The kappa opioid receptor: from addiction to depression, and back

Abstract

Comorbidity is a major issue in psychiatry that notably associates with more severe symptoms, longer illness duration, and higher service utilization. Therefore, identifying key clusters of comorbidity and exploring the underlying pathophysiological mechanisms represent important steps toward improving mental health care. In the present review, we focus on the frequent association between addiction and depression. In particular, we summarize the large body of evidence from preclinical models indicating that the kappa opioid receptor (KOR), a member of the opioid neuromodulatory system, represents a central player in the regulation of both reward and mood processes. Current data suggest that the KOR modulates overlapping neuronal networks linking brainstem monoaminergic nuclei with forebrain limbic structures. Rewarding properties of both drugs of abuse and natural stimuli, as well as the neurobiological effects of stressful experiences, strongly interact at the level of KOR signaling. In addiction models, activity of the KOR is potentiated by stressors and critically controls drug-seeking and relapse. In depression paradigms, KOR signaling is responsive to a variety of stressors, and mediates despair-like responses. Altogether, the KOR represents a prototypical substrate of comorbidity, whereby life experiences converge upon common brain mechanisms to trigger behavioral dysregulation and increased risk for distinct but interacting psychopathologies.

Keywords: addiction; anhedonia; animal models; comorbidity; depression; kappa opioid receptor; place conditioning; reward.

Figure 1

A simplified scheme of neuronal circuits implicated in the regulation of reward (green) and stress (orange), which are both modulated by dynorphins and the kappa opioid receptor (KOR). KOR-mediated inhibition of ventral tegmental area (VTA) dopaminergic neurons projecting to the prefrontal cortex (PFC) is responsible for dysphoria and conditioned place aversion (13, 27, 33). Dynorphinergic medium spiny neurons, located in the nucleus accumbens (NAc) and expressing D1 dopamine receptors, send axonal projections back to the VTA (36), further supporting the importance of KOR in dopamine modulation and as an anti-reward agent. In addition, stressful experiences trigger widespread corticotropin releasing factor (CRF) release in the central nervous system (37), leading to dynorphin release and KOR phosphorylation, notably in the dorsal raphe nucleus (DRN) (38) and locus coeruleus (LC) (39). Stress-induced signaling events have been extensively characterized in the DRN, where activation of KOR stimulates G protein-coupled inwardly rectifying potassium channels [GIRK, see in Ref. (40)] and phosphorylation of the p38α kinase, in turn leading to translocation of the serotonin reuptake transporter to the plasma membrane and increased 5-HT reuptake (14). Similar stress-induced activation of KOR has also been documented at the level of the NAc, which appears to be the site where SERT translocation occurs (16). Available evidence also suggests that KOR regulation of 5-HT and DA neurotransmissions converge at the level of the NAc (red arrows), with important implications for comorbidity (see text for details). Further, recruitment of KOR signaling during stressful experiences has been shown: (i) in the amygdala, to potentiate conditioned place preference for drugs of abuse (20), and (ii) in the DRN (14) and LC (39), to mediate reinstatement of drug-seeking. KOR-dependent modulation of monoaminergic pathways has important implications for mood regulation. Systemic treatments with KOR agonist and antagonist have pro- and antidepressant-like effects, respectively. KOR activation locally in the NAc is sufficient to achieve a prodepressant-like effect (–45), while knock-down of dynorphins in the NAc has opposite effect (46). Recently, hypocretin (blue) and dynorphin/KOR systems in the hypothalamus (Hyp) have been shown to stimulate and inhibit VTA DA neurons, respectively (47, 48). Avenues for future investigations include the identification of: (i) the signaling events following KOR activation in the LC and VTA; (ii) the brain regions receiving innervation from amygdala (Amy) and LC KOR-positive neurons; (iii) the brain sites where CRF acts to stimulate dynorphinergic neurons, and (iv) the neurochemical identity and projections targets of VTA neurons expressing hypocretin receptors. Altogether, data indicate that the KOR inhibits the activity of all three monoaminergic centers at multiple sites, thereby critically controlling their interactions in rodent models of addiction, depression, and dual diagnosis.