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3. Strain and sex-related behavioral variability of oxycodone dependence in rats

Author

Doyle, Michelle R, Martinez, Angelica R, Qiao, Ran, Dirik, Selen, Di Ottavio, Francesca, Pascasio, Glenn, Martin-Fardon, Rémi, Benner, Christopher, George, Olivier, Telese, Francesca, and de Guglielmo, Giordano

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Prescription Drug Abuse, Substance Misuse, Brain Disorders, Behavioral and Social Science, Neurosciences, Opioid Misuse and Addiction, Pain Research, Drug Abuse (NIDA only), Chronic Pain, Opioids, Basic Behavioral and Social Science, Mental health, Good Health and Well Being, Rats, Female, Male, Animals, Oxycodone, Rats, Inbred ACI, Rats, Inbred F344, Rats, Inbred WKY, Analgesics, Opioid, Opioid-Related Disorders, Self Administration, Opioid use disorder, Rat, Self-administration, Sex, Strain, Neurology & Neurosurgery, Pharmacology and pharmaceutical sciences, Biological psychology
Abstract

Over the past two decades, the escalating prescription of opioid medications for pain management has culminated in a widespread opioid epidemic, significantly impacting public health, social dynamics, and economic stability. The urgent need for improved treatments for opioid addiction necessitates a deeper understanding of its biological underpinnings, with genetic variations playing a crucial role in individual susceptibility to opioid use disorder (OUD) and influencing clinical practices. In this study, we leverage the genetic diversity of four rat strains (ACI/N, BN/NHsd, WKY/N, and F344/N) to examine the contribution of genetic factors to oxycodone metabolism and addiction-like behaviors. We used the extended access to intravenous oxycodone self-administration procedure (12 h/day, 0.15 mg/kg/injection) to comprehensively characterize oxycodone-related behaviors and pharmacokinetics. We measured escalation of oxycodone self-administration, motivation for drug consumption, tolerance to the analgesic effects of oxycodone, withdrawal-induced hyperalgesia, and oxycodone-induced respiratory depression. Additionally, we examined oxycodone-seeking behavior after four weeks of withdrawal by reintroducing the animals to environmental and cue stimuli previously associated with oxycodone self-administration. The findings revealed notable strain differences in several behavioral measures, including oxycodone metabolism. Intriguingly, BN/NHsd and WKY/N strains exhibited similar drug intake and escalation patterns but displayed significant disparities in oxycodone and oxymorphone metabolism. Minimal sex differences were observed within strains, primarily relating to oxycodone metabolism. In conclusion, this study identifies strain differences in the behavioral responses and pharmacokinetics associated with oxycodone self-administration in rats, providing a robust foundation for identifying genetic and molecular variants associated with various facets of the opioid addiction process.

Published
2023

4. Sensitivity of Hypocretin System to Chronic Alcohol Exposure: A Human and Animal Study

Author

McGregor, Ronald, Matzeu, Alessandra, Thannickal, Thomas C, Wu, Frank, Cornford, Marcia, Martin-Fardon, Rémi, and Siegel, Jerome M

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Substance Misuse, Behavioral and Social Science, Alcoholism, Alcohol Use and Health, Brain Disorders, Neurosciences, Mental health, Good Health and Well Being, Humans, Male, Rats, Mice, Animals, Orexins, Neuropeptides, Histamine, Hypothalamic Hormones, Hypothalamus, Melanins, Neurons, Ethanol, hypocretin, melanin concentrating hormone, histamine human, alcohol, microglia, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse.

Published
2023

10. Thalamic circuits

Author

Matzeu, Alessandra, primary, Flores-Ramirez, Francisco J., additional, and Martin-Fardon, Rémi, additional

Published
2023
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11. Contributors

