Research ReportDynorphin, stress, and depression
Introduction
The endogenous opioid system is an important mediator of emotional and behavioral responses to stress. It comprises three families of neuropeptides (endorphins, enkephalins, and dynorphins) and three cognate receptor subtypes (mu [MOR], delta [DOR], and kappa [KOR]). The dynorphin family of neuropeptides (herein referred to as “dynorphin”) comprises six peptides of varying lengths that are formed from the precursor prodynorphin (PDyn; see Schwarzer, 2009) and which activate KORs located in the peripheral and central nervous systems (Chavkin et al., 1982). Although activation of all three opioid receptor subtypes produces analgesia via inhibition of ascending pain fibers, central opioid receptor signaling produces opposing effects on mood: MOR or DOR activation elevates mood (Filliol et al., 2000, Shippenberg et al., 2008) whereas KOR activation produces dysphoria (defined here as an unpleasant or aversive state) in humans (Pfeiffer et al., 1986, Wadenberg, 2003) and prodepressive-like behaviors (including those thought to reflect anhedonia, dysphoria, and anxiety) in rodents (Bals-Kubik et al., 1993, Mague et al., 2003, Carlezon et al., 2006, Carlezon et al., 2009). Even salvinorin A—a selective KOR agonist currently marketed as a safe and legal hallucinogen—produces anxiogenic and otherwise unpleasant effects in humans that deter repeated or compulsive use (Gonzalez et al., 2006).
During acute stress, KOR signaling may increase physical ability (by producing analgesia) and motivation to escape threat (by producing aversion) and thereby facilitate adaptive responses. However, prolonged KOR signaling in response to chronic or uncontrollable stress may lead to persistent changes in behavior that are characteristic of those seen in human depressive disorders (see Kessler, 1997, Nestler and Carlezon, 2006, Pittenger and Duman, 2008). Animal models have been instrumental in the study of KORs within the context of stress and depressive disorders: tests such as place conditioning and intracranial self stimulation (ICSS) are sensitive to treatments that cause aversion (dysphoria) or reduced sensitivity to rewarding stimuli (anhedonia), and the intensity of these signs can be quantified. Behavioral signs in rodents that resemble the behavioral signs that are observable in humans with depressive disorders are often qualified with the suffix “-like”, to acknowledge the imperfection inherent in models where individuals cannot articulate their symptoms.
The prodepressive-like consequences of stress in rodents are decreased by KOR antagonists or by ablation of the genes encoding KORs or PDyn (Newton et al., 2002, Mague et al., 2003, McLaughlin et al., 2003, Beardsley et al., 2005, McLaughlin et al., 2006a, Bruchas et al., 2007b). These antidepressant-like effects are often most apparent after repeated stress, suggesting that the KOR system may be especially important in mediating the amplification or sensitization of stress responses. Many other stress-responsive systems have been implicated in the etiology and pathophysiology of mood disorders, including those utilizing cortisol, corticotropin releasing factor (CRF), vasopressin, and brain derived neurotrophic factor (BDNF) (de Kloet et al., 2005, Duman and Monteggia, 2006, Zhang et al., 2007, Koob, 2008, Mathew et al., 2008). Dynorphin signaling also affects—and is affected by—these other stress-responsive systems, highlighting the coordinated role these systems play in regulating the stress response and in establishing individual vulnerability or resiliency to stress-related disorders (Nair et al., 2005, Feder et al., 2009).
