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Panel and Study Groups Neuropsychopharmacology (2012) 38, S1–S78 & 2012 American College of Neuropsychopharmacology All rights reserved 0893-133X/12 www.neuropsychopharmacology.org S1 Monday, December 03, 2012 Conclusions: The signaling differences identified in this study have important implications in screening different KOR agonists and antago- nists having distinctly different ligand directed signaling properties. Mini Panel Disclosure: C. Chavkin, Part 1: Consulting for Trevena 2010-2011, 1. Renaissance in Opioid Biology: From Preclinical Concepts to Part 2: Contract with Trevena 2010-2011. Clinical Practice 1.2 The Place of Opiates in the Cortico-basal Ganglia Reward 1.1 Molecular Basis for Kappa Opioid Receptor Antagonism: Circuit Implications of Ligand-directed Signaling for the Development of Novel Antidepressants Suzanne Haber* Charles Chavkin* University of Rochester, Rochester, New York University of Washington, Seattle, Washington Background: Reward is a central component for driving incentive- based learning, appropriate responses to stimuli, and habit Background: Preclinical studies have demonstrated the role of formation. Pathology in this circuit is associated with several stress-induced dynorphin release in mediating a component of the diseases including addition. The ventral medial prefrontal cortex anxiogenic and aversive effects of stress exposure. These results (vmPFC), orbital prefrontal cortex (OFC), dorsal anterior cingulate suggest that kappa opioid receptor (KOR) antagonists or low cortex (dACC), striatum, ventral pallidum, and midbrain dopamine efficacy partial agonists may promote stress-resilience in humans neurons are at the center of the circuit associated with reward in and may potentially be useful in treating certain forms of mood general and, in particular addiction. Connectivity between these disorders exacerbated by stressful experience. In rodent models, areas forms a complex neural network that mediates different stress-induced stimulation of dynorphin release produces aversion, aspects of reward processing, that can lead to habit formation. The reduces open arm time, potentiates cocaine and nicotine condi- opiates are differentially distributed through the striatum and basal tioned place preference, inhibits social interaction and reinstates ganglia output structures. The goal of this study was to gain a better extinguished drug seeking. Each of these responses have been understanding of place of opiates within this network. shown to be blocked by prior treatment with KOR antagonists or Methods: Tracing methods were used to define the projection gene deletion of either KOR or prodynorphin. Two classes of KOR pathways from the vmPFC and OFC through basal ganglia antagonists have been developed and clinical trials of both types structures in non-human primates. Specific nodal points conver- have begun, but important differences in the molecular mechanisms gence of these connections and opiate distributions were identified. of antagonism have been revealed. In addition, partial agonists that Results: Previous results have shown a convergence between vmPFC, activate KOR without stimulating p38 MAPK may also effectively OFC, and dACC terminals in the striatum, suggesting functional promote analgesia and stress-resilience. Understanding these integration. Moreover, inputs from the amygdala also converge with ligand-directed signaling differences has important implications these inputs in the ventral striatum. These convergent regions appear for the optimization of future therapeutics that manipulate the to have high levels of enkephalin immunoreactivity (Enk ICC). Of functioning of the KOR system to affect mood. particular note is that convergent inputs and high levels of opiates are Methods: Mouse genetic and behavioral data were generated using also found in the rostral dorsal striatum, particularly along the medial conditional gene deletion approaches and behavioral stress wall of the caudate nucleus, an area not typically included in the response assays. ventral striatum. Interestingly, the dense patches of mu receptor ICC Results: Long-acting KOR antagonists including norBNI, JDTic, and is somewhat more limited, and concentrated in the ventral part of the GNTI fail to evoke Gbg signaling typical of KOR agonists, but do rostral caudate and putamen. Projections from these striatal areas initiate a Protein Kinase C (PKC) cascade resulting in C-Jun were followed to the globus pallidus and substantia nigra and N-terminal Kinase (JNK) activation. Inhibition of PKC by Go6976 compared to the opiate distributioninthosestructures.Therewasa blocked norBNI increase in phospho-JNK-ir, and inhibition of JNK clear convergence between the limbic projections and high levels of by SP600125 or gene deletion