Author

Abshire, Kelly M., primary, Addy, Nii A., additional, Bedard, Madigan L., additional, Bravo, Isabel M., additional, Brown, Jordan A., additional, Carrette, Lieselot L.G., additional, Centanni, Samuel W., additional, Cogan, Elizabeth S., additional, Conley, Sara Y., additional, Downs, Anthony M., additional, Flavia Barbano, M., additional, Flook, Elizabeth A., additional, Flores-Ramirez, Francisco J., additional, Fowler, Christie D., additional, Gamble, Mackenzie C., additional, George, Olivier, additional, Hearing, Matthew C., additional, Ibrahim, Christine, additional, Le Foll, Bernard, additional, Leggio, Lorenzo, additional, Logan, Ryan W., additional, Luchsinger, Joseph R., additional, Mandyam, Chitra D., additional, Mantsch, John R., additional, Martin-Fardon, Rémi, additional, Mathur, Brian N., additional, Matzeu, Alessandra, additional, McElligott, Zoé A., additional, Morales, Marisela, additional, Patton, Michael S., additional, Salling, Michael C., additional, Sneddon, Elizabeth A., additional, Wickham, Robert J., additional, Williford, Kellie M., additional, and Winder, Danny G., additional

Published
2023
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12. The Amygdala Noradrenergic System Is Compromised With Alcohol Use Disorder

Author

Varodayan, Florence P., Patel, Reesha R., Matzeu, Alessandra, Wolfe, Sarah A., Curley, Dallece E., Khom, Sophia, Gandhi, Pauravi J., Rodriguez, Larry, Bajo, Michal, D’Ambrosio, Shannon, Sun, Hui, Kerr, Tony M., Gonzales, Rueben A., Leggio, Lorenzo, Natividad, Luis A., Haass-Koffler, Carolina L., Martin-Fardon, Rémi, and Roberto, Marisa

Published
2022
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14. Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence

Author

Matzeu, Alessandra, Kallupi, Marsida, George, Olivier, Schweitzer, Paul, and Martin-Fardon, Rémi

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Behavioral and Social Science, Brain Disorders, Opioids, Neurosciences, Basic Behavioral and Social Science, Drug Abuse (NIDA only), Substance Misuse, Good Health and Well Being, Animals, Behavior, Addictive, Cocaine, Cocaine-Related Disorders, Drug Interactions, Dynorphins, Excitatory Postsynaptic Potentials, Extinction, Psychological, Male, Microinjections, Miniature Postsynaptic Potentials, Naltrexone, Orexins, Paraventricular Hypothalamic Nucleus, Rats, Reward, Self Administration, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological psychology
Abstract

The orexin (Orx) system plays a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orx and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Previous studies suggested that OrxA transmission in the posterior paraventricular nucleus of the thalamus (pPVT) participates in cocaine-seeking behavior. This study determined whether Orx and Dyn interact in the pPVT. Using the brain slice preparation for cellular recordings, superfusion of DynA onto pPVT neurons decreased the frequency of spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs). OrxA increased the frequency of sEPSCs but had no effect on mEPSCs, suggesting a network-driven effect of OrxA. The amplitudes of s/mEPSCs were unaffected by the peptides, indicating a presynaptic action on glutamate release. Augmentation of OrxA-induced glutamate release was reversed by DynA. Utilizing a behavioral approach, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After extinction, rats received intra-pPVT administration of OrxA±DynA±the κ-opioid receptor antagonist nor-binaltorphimine (NorBNI) under extinction conditions. OrxA reinstated cocaine- and SCM-seeking behavior, with a greater effect in cocaine animals. DynA blocked OrxA-induced cocaine seeking but not SCM seeking. NorBNI did not induce or potentiate cocaine-seeking behavior induced by OrxA but reversed DynA effect. This indicates that the κ-opioid system in the pPVT counteracts OrxA-induced cocaine seeking, suggesting a novel therapeutic target to prevent cocaine relapse.

Published
2018

15. Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats

Author

de Guglielmo, Giordano, Matzeu, Alessandra, Kononoff, Jenni, Mattioni, Julia, Martin-Fardon, Rémi, and George, Olivier

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Opioids, Drug Abuse (NIDA only), Behavioral and Social Science, Brain Disorders, Substance Misuse, Mental health, Good Health and Well Being, Animals, Behavior, Animal, Cocaine-Related Disorders, Conditioning, Operant, Extinction, Psychological, Indoles, Male, Motor Activity, Rats, Rats, Wistar, Recurrence, Reward, Self Administration, Spiro Compounds, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 μg/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 hour) access to cocaine, whereas it did not affect the self-administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects.

Published
2017

18. Pivotal role of orexin signaling in the posterior paraventricular nucleus of the thalamus during the stress-induced reinstatement of oxycodone-seeking behavior.

