Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Mague, Stephen D.; Pliakas, Andrea M.; Todtenkopf, Mark S.; Tomasiewicz, Hilarie C.; Zhang, Yan; Stevens, William C.; Jones, Robert M.; Portoghese, Philip S.; Carlezon, William A.

doi:10.1124/jpet.102.046433

Cited by 439 publications

(461 citation statements)

References 39 publications

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“…The notion that KOR antagonists block the effects of stress fits well with other evidence that these agents have antidepressant-like (Pliakas et al, 2001;Newton et al, 2002;Mague et al, 2003;Shirayama et al, 2004) and anxiolytic-like effects, including the ability to block acquisition of fear-potentiated startle (Knoll et al, 2007(Knoll et al, , 2011, a procedure often used to study PTSD (Mahan and Ressler, 2012). In addition, KOR agonists can produce key behavioral signs of stress (McLaughlin et al, 2003(McLaughlin et al, , 2006Mague et al, 2003;Todtenkopf et al, 2004). When considered together, these findings raise the possibility that pretreatment with KOR antagonists could reduce or prevent the effects of stress, representing an alternative approach to modulating the behavior-disrupting effects of CRF.…”

Section: Introductionsupporting

confidence: 57%

“…Interactions between these systems have been thoroughly characterized within the raphe nucleus (Bruchas et al, 2011) but may also occur in other brain regions (Pliakas et al, 2001;Newton et al, 2002;Shirayama et al, 2004;Muschamp et al, 2011b;Knoll et al, 2011). The notion that KOR antagonists block the effects of stress fits well with other evidence that these agents have antidepressant-like (Pliakas et al, 2001;Newton et al, 2002;Mague et al, 2003;Shirayama et al, 2004) and anxiolytic-like effects, including the ability to block acquisition of fear-potentiated startle (Knoll et al, 2007(Knoll et al, , 2011, a procedure often used to study PTSD (Mahan and Ressler, 2012). In addition, KOR agonists can produce key behavioral signs of stress (McLaughlin et al, 2003(McLaughlin et al, , 2006Mague et al, 2003;Todtenkopf et al, 2004).…”

Section: Introductionmentioning

confidence: 49%

“…Although some of the JDTic effects might be suggestive of behavioral activation, stimulant effects have not been observed with this class of drugs. For example, we did not observe any effects of KOR antagonists on locomotor activity at doses that produce antidepressant-like or anxiolytic-like effects (Mague et al, 2003;Knoll et al, 2007), or alterations in reward-driven behavior or response capabilities at doses that block the prodepressive-like effects of KOR agonists on motivation (Todtenkopf et al, 2004). JDTic also blocks (rather than primes) stress-induced reinstatement of cocaine self-administration in rats (Beardsley et al, 2005), another indicator of a lack of effects that would raise concerns about stimulant effects or abuse potential of this class of drugs.…”

Section: Kor Antagonism Blocks Crf Effects On Attentionmentioning

confidence: 89%

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Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

Veer

Yano

Carroll

et al. 2012

Neuropsychopharmacol

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Stress often disrupts behavior and can lead to psychiatric illness. Considerable evidence suggests that corticotropin-releasing factor (CRF) plays an important role in regulating the effects of stress. CRF administration produces stress-like effects in humans and laboratory animals, and CRF levels are elevated in individuals with stress-related illness. Recent work indicates that k-opioid receptor (KOR) antagonists can block CRF effects, raising the possibility that at least some of the effects of stress are mediated via KORs. Here we examined the effects of CRF on performance in the 5-choice serial reaction time task (5CSRTT), a test used to quantify attention in rodents, as well as functional interactions between CRF and KORs. Male Sprague-Dawley rats were trained in the 5CSRTT and then each was implanted with an intracerebroventricular (ICV) cannula. After recovery and restabilization of performance, they received a single intraperitoneal (IP) injection of vehicle or JDTic (10 mg/kg), a KOR antagonist with long-lasting (414 days) effects. In subsequent sessions, rats received ICV infusions of CRF (0.25-1.0 mg) or vehicle and were tested 60 min later. CRF dose-dependently disrupted performance as reflected by decreases in correct responding, increases in omission errors, increases in latencies to respond correctly, and increases in time to complete the session. JDTic attenuated each of these CRF-induced deficits while having no effects on its own. The persistent ability of JDTic to disrupt KOR function was confirmed using the tail immersion assay. These findings indicate that KOR antagonists can prevent acute stress-related effects that degrade performance in tasks requiring attention.

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Section: Introductionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 49%

Section: Kor Antagonism Blocks Crf Effects On Attentionmentioning

confidence: 89%

See 1 more Smart Citation

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

Veer

Yano

Carroll

et al. 2012

Neuropsychopharmacol

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“…It is well known that various stresses increase brain dynorphin levels. For example, immunobilization and forced swim stress increase dynorphin A levels in the hippocampus and nucleus accumbens (Shirayama et al 2004), and infusion of an antagonist of dynorphin receptor, nor-BNI produces an antidepressant effect (Pliakas et al 2001;Mague et al 2003). In general, stress is classified as either acute and clonical.…”

Section: Discussionmentioning

confidence: 99%

“…Gene expression of prodynorphin is increased in the limbic system by stress (Shirayama et al 2004). In addition, injection of an antagonist of the κ-receptor causes stress-inducing behavior similar to those caused by immobility and forced swim stress (Mague et al 2003;McLaughlin et al 2003;Shirayama et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Occlusal Disharmony Transiently Impairs Learning and Memory in the Mouse by Increasing Dynorphin A Levels in the Amygdala

Yamada

Ono

Kubo

et al. 2013

Tohoku J. Exp. Med.