The objective of this review is to summarize currently available data on how the KOR system contributes to molecular and behavioral effects of stress. We focus on behavioral paradigms that differentiate between the role of KORs in mediating acute (rapid), delayed, and cumulative effects of stress. For the purposes of developing testable hypotheses, we divide KOR-mediated stress responses into three temporal categories: 1) acute responses to stress—such as changes in behavior thought to reflect dysphoria or anhedonia—that do not require prior stress exposure and are primarily mediated by KOR-induced changes in the activity of limbic circuits [acute expose, acute outcomes]; 2) delayed or sensitized responses to stress—such as changes in behavior thought to reflect altered coping strategies (e.g., increased immobility in the forced swim test)—that require prior stress exposure to occur and are mediated at least in part by neural adaptations that are a consequence or cause of increased KOR signaling [acute exposure, delayed outcomes]; and 3) delayed responses to stress that are produced by repeated stress exposure and likely require multiple rounds of neural adaptations to occur (e.g., changes in behavior thought to reflect learned helplessness) [repeated exposure, mixed outcomes] (Fig. 1). Using this simplified model, we consider the time course and mechanisms of KOR-mediated effects in stress. It is important to note that many studies using KOR antagonists have been designed to accommodate the slow onset of maximal antagonism (4–24 h) and extended duration of action (> 3 weeks) of currently available antagonists (e.g., norBNI, JDTic) (Endoh et al., 1992, Horan et al., 1992, Jones and Holtzman, 1992, Carroll et al., 2004, Beardsley et al., 2005, Bruchas et al., 2007a). The unusual pharmacology of these compounds limits some of the conclusions that can be drawn about the role of KORs in the development and expression of stress-induced behaviors. In the final section we compare the effects of KOR antagonists when they have been given before, between, or after stress exposure, and suggest future directions that may be helpful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.
The signaling mechanisms of neuropeptides and classical neurotransmitters (e.g., glutamate, GABA) differ considerably across a number of parameters, suggesting they have different roles in information processing (see Hokfelt et al., 2000, Ludwig and Leng, 2006). Classical neurotransmitters are released primarily at synaptic active zones in response to single action potentials and typically activate cognate receptors on one postsynaptic target. The high fidelity and specificity of this signal depends on several mechanisms that restrict its spatiotemporal profile, including rapid neurotransmitter degradation, reuptake mechanisms, and low (μM) receptor affinity. In contrast, neuropeptides are released at both synaptic and extrasynaptic sites in response to sustained neuronal activity. Upon release, neuropeptides are more slowly degraded by extracellular peptidases and are therefore able to diffuse much greater distances (∼50–100 μm). This mode of action enables neuropeptides to more broadly activate their receptors, which have a high (nM) affinity (see Chavkin, 2000). Based on these differences, recent hypotheses suggest that classical neurotransmitters convey information between pairs of neurons whereas neuropeptides convey information and coordinate activity across broader networks of neurons (Ludwig and Leng, 2006). It is important to note that these distinctions are less apparent for neuromodulators such as dopamine (DA) or serotonin, which often signal extrasynaptically (Benfenati and Agnati, 1991, Hensler, 2006, Rice and Cragg, 2008).
Similar to other neuropeptides, dynorphin is released from large dense core vesicles (Cho and Basbaum, 1989, Drake et al., 1994) in response to sustained neuronal activity and activates KORs (Weisskopf et al., 1993). KORs are coupled to inhibitory Gi/o-proteins and typically decrease synaptic transmission by inhibiting adenylate cyclase, inhibiting voltage-gated Ca2+ channels (Rusin et al., 1997, Hjelmstad and Fields, 2003), and activating voltage-gated K+ channels (Simmons and Chavkin, 1996, Vaughan et al., 1997). Activation of presynaptic KORs may also decrease synaptic transmission by directly inhibiting vesicle fusion (Iremonger and Bains, 2009). In addition to rapid effects on ion channel conductance, KORs also activate signal transduction cascades, including mitogen-activated protein kinases (MAPKs), which in turn activate transcription factors and alter gene expression (see Thomas and Huganir, 2004). Growing evidence indicates that activity-dependent dynorphin release, especially from dendritic sites, may be a particularly effective mechanism by which neurons regulate their own activity (Drake et al., 1994, Brown and Bourque, 2004, Ludwig and Leng, 2006, Kreibich et al., 2008, Iremonger and Bains, 2009). Indeed, dendritic dynorphin release in the hippocampus and hypothalamus negatively regulates excitatory inputs via retrograde activation of presynaptic KORs (Drake et al., 1994, Iremonger and Bains, 2009). This inhibitory mechanism may generalize to other neuronal populations often implicated in the regulation of mood and motivation, such as the amygdala and striatum, which express dendritic dynorphin (Yakovleva et al., 2006, Reyes et al., 2007). Dendritic neuropeptide release may serve as an independent (auxiliary) mechanism of inhibition that can be engaged rapidly and broadly in response to high neuronal activity, without compromising or taxing existing feedforward and feedback inhibitory circuits. Because existing inhibitory circuits have a critical role in the computational processes of neurons (Mittmann et al., 2004), this auxiliary mechanism of inhibition may help to preserve information processing during conditions of high neuronal activity, such as during stress, which triggers dynorphin release in limbic brain regions (see Schwarzer, 2009).