Author

Illenberger, Jessica M, Flores-Ramirez, Francisco J, Pascasio, Glenn, Franco, Marissa, Mendonsa, Brandon, and Martin-Fardon, Rémi

Subjects
OPIOID abuse, ORAL drug administration, PARAVENTRICULAR nucleus, DEPENDENCY (Psychology), LABORATORY rats, OREXINS
Abstract

Background: The orexin (OX) system has received increasing interest as a potential target for treating substance use disorder. OX transmission in the posterior paraventricular nucleus of the thalamus (pPVT), an area activated by highly salient stimuli that are both reinforcing and aversive, mediates cue- and stress-induced reinstatement of reward-seeking behavior. Oral administration of suvorexant (SUV), a dual OX receptor (OXR) antagonist (DORA), selectively reduced conditioned reinstatement of oxycodone-seeking behavior and stress-induced reinstatement of alcohol-seeking behavior in dependent rats. Aims: This study tested whether OXR blockade in the pPVT with SUV reduces oxycodone or sweetened condensed milk (SCM) seeking elicited by conditioned cues or stress. Methods: Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i.v., 8 h/day) or SCM (0.1 ml, 2:1 dilution [v/v], 30 min/day). After extinction, we tested the ability of intra-pPVT SUV (15 µg/0.5 µl) to prevent reinstatement of oxycodone or SCM seeking elicited by conditioned cues or footshock stress. Results: The rats acquired oxycodone and SCM self-administration, and oxycodone intake correlated with signs of physical opioid withdrawal, confirming dependence. Following extinction, the presentation of conditioned cues or footshock elicited reinstatement of oxycodone- and SCM-seeking behavior. Intra-pPVT SUV blocked stress-induced reinstatement of oxycodone seeking but not conditioned reinstatement of oxycodone or SCM seeking or stress-induced reinstatement of SCM seeking. Conclusions: The results indicate that OXR signaling in the pPVT is critical for stress-induced reinstatement of oxycodone seeking, further corroborating OXRs as treatment targets for opioid use disorder. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Contributors

Author

Berrendero, Fernando, primary, Black, Emily M., additional, Blumenthal, Sarah A., additional, Burk, Joshua A., additional, de Lecea, Luis, additional, España, Rodrigo A., additional, Fadel, Jim R., additional, Flores, África, additional, Jennings, Kimberly J., additional, Kotz, Catherine M., additional, Kukkonen, Jyrki P., additional, Maness, Eden B., additional, Martin-Fardon, Rémi, additional, Matzeu, Alessandra, additional, Perez-Leighton, Claudio, additional, Petrovich, Gorica D., additional, Shaw, Jessica K., additional, Teske, Jennifer A., additional, and Zhang, Yanan, additional

Published
2019
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25. Strain and sex-related behavioral variability of oxycodone dependence in rats.

Author

Doyle, Michelle, Doyle, Michelle, Martinez, Angelica, Qiao, Ran, Dirik, Selen, Di Ottavio, Francesca, Pascasio, Glenn, Martin-Fardon, Rémi, Benner, Christopher, de Guglielmo, Giordano, Telese, Francesca, George, Olivier, Doyle, Michelle, Doyle, Michelle, Martinez, Angelica, Qiao, Ran, Dirik, Selen, Di Ottavio, Francesca, Pascasio, Glenn, Martin-Fardon, Rémi, Benner, Christopher, de Guglielmo, Giordano, Telese, Francesca, and George, Olivier

Abstract

Over the past two decades, the escalating prescription of opioid medications for pain management has culminated in a widespread opioid epidemic, significantly impacting public health, social dynamics, and economic stability. The urgent need for improved treatments for opioid addiction necessitates a deeper understanding of its biological underpinnings, with genetic variations playing a crucial role in individual susceptibility to opioid use disorder (OUD) and influencing clinical practices. In this study, we leverage the genetic diversity of four rat strains (ACI/N, BN/NHsd, WKY/N, and F344/N) to examine the contribution of genetic factors to oxycodone metabolism and addiction-like behaviors. We used the extended access to intravenous oxycodone self-administration procedure (12 h/day, 0.15 mg/kg/injection) to comprehensively characterize oxycodone-related behaviors and pharmacokinetics. We measured escalation of oxycodone self-administration, motivation for drug consumption, tolerance to the analgesic effects of oxycodone, withdrawal-induced hyperalgesia, and oxycodone-induced respiratory depression. Additionally, we examined oxycodone-seeking behavior after four weeks of withdrawal by reintroducing the animals to environmental and cue stimuli previously associated with oxycodone self-administration. The findings revealed notable strain differences in several behavioral measures, including oxycodone metabolism. Intriguingly, BN/NHsd and WKY/N strains exhibited similar drug intake and escalation patterns but displayed significant disparities in oxycodone and oxymorphone metabolism. Minimal sex differences were observed within strains, primarily relating to oxycodone metabolism. In conclusion, this study identifies strain differences in the behavioral responses and pharmacokinetics associated with oxycodone self-administration in rats, providing a robust foundation for identifying genetic and molecular variants associated with various facets of the opioid ad