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Occlusal disharmony sometimes causes not only stiffness of neck but also psychiatric depression, suggesting that the condition of oral cavity may affect the central nervous system. Dynorphin A is an endogenous opioid peptide that specifically binds the κ-opioid receptor and has a protective role against stress. Dynorphinergic nervous system is intensely distributed in the amygdala and hippocampus that are coping areas with stress. As a model of malocclusion, we placed dental resin on the molars to increase the occlusal vertical dimension (bite-raise). After various survival times, we analyzed the amygdala and hippocampus by immunohistochemistry and immunosorbent assay (ELISA). Furthermore, the effects on learning and memory were assessed by Morris water maze test. In the amygdala, the levels of dynorphin A were increased on the 1st day after increasing the vertical dimension as indicated by immunohistochemical and ELISA assessments. The levels of dynorphin A returned to control levels on the 5th day. In the hippocampus, there were no noticeable changes in dynorphin A levels. The water maze test indicated that increasing the vertical dimension caused longer escape latency times on the 3rd day compared to those of sham-operated group. However, the bite-raised mice treated with a dynorphin antagonist, nor-binaltorphimine, showed similar escape latency times to the times of sham-operated group, even on the 3rd day. These results suggest that occlusal disharmony causes stress resulting in a transient increase of dynorphin A levels at least in the amygdala and that the increased dynorphin A levels transiently impair learning and memory.

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Association of In Vivo κ-Opioid Receptor Availability and the Transdiagnostic Dimensional Expression of Trauma-Related Psychopathology

et al. 2014

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IMPORTANCE Exposure to trauma increases the risk for developing threat (ie, fear) symptoms, such as reexperiencing and hyperarousal symptoms, and loss (ie, dysphoria) symptoms, such as emotional numbing and depressive symptoms. While preclinical data have implicated the activated dynorphin/κ-opioid receptor (KOR) system in relation to these symptoms, the role of the KOR system in mediating these phenotypes in humans is unknown. Elucidation of molecular targets implicated in threat and loss symptoms is important because it can help inform the development of novel, mechanism-based treatments for trauma-related psychopathology.OBJECTIVE To use the newly developed [ 11 C]LY2795050 radiotracer and high-resolution positron emission tomography to evaluate the relation between in vivo KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit and the severity of threat and loss symptoms. We additionally evaluated the role of 24-hour urinary cortisol levels in mediating this association. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional positron emission tomography study under resting conditions was conducted at an academic medical center. Thirty-five individuals representing a broad transdiagnostic and dimensional spectrum of trauma-related psychopathology, ranging from nontrauma-exposed psychiatrically healthy adults to trauma-exposed adults with severe trauma-related psychopathology (ie, posttraumatic stress disorder, major depressive disorder, and/or generalized anxiety disorder).MAIN OUTCOMES AND MEASURES [ 11 C]LY2795050 volume of distribution values in amygdala-anterior cingulate cortex-ventral striatal neural circuit; composite measures of threat (ie, reexperiencing, avoidance, and hyperarousal symptoms) and loss (ie, emotional numbing, major depressive disorder, and generalized anxiety disorder symptoms) symptoms as assessed using the Clinician-Administered PTSD Scale, Hamilton Depression Rating Scale, and Hamilton Rating Scale for Anxiety; and 24-hour urinary cortisol levels.RESULTS [ 11 C]LY2795050 volume of distribution values in an amygdala-anterior cingulate cortex-ventral striatal neural circuit were negatively associated with severity of loss (r = −0.39; 95% CI, −0.08 to −0.66), but not threat (r = −0.03; 95% CI, −0.30 to 0.27), symptoms; this association was most pronounced for dysphoria symptoms (r = −0.45; 95% CI, −0.10 to −0.70). Path analysis revealed that lower [ 11 C]LY2795050 volume of distribution values in this circuit was directly associated with greater severity of loss symptoms and indirectly mediated by 24-hour urinary cortisol levels. CONCLUSIONS AND RELEVANCEResults of this study suggest that KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit mediates the phenotypic expression of trauma-related loss (ie, dysphoria) symptoms. They further suggest that an activated corticotropin-releasing factor/hypothalamic-pituitary-adrenal axis system, as assessed by 24-hour urinary cortisol levels, may indirectly mediate this associ...

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Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Cited by 439 publications

References 39 publications

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

Occlusal Disharmony Transiently Impairs Learning and Memory in the Mouse by Increasing Dynorphin A Levels in the Amygdala

Association of In Vivo κ-Opioid Receptor Availability and the Transdiagnostic Dimensional Expression of Trauma-Related Psychopathology

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