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

Abstract

Summary 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 (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 LTPGABA 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.

Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release

“…We-and others-argue that the rewarding valence of cocaine is defined by the magnitude of change (delta) from precocaine to post-cocaine hedonic state Ehrich et al, 2014;Schindler et al, 2010). Although ICSS does not directly model addiction, our findings are consistent with those showing that KOR activation can increase motivation to seek cocaine and precipitate relapse (Beardsley et al, 2005;Graziane et al, 2013;Negus, 2004;Redila and Chavkin, 2008). KOR-triggered rebound positive affective states are short-lived, as ICSS thresholds return to pre-salvA baseline levels by 48 hr.…”

Locus Coeruleus Kappa-Opioid Receptors Modulate Reinstatement of Cocaine Place Preference Through a Noradrenergic Mechanism

“…The absence or presence of KORs in the LC did not significantly alter basal or cocaine-induced locomotor activity (Figure 5c), consistent with our findings in Figure 2. These results show that LC KORs are sufficient to partially restore a component of KOR-mediated reinstatement, but importantly these data also suggest that the NA component of kappa-opioid reinstatement may occur via influence over KOR-containing circuits outside the LC, as previously reported Graziane et al, 2013;Van't Veer et al, 2013).…”

“…The resulting evidence indicates a role for interactions between the NA system and KORs in the modulation of downstream KOR circuits. This circuitry has recently been well established to control KOR-and stress-induced reinstatement of cocaine seeking and cocaine place preference (Figure 5d; Bruchas et al, 2011;Graziane et al, 2013). The results presented here support the Noradrenergic-KOR interactions in cocaine place preference R Al-Hasani et al hypothesis that KOR function and b-adrenergic receptor modulation act together to negatively modulate KORmediated reinstatement behavior at known downstream circuits (ie, dopaminergic, serotonergic) reported to be critical for KOR function in behavioral affect (Figure 5d).…”

“…Dynorphins are released during stress exposure and the dynorphin/KOR system has been shown to be critical for stress-induced depression-like and anxiety-like behaviors as well as reinstatement to drug seeking (Beardsley et al, 2005;Carey et al, 2007;Carlezon et al, 2006;Chartoff et al, 2012;Ebner et al, 2010;Land et al, 2008;Mague et al, 2003;McLaughlin et al, 2003). It has been shown that following stress, the subsequent release of dynorphin activates KORs within dopaminergic and serotonergic nuclei to produce reinstatement, aversion, and negative affective-like behavioral states Graziane et al, 2013;Land et al, 2009;Tejeda et al, 2013;Van't Veer et al, 2013). In addition to decreasing striatal dopamine levels and inhibiting the firing of dopamine neurons, several reports demonstrate that KOR agonists inhibit dopamine release and alter behavioral affect via action within the nucleus accumbens and/or VTA dopaminergic system (Ebner et al, 2010;Graziane et al, 2013;Shippenberg et al, 2007).…”

“…It has been shown that following stress, the subsequent release of dynorphin activates KORs within dopaminergic and serotonergic nuclei to produce reinstatement, aversion, and negative affective-like behavioral states Graziane et al, 2013;Land et al, 2009;Tejeda et al, 2013;Van't Veer et al, 2013). In addition to decreasing striatal dopamine levels and inhibiting the firing of dopamine neurons, several reports demonstrate that KOR agonists inhibit dopamine release and alter behavioral affect via action within the nucleus accumbens and/or VTA dopaminergic system (Ebner et al, 2010;Graziane et al, 2013;Shippenberg et al, 2007). Recently, we also demonstrated that activation of KORs within dorsal raphe serotoninergic circuits reduces serotonergic tone to influence cocaine place preference and reinstatement (Land et Proposed model shows that KOR activity in the LC is likely to act upstream of previously identified KOR circuits involved in KORmediated behavioral responses.…”