Published
2023

27. Modeling Relapse in Animals

Author

Martin-Fardon, Rémi, Weiss, Friedbert, Geyer, Mark A., Series Editor, Ellenbroek, Bart A., Series Editor, Marsden, Charles A., Series Editor, Sommer, Wolfgang H., editor, and Spanagel, Rainer, editor

Published
2013
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33. List of Contributors

Author

Abbas, Ghulam, primary, Adamowicz, Piotr, additional, Adan, Ana, additional, Agay, Nirit, additional, Al-Halabí, S., additional, Altun, Hatice, additional, Amini, Maryam, additional, Andersen, Monica L., additional, Andreassen, Cecilie Schou, additional, Anthony, James C., additional, Ardakani, Yalda Hosseinzadeh, additional, Aromatario, Mariarosaria, additional, Arun, Priti, additional, Atik, Anzari, additional, Atti, Anna Rita, additional, Baird, Alison L., additional, Balconi, Michela, additional, Ballóková, Anna Lukačišinová, additional, Bascarán, M.T., additional, Battagliese, Gemma, additional, Benaiges, Irina, additional, Bergen-Cico, Dessa, additional, Berrettini, Wade H., additional, Berro, Laís F., additional, Bertol, Elisabetta, additional, Bian, Jin-Song, additional, Bobes-Bascarán, M.T., additional, Bobes, J., additional, Bocarsly, Miriam E., additional, Bocca, Marie-Laure, additional, Bonafede, Roberta, additional, Borroto-Escuela, Dasiel O., additional, Bottoni, Edoardo, additional, Bousoño, M., additional, Bowen, Michael T., additional, Bramanti, Placido, additional, Buck, Kari J., additional, Buisman-Pijlman, Femke T.A., additional, Büttner, Andreas, additional, Calabrò, Rocco S., additional, Çamsari, Ulaş M., additional, Cappelletti, Simone, additional, Carbo-Gas, María, additional, Casadio, Paola, additional, Casadó-Anguera, Verònica, additional, Casadó, Vicent, additional, Ceccanti, Mauro, additional, Chang, Yong-Yuan, additional, Chang, Young-Tae, additional, Chiu, Meng-Chun, additional, Chiu, Nan-Ying, additional, Cho, Zang-Hee, additional, Chung, Yemina, additional, Ciallella, Costantino, additional, Cinosi, Eduardo, additional, Conigrave, Katherine M., additional, Coogan, Andrew N., additional, Coppola, Maurizio, additional, Cortés, Antoni, additional, Costa, Giulia, additional, Cox, Stephen, additional, Dafny, Nachum, additional, Das, Subhash, additional, Davis, Jonathan M., additional, De Matteo, Robert, additional, Demetrovics, Zsolt, additional, Demirkol, Apo, additional, Denovan-Wright, Eileen M., additional, di Giannantonio, Massimo, additional, Edgunlu, Tuba, additional, Elliott, Simon, additional, Enman, Nicole M., additional, Ensafi, Ali A., additional, Faccini, Marco, additional, Falls, Brian A., additional, Fang, Chiu-Ping, additional, Fan, Lir-Wan, additional, Farooq, Ahsana Dar, additional, Feingold, Daniel, additional, Ferraro, Luca, additional, Fialová, Daniela, additional, Filip, Malgorzata, additional, Findikli, Ebru, additional, Finocchiaro, Roberta, additional, Fiore, Paola A., additional, Font-Mayolas, Sílvia, additional, Fox, Jonah, additional, Fragou, Domniki, additional, Fu, Qiang, additional, Fuxe, Kjell, additional, Gahr, Maximilian, additional, García-Portilla, M.P., additional, George, Preeta, additional, Gil-Miravet, Isis, additional, Gorwood, Philip, additional, Gras, Maria Eugènia, additional, Gravielle, María Clara, additional, Griffiths, Mark D., additional, Haber, Paul S., additional, Hadad, Natalie A., additional, Hall, F. Scott, additional, Han, Doug Hyun, additional, Harding, Richard, additional, Hashmi, Rida, additional, Hassanian-Moghaddam, Hossein, additional, Hernández-Serrano, Olga, additional, Herrmann, Evan S., additional, Herzog, Thaddeus A., additional, Heydari-Bafrooei, Esmaeil, additional, Hirota, Kiichi, additional, Ho, Ming-Chou, additional, Howell, Leonard L., additional, Hsu, Wen-Yu, additional, Huang, Chieh-Liang, additional, Hughes, Robert N., additional, Hymel, Kristen A., additional, Hyun, Gi Jung, additional, Inoue, Koichi, additional, Islam, M. Mofizul, additional, Jamali, Bardia, additional, Jerzemowska, Grażyna, additional, Job, Martin O., additional, Johannessen, Jan Olav, additional, Johansen, Helen J., additional, Johnson, Matthew W., additional, Johnson, Patrick S., additional, Kang, Chang-Ki, additional, Karakaş-Çelik, Sevim, additional, Kharas, Natasha, additional, Kim, Young-Bo, additional, Knackstedt, Lori