of JNK1 isoform blocked the long Enk ICC, in both the external and a portion of the internal globus duration of norBNI antagonism. The JNK phosphorylation site has pallidus, in addition to the ventral pallidum. been localized to the KOR signaling complex, and ongoing site- Conclusions: The data illustrate the relationship between cortical directed mutagenesis are being used to determine the regulatory site networks and the opiates outside the conventional ventral striatal within KOR. Short acting antagonists (e.g. naloxone and buprenor- system. These results suggest that by focusing research and phine) failed to activate PKC/JNK regulation of KOR. Interestingly, development on the conventional ventral striatum and ventral KOR agonists (U50,488 and dynorphin A(1-17)) activate phospho- pallidum may too limiting and that opiates within the rostral dorsal JNK-ir following ligand binding, but do so through a G-protein striatum may play a key role in modulating behavior. The rostral kinase 3/beta arrestin dependent mechanism that does not result in striatum also receives a major input from the dorsal prefrontal long-lasting receptor inactivation. These strong agonists also cortex, including areas 9 and 46, suggesting a striatal region activate p38a MAPK mechanisms resulting in aversion. KOR partial involved in not only limbic processing, but also top-down control. agonists have distinctly different signaling properties. For example, Disclosure: S. Haber, Part 1: Pfizer. the mixed MOR/KOR partial agonist, pentazocine was significantly more potent in activating p38-MAPK in hKOR than rKOR in transfected HEK293 cells. In contrast, pentazocine was equally 1.3 New Clinical Research in Opioid Modulation Indicates Novel potent in arrestin-independent activation of ERK1/2 in hKOR and Utility in Treating Resistant Depression rKOR. We confirmed that pentazocine was a partial agonist at both Elliot W. Ehrich* receptors for both signaling pathways. Although pentazocine is reported to produce dysphoria in humans, its lower efficacy at p38 Alkermes Plc., Waltham, Massachusetts activation of rKOR suggests that it may be unlikely to produce aversion in rodents. Consistent with this prediction, pentazocine Background: The endogenous opioid system is thought to play a (10 mg/kg i.p.) produced analgesia and a MOR-dependent place key role in the regulation of mood. Indeed, the ‘‘opium cure’’ was a preference but did not produce KOR-dependent aversion. pharmacologic mainstay of depression therapy prior to the advent ACNP 51st Annual Conference Abstracts S2 of tricyclic and monoamine oxidase inhibitor anti-depressants in brain development and drug action intersect to create this vulner- the 1950’s. The precise mechanism of endogenous opioids in mood ability is controversial. This risk may be especially great for regulation, however, is uncertain. individuals who manifest extremes of the adolescent behavioral The contemporary use of opioids for depression is limited by abuse phenotype of being sensitive to reward and/or less sensitive to the potential, presumably a result of mu opioid agonism. ALKS 5461 aversive experience. Adolescent rats will consume more ethanol, consists of buprenorphine (BUP), a partial mu agonist, combined nicotine and cocaine than adults. In most individuals, this excess with ALKS 33, a counter-acting mu antagonist, co-formulated for consumptiondeclinesastheanimalsmature.Forexample,wehave sublingual administration. The ALKS 33 component was designed to shown that adolescent rats that are self-administering cocaine or be highly potent and sublingually bioavailable with the latter two drinking ethanol decrease consumption as they enter adulthood. properties being essential for sublingual co-formulation. However, specific individuals do not show this normal developmental Initial clinical evaluation included a remifentanyl challenge study decline: these may provide an animal analog of at-risk humans. We to establish mu opioid blockade by ALKS 33, and a pharmacoki- have been exploring the relative contribution of immature neural netic and pharmacodynamic interaction study of BUP and ALKS 33 circuits and individual differences to the pattern of behaviors that to ascertain appropriate ratios of the two ALKS 5461 components. confers addiction vulnerability to adolescents. Subsequently a pilot assessment of safety and efficacy of ALKS 5461 Methods: Our laboratory has used behavioral and neurochemical in treatment resistant depression (TRD) was conducted. approaches to studying the responses to addictive drugs in Methods: 1. Remifentanyl challenge study in N ¼ 20 non-addicted adolescent (PN 28-45) and adult rats. To study reinforcement opioid-experienced volunteers. Serial remifentanyl or saline challenges circuits, behavioral strategies
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