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

Abstract

Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation-as occurs upon withdrawal from chronic cocaine-modulates vulnerability to cocaine in a time-dependent manner.

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

“…The dynorphin/KOR system is involved in mediating negative affective states (Bruchas et al, 2010; Berger et al, 2013). For example, elevations in intracranial self-stimulation thresholds, which model anhedonia, are found after prolonged activation of KORs (Chartoff et al, 2015). The current data and previous studies have shown that excessive exposure to drugs of abuse results in an upregulated dynorphin/KOR system (Lindholm et al, 2000; Kissler et al, 2014; Rose et al, 2015).…”

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

“…For example, one study showed that the KOR agonist, U50,488, attenuated, rather than increased, ethanol intake in Lewis rats (Lindholm et al, 2001). However, KOR activation time-dependently modulates vulnerability to drugs of abuse and reward processing; for example, a recent study showed that administration of cocaine 15 min after KOR activation with salvinorin A (salA; the time point used in Lindholm et al, 2001) decreased ICSS thresholds and increased DA release, consistent with increased positive affect, while cocaine administration 24 h after KOR activation increased ICSS thresholds and decreased DA release, indicating a negative affective state (Chartoff et al, 2016). Finally, another study showed that nor-BNI increased ethanol intake in rats that were housed in a manner similar to GH animals in the current study (Mitchell et al, 2005).…”

“…Previous data suggest that exposure to chronic stress, such as repeated withdrawal from chronic intermittent ethanol (CIE) exposure, leads to prolonged activation of KORs (Walker and Koob, 2008), possibly contributing to reduced DA function, which is positively correlated with negative affect (see Koob et al, 2014 for a review). Elevations in intra-cranial self-stimulation (ICSS) thresholds are associated with anhedonia, and a recent study showed that prolonged activation of KORs resulted in significantly elevated ICSS thresholds (Chartoff et al, 2016). Notably, negative affective states such as anhedonia facilitate motivation to increase the intake of drugs (Baarendse et al, 2014).…”

A Trigger for Opioid Misuse: Chronic Pain and Stress Dysregulate the Mesolimbic Pathway and Kappa Opioid System

“…Blocking KOR, however, inhibits stress-induced escalations in cocaine self-administration, alcohol intake, and preference for nicotine (Redila and Chavkin, 2008; Sperling et al, 2010). Prolonged activation of KORs causes a significant elevation in ICSS thresholds, a behavior indicative of anhedonia (Chartoff et al, 2016). It is this anhedonia and negative affective state that motivates increased drug taking (Baarendse and Vanderschuren, 2012).…”