A., additional, Kokki, Hannu, additional, Kokki, Merja, additional, Konopka, Anna, additional, Kopcza, Kathleen, additional, Kouvelas, Dimitrios, additional, Kovatsi, Leda, additional, Kruse, Lauren C., additional, Lai, Chien-Wen, additional, Lapeyre-Mestre, Maryse, additional, Lauterbach, Edward C., additional, Le Strat, Yann, additional, Lee, Chen-Yi, additional, Lejoyeux, Michel, additional, Leone, Roberto, additional, Lev-Ran, Shaul, additional, Li, Ren-Hau, additional, Liang, Willmann, additional, Liu, Jiajun, additional, Liu, Ling-Jun, additional, Liu, Liwei, additional, Liu, Sheng-Wen, additional, Liu, Yu-Li, additional, Li, Zia, additional, Lobo, Daniela S.S., additional, Lou, Jingsheng, additional, Luigi Picci, Rocco, additional, Lupi, Matteo, additional, Lutz, Brianna M., additional, MacClurg, Kendra, additional, Magro, Lara, additional, Manchia, Mirko, additional, Maraz, Aniko, additional, Martin-Fardon, Rémi, additional, Martinotti, Giovanni, additional, Matzeu, Alessandra, additional, McLaughlin, Jay P., additional, McRae, Ian S., additional, Meyerhoff, Dieter J., additional, Miquel, Marta, additional, Mondola, Raffaella, additional, Moore, Robert, additional, Morelli, Micaela, additional, Moreno, Estefanía, additional, Mori, Tomohisa, additional, Murnion, Bridin, additional, Murphy, Kelle L., additional, Nagpure, Bhushan Vijay, additional, Naro, Antonino, additional, Neutel, C. Ineke, additional, Nielsen, Suzanne, additional, Nomura, Motoo, additional, Oliva, Francesco, additional, Olive, M. Foster, additional, Olivoni, Deanna, additional, Ouyang, Qin, additional, Pallesen, Ståle, additional, Palmaro, Aurore, additional, Papazisis, Georgios, additional, Paris, Jason J., additional, Park, Chan-A, additional, Park, Jeong Ha, additional, Pełka Wysiecka, Justyna, additional, Pearson-Dennett, Verity, additional, Phillips, Daniel E., additional, Pinna, Martina, additional, Plener, Paul L., additional, Ramoz, Nicolas, additional, Renshaw, Perry F., additional, Reyes, Beverly A.S., additional, Rivera, Alicia, additional, Robinson, Susan E., additional, Romolo, Francesco S., additional, Roohbakhsh, Ali, additional, Rouini, Mohammadreza, additional, Roussin, Anne, additional, Roussotte, Florence F., additional, Saiz, P.A., additional, Samochowiec, J., additional, Sanchis-Segura, Carla, additional, Santacroce, Rita, additional, Sato-Bigbee, Carmen, additional, Sayin, H. Umit, additional, Searles Quick, Veronica B., additional, Şenormanci, Ömer, additional, Seseña, Emmanuel, additional, Shamsizadeh, Ali, additional, Sheikholeslami, Behjat, additional, Shen, Bin, additional, Shibasaki, Masahiro, additional, Shillcutt, Samuel D., additional, Simola, Nicola, additional, Singh, Rachana, additional, Soraisham, Amuchou Singh, additional, Soto, Enrique, additional, Soyka, Michael, additional, Stepens, Ainars, additional, Sullman, Mark J.M., additional, Sun, Linlin, additional, Suzuki, Tsutomu, additional, Szabo, Attila, additional, Taba, Pille, additional, Tang, Hong Chai, additional, Tang, Tze-Chun, additional, Tao, Yuan-Xiang, additional, ten Velden Hegelstad, Wenche, additional, Thome, Johannes, additional, Thompson, Paul M., additional, Tien, Lu-Tai, additional, Tietz, Elizabeth I., additional, Todd, Gabrielle, additional, Tolcos, Mary, additional, Torkamanian, Meshkat, additional, Tsung, Jieh-Hen, additional, Tufik, Sergio, additional, Ullah, Mafaz, additional, Vaiano, Fabio, additional, Van Bockstaele, Elisabeth J., additional, Vandrey, Ryan, additional, Vazquez-Sanroman, Dolores, additional, Vega, Rosario, additional, Vitali, Mario, additional, Wai, Maria S.M., additional, Wang, Junmei, additional, Wang, Lirong, additional, Wang, Sheng-Chang, additional, Weibell, Melissa A., additional, Weinstein, Aviv, additional, White, Jason M., additional, Wilcox, Robert A., additional, Wilson, Hester, additional, Wouldes, Trecia A., additional, Wydra, Karolina, additional, Xie, Xiang-Qun, additional, Xie, Zhaojun, additional, Xi, Zheng-Xiong, additional, Xu, Wang, additional, Yang, Hai-Yu, additional, Yang, Peng, additional, Yechiam, Eldad, additional, Yew, David T., additional, Yong, Andrew W.S., additional, Zamani, Nasim, additional, Zoellner, Hans, additional, and Zuba, Dariusz, additional

