Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of dysphoria and cognitive disruption. KOR activation in rodents by agonists or by stress-evoked dynorphin release have been shown to produce aversion, increase anxiety-like behaviors, increase the rewarding effects of drugs of abuse (e.g. cocaine, ethanol & nicotine), increase addictive drug self-administration, and reinstate extinguished drug-seeking behaviors. The cellular and molecular mechanisms responsible for these dynorphin- dependent, pro-addictive behaviors are not fully understood, and a better understanding may suggest new therapeutic approaches to the treatment and prevention of stress-related diseases including some forms of drug addiction. Prior studies supported by this award demonstrated that KOR activation by stress-induced release of dynorphin or pharmacological KOR agonist administration produces aversion in mice and potentiates cocaine conditioned place preference by activating p38? MAPK in serotonergic and dopaminergic neurons to regulate excitability and serotonin transport. Conditional knockout of p38? MAPK in either serotonergic neurons of the dorsal raphe or dopaminergic neurons in the ventral tegmental area (VTA), blocked the aversive and pro-addictive effects of KOR activation. It is not yet clear how KOR regulation of the serotonergic, glutamatergic, and dopaminergic circuits individually contribute to the behaviors, and the studies proposed in this renewal are designed to better define how dynorphin regulation of each of these neural circuits results in the dysphoric and pro-addictive effects of stress. To accomplish these aims, we propose to: 1) use optogenetic activation and inhibition of dorsal raphe neurons that project to nucleus accumbens or VTA to define the circuits and mechanisms responsible for dynorphin-dependent, stress-induced potentiation of cocaine place preference; 2) identify the sources of dynorphin responsible for these behavioral effects by excising prodynorphin in pDynflox mice from candidate neurons then assessing the effects on stress-induced potentiation of cocaine place preference; 3) use whole cell voltage clamp recordings of VTA dopamine neurons to characterize the pre and postsynaptic effects of KOR activation of p38? MAPK, which has been previously shown to be required for these stress-induced behaviors. Kappa opioid receptor antagonists may have therapeutic potential in the treatment of addiction by promoting stress resilience, and the proposed studies would advance that concept by defining the actions of stress-induced dynorphin on the reward circuit. Functionally selective kappa opioid receptor agonists that activate G-protein signaling without stimulating p38? MAPK may be effective analgesics without producing the euphorigenic effects of mu opioid agonists or the dysphoric effects of conventional kappa agonists. The proposed studies would advance our understanding of the therapeutic potential of kappa selective ligands in the treatment of chronic pain and drug addiction.

Public Health Relevance

Although the stress response is generally protective, repeated and uncontrollable stress exposure can increase the risks of mood disorders and drug addiction. The mechanisms underlying these adverse effects need to be understood before better treatments for stress related diseases can be developed. Activation of p38? MAPK by the dynorphin/kappa opioid receptors in serotonergic and dopaminergic systems in brain has been shown to encode the dysphoric effects of stress. The proposed studies would define the dynorphin- activated p38? MAPK mechanisms responsible and would advance the hypothesis that a selective KOR antagonist may have therapeutic potential in the treatment of drug addiction by increasing stress-resilience.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030074-07
Application #
9322516
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sorensen, Roger
Project Start
2011-03-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
7
Fiscal Year
2017
Total Cost
$340,454
Indirect Cost
$115,454
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Abraham, Antony D; Fontaine, Harrison M; Song, Allisa J et al. (2018) ?-Opioid Receptor Activation in Dopamine Neurons Disrupts Behavioral Inhibition. Neuropsychopharmacology 43:362-372
Abraham, Antony D; Schattauer, Selena S; Reichard, Kathryn L et al. (2018) Estrogen Regulation of GRK2 Inactivates Kappa Opioid Receptor Signaling Mediating Analgesia, But Not Aversion. J Neurosci 38:8031-8043
Ehrich, Jonathan M; Messinger, Daniel I; Knakal, Cerise R et al. (2015) Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons. J Neurosci 35:12917-31
Lowe, Janet D; Sanderson, Helen S; Cooke, Alexandra E et al. (2015) Role of G Protein-Coupled Receptor Kinases 2 and 3 in ?-Opioid Receptor Desensitization and Internalization. Mol Pharmacol 88:347-56
Groblewski, Peter A; Zietz, Chad; Willuhn, Ingo et al. (2015) Repeated stress exposure causes strain-dependent shifts in the behavioral economics of cocaine in rats. Addict Biol 20:297-301
Chavkin, Charles; Schattauer, Selena S; Levin, Jamie R (2014) Arrestin-mediated activation of p38 MAPK: molecular mechanisms and behavioral consequences. Handb Exp Pharmacol 219:281-92
Ehrich, Jonathan M; Phillips, Paul E M; Chavkin, Charles (2014) Kappa opioid receptor activation potentiates the cocaine-induced increase in evoked dopamine release recorded in vivo in the mouse nucleus accumbens. Neuropsychopharmacology 39:3036-48
Chavkin, Charles; Ehrich, Jonathan M (2014) How does stress-induced activation of the kappa opioid system increase addiction risk? Biol Psychiatry 76:760-2
Chavkin, Charles (2013) Dynorphin--still an extraordinarily potent opioid peptide. Mol Pharmacol 83:729-36
Schindler, Abigail G; Messinger, Daniel I; Smith, Jeffrey S et al. (2012) Stress produces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J Neurosci 32:17582-96

Showing the most recent 10 out of 16 publications