Although the role of KORs in the regulation of mood is not fully understood, dynorphin and KORs are expressed throughout limbic brain areas implicated in the pathophysiology of depression and anxiety disorders. Such areas include the mesocorticolimbic DA system [comprising the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC)], the serotonergic and noradrenergic systems [comprising major cell groups in the dorsal raphe nucleus and locus coeruleus, respectively], the extended amygdala [comprising the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), and NAc shell], the basolateral amygdala, hippocampus (HIP), and hypothalamus in humans and rodents (Fallon and Leslie, 1986, Mansour et al., 1995, Sukhov et al., 1995, Hurd, 1996, Peckys and Landwehrmeyer, 1999, Shuster et al., 2000, Alheid, 2003, Nestler and Carlezon, 2006, Koob, 2008, Schwarzer, 2009). In this review we focus primarily on interactions between KORs and dopaminergic systems because much is known about how manipulations of DA function affect motivation, which is invariably dysregulated in depressive disorders. However, it is clear that KORs are also involved in the regulation of serotonergic (Tao and Auerbach, 2002, Tao and Auerbach, 2005, Berger et al., 2006, Land et al., 2008, Zakharova et al., 2008) and noradrenergic (Pinnock, 1992, Berger et al., 2006, Reyes et al., 2007, Reyes et al., 2009, Kreibich et al., 2008) systems, which are the primary targets of standard antidepressant drugs (Frazer, 1997, Millan, 2004). Given the important roles of serotonin and norepinephrine in stress and behavior (Vergne and Nemeroff, 2006, Lowry et al., 2008, Smith and Aston-Jones, 2008, Valentino and Van Bockstaele, 2008), a more thorough characterization of these interactions will be essential for a complete understanding of the neurobiology of mood. Finally, dynorphin expression overlaps with that of other neuropeptide systems involved in stress and motivation, including CRF, neuropeptide Y, and vasopressin (Lin et al., 2006, Marchant et al., 2007, Reyes et al., 2008, Iremonger and Bains, 2009). Thus the KOR system is ideally positioned to produce broad effects on behavior, perhaps by serving as a braking mechanism to counteract elevations in neuronal activity induced by stress.
It is important to differentiate between the effects of KOR signaling on the activity of individual neurons, the activity of neural networks, and on behavior. Although KOR activation typically inhibits neurotransmission, depending on the circuit, this inhibitory effect might result in disinhibition of other circuits. We focus here on evidence that a key behavioral effect of KOR activation is the production of depressive-like behavioral signs, including those thought to reflect dysphoria, anhedonia, and anxiety. These behavioral signs may be mediated by KOR-induced increases or decreases in the activity of neural networks involved in mood.
Section snippets
Stress and the time course of KOR-mediated effects
Acute stress activates the hypothalamic–pituitary–adrenal (HPA) axis and releases numerous stress hormones and peptides (e.g., CRF, corticosterone, glucocorticoids, endogenous opioids). Release of these molecules has acute and delayed effects on the function of limbic circuits, including activation of the mesocorticolimbic system (Marinelli and Piazza, 2002, Sheline, 2003, Pittenger and Duman, 2008, Feder et al., 2009). These cascades contribute to adaptive behavioral responses by triggering
Conclusions and implications
Stimulation of KORs mimics or exacerbates many of the acute and delayed behavioral effects of stress. Disruption of KOR function tends to block these same effects. The fact that KOR function appears to have a profound influence on behaviors that are thought to reflect motivation and emotion in animal models suggests that KORs might represent a viable target for psychiatric medications. An obvious indication for KOR antagonists is in the treatment of depressive and anxiety-related disorders,
Disclosures
Dr. Carlezon has a US patent covering the use of kappa antagonists in the treatment of depression (Assignee: McLean Hospital) and is a member of a collaborative group that has submitted a patent application covering the synthesis and use of salvinorin derivatives (Assignees: McLean Hospital and Temple University). Ms. Knoll has nothing to disclose.
Acknowledgments
This work was supported by the National Institutes of Health (MH063266, to WAC and MH078473, to ATK).
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