Published
2016
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39. Understanding the Role of Orexin Neuropeptides in Drug Addiction: Preclinical Studies and Translational Value

Author

Matzeu, Alessandra and Martin-Fardon, Rémi

Subjects
alcohol, Cognitive Neuroscience, digestive, oral, and skin physiology, cocaine, opioids, Neurosciences. Biological psychiatry. Neuropsychiatry, Review, Behavioral Neuroscience, Neuropsychology and Physiological Psychology, nervous system, orexin, mental disorders, psychological phenomena and processes, RC321-571, Neuroscience, nicotine
Abstract

Orexins (also known as hypocretins) are neuropeptides that participate in the regulation of energy metabolism, homeostasis, sleep, feeding, stress responses, arousal, and reward. Particularly relevant to the scope of the present review is the involvement of the orexin system in brain mechanisms that regulate motivation, especially highly motivated behavior, arousal, and stress, making it an ideal target for studying addiction and discovering treatments. Drug abuse and misuse are thought to induce maladaptive changes in the orexin system, and these changes might promote and maintain uncontrolled drug intake and contribute to relapse. Dysfunctional changes in this neuropeptidergic system that are caused by drug use might also be responsible for alterations of feeding behavior and the sleep-wake cycle that are commonly disrupted in subjects with substance use disorder. Drug addiction has often been associated with an increase in activity of the orexin system, suggesting that orexin receptor antagonists may be a promising pharmacological treatment for substance use disorder. Substantial evidence has shown that single orexin receptor antagonists that are specific to either orexin receptor 1 or 2 can be beneficial against drug intake and relapse. Interest in the efficacy of dual orexin receptor antagonists, which were primarily developed to treat insomnia, has grown in the field of drug addiction. Treatments that target the orexin system may be a promising strategy to reduce drug intake, mitigate relapse vulnerability, and restore “normal” physiological functions, including feeding and sleep. The present review discusses preclinical and clinical evidence of the involvement of orexins in drug addiction and possible beneficial pharmacotherapeutic effects of orexin receptor antagonists to treat substance use disorder.

Published
2021

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