplitudes: naive animal, 131 ± 7% of pre-forskolin
values, n = 9; stressed animal, 136 ± 5% of pre-forskolin values,
n = 5). We also recorded miniature IPSCs (mIPSCs) in dopamine
neurons from stressed animals. Because GABAergic synapses
on VTA dopamine neurons are potentiated via increased presyn-
aptic GABA release (Nugent et al., 2007), we examined paired
pulse ratios and mIPSC frequency in animals after stress.
Because LTPGABAis associated with a decrease in the paired-
pulse ratio (PPR), a lower PPR in stressed animals versus
controls would indicate that LTPGABAwas occluded by stress.
Instead, paired-pulse ratios in dopamine neurons from stressed
animals were not significantly different from those in slices from
naive animals (PPR: nonstressed animals, 0.61 ± 0.04, n = 28;
stressed animals, 0.65 ± 0.06, n = 21, p > 0.05, Student’s
t test). Similarly, if potentiation at GABAergic synapses were
maximally induced by stress in vivo, we would expect an
increased mIPSC frequency. Instead, there was no significant
jected stressed animals (control, 5.65 ± 1.0 Hz, n = 10; saline +
forced swim stress, 5.49 ± 1.2 Hz, n = 10, p > 0.05, Student’s
t test) (Figure S1 available online). Together these experiments
Blocking Kappa Opioid Receptors Rescues the
Stress-Induced Block of LTPGABA
How might stress block LTPGABA? Our previous work demon-
strated that LTPGABAwas blocked 24 hr after an in vivo injection
of morphine (Nugent et al., 2007), suggesting the possibility that
stress might act via the release of endogenous opioids. To test
this idea, animals were pretreated with either saline or the opioid
receptor antagonist, naloxone (10 mg/kg), prior to forced swim
stress, and midbrain slices were cut 24 hr later. Stress blocked
LTPGABAin slices from saline-treated animals (Figure 2B), but
this block was rescued in animals pretreated with naloxone (Fig-
ure 2C) (IPSC amplitudes: saline + FSS, 112 ± 5%, n = 14;
naloxone + FSS, 129 ± 5%, n = 9; p < 0.05). These data support
our hypothesis that opioid receptor activation is required for
stress-induced block of LTPGABA.
Naloxone at the concentration used (10 mg/kg) blocks m, d,
and k opioid receptors (Lewanowitsch and Irvine, 2003). Kappa
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