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Abstract: Activation of the NOP receptor by the endogenous ligand nociceptin/orphanin FQ (N/OFQ) reduces alcohol consumption in genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The present study evaluated the effect of three newly synthesized peptidergic and one brain-penetrating heterocyclic NOP receptor agonists on alcohol drinking in the two bottle choice paradigm. MsP rats were intracerebroventricularly (ICV) injected with the NOP receptor agonists OS-462 (0.5 and 1.0μg), UFP-102 (0.25 and 1.0μg) or UFP-112 (0.01 and 0.05μg), or with Ro 64-6198 (0.3 and 1.0mg/kg) given intraperitoneally (i.p.) and tested for 10% alcohol consumption. Results showed decreased alcohol consumption after treatment with all three peptidergic NOP receptor agonists (OS-462, UFP-102 and UFP-112). OS-462 (at the 1.0μg dose) and UFP-102 (at the 0.25μg dose) induced a significant increase in food intake as well. Surprisingly, Ro 64-6198 was ineffective at the 0.3mg/kg dose, whereas it increased ethanol and food consumption at the 1.0mg/kg dose. Pre-treatment with the selective μ-receptor antagonist naloxone (0.5mg/kg, i.p.) reduced these effects of 1.0mg/kg of Ro 64-6198. These findings confirm that activation of brain NOP receptors reduces alcohol drinking in msP rats and demonstrate that OS-462, UFP-102 and UFP-112 act as potent NOP receptor agonists. On the other hand, Ro 64-6198 increased alcohol drinking, an effect probably induced by a residual agonist activity of this compound at μ-opioid receptors. Overall, the results indicate that OS-462, UFP-102 and UFP-112 may represent valuable pharmacological tools to investigate the functional role of the brain N/OFQ system. [Copyright &y& Elsevier]

Naltrexone (NTX), a homolog of the opiate antidote naloxone, is an orally active long-acting general opioid receptor antagonist used in the treatment of opiate dependence. NTX is also found to relieve craving for alcohol and is one of few FDA-approved medications for treatment of alcohol use disorder (AUD). While it was early on established that NTX acts by blocking the binding of endogenous opioid peptide ligands released by alcohol, experimental evidence emerged that could not be fully accounted for by this explanation alone, suggesting that NTX may have additional modes of action. Mu- and kappa-opioid receptors (MOP and KOP, respectively) are structurally related G-protein-coupled receptors (GPCRs), but they are anatomically differently distributed and functionally distinct, often mediating opposite responses, with MOP typically promoting euphoria and reward, while KOP is associated with dysphoria and aversive states. While the actions of NTX on MOP are extensively characterized, the interactions with KOP are not. Here, we used sensitive fluorescence-based methods with single-molecule sensitivity to study in live cells the influence of alcohol (ethanol, EtOH) on KOP and the interaction between KOP and NTX. Our data show that alcohol, at relevant concentrations (10-40 mM), alters KOP interactions with the lipid environment in the plasma membrane. The counteracting effects of NTX are exerted by both its canonical action on KOP and its hitherto unrevealed effects on the lateral dynamics and organization of lipids in the plasma membrane. The KOP-specific antagonist LY2444296, in clinical trial for major depressive disorder (MDD), blocks KOP but does not show the full action profile of NTX. The therapeutic effect of NTX treatment in AUD may in part be due to direct actions on KOP and in part due to its effect on the surrounding lipid environment., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All experiments were done in the laboratory and did not involve humans or animals. The experiments did not involve tissues from humans or other vertebrates. All experiments were done in accordance with scientific standards., (© 2024. The Author(s).)

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats at 8 h abstinence. Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent alcohol vapor exposure for 6 weeks or exposed to air (nondependent). After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel, and their somatic withdrawal signs and alcohol self-administration were measured after LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence. LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats at 8 h abstinence, only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats at only 8 h abstinence. These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD., (© 2024. The Author(s).)

Chronic opioid use disturbs circadian rhythm and sleep, encouraging opioid use and relapse. The orexin (OX) system is recruited by opioids and regulates physiological processes including sleep. Dual OX receptor antagonists (DORAs), developed for insomnia treatment, may relieve withdrawal-associated sleep disturbances. This study investigated whether DORA-12, a recently developed DORA, reduces physiological activity disturbances during oxycodone abstinence and consequently prevents oxycodone-seeking behavior. Male and female Wistar rats were trained to intravenously self-administer oxycodone (0.15 mg/kg, 21 sessions; 8 h/session) in the presence of a contextual/discriminative stimulus (S D ). The rats were subsequently housed individually (22 h/day) to monitor activity, food and water intake. They received DORA-12 (0-30 mg/kg, p.o.) after undergoing daily 1-h extinction training (14 days). After extinction, the rats were tested for oxycodone-seeking behavior elicited by the S D . Hypothalamus sections were processed to assess oxycodone- or DORA-12-associated changes to the OX cell number. In males, oxycodone-associated increases in activity during the light-phase, reinstatement, and decreases in the number of OX cells observed in the vehicle-treated group were not observed with DORA-12-treatment. Oxycodone-associated increases in light-phase food and water intake were not observed by day 14 of 3 mg/kg DORA-12-treatment and dark-phase water intake was increased across treatment days. In females, OX cell number was unaffected by oxycodone or DORA-12. Three and 30 mg/kg DORA-12 increased females' day 7 dark-phase activity and decreased reinstatement. Thirty mg/kg DORA-12 reduced oxycodone-associated increases in light-phase food and water intake. The results suggest that DORA-12 improves oxycodone-induced disruptions to physiological activities and reduces relapse., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Opioid abuse and overdose have risen to epidemic proportions in the United States. Oxycodone is the most abused prescription opioid. Treatments for opioid use disorder (OUD) seek to reduce vulnerability to relapse by reducing sources of reinforcement to seek drug (i.e., acute drug effects or drug withdrawal/craving). Accumulating evidence that glutamate release elicits drug-seeking behaviors has generated interest in pharmacotherapies targeting the glutamate system. Agonists and positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor decrease glutamate activity, reducing drug taking and seeking. The present study tested whether the mGlu2 receptor positive allosteric modulator ADX106772 reduces oxycodone self-administration and the conditioned reinstatement of oxycodone seeking without affecting behaviors directed toward a highly palatable nondrug reinforcer (sweetened condensed milk). Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg/infusion, i.v., 12 h/day) or sweetened condensed milk (SCM; diluted 2:1 v/v in H 2 O, orally, 30 min/day) for 13 days in the presence of a contextual/discriminative stimulus (S D ), and the ability of ADX106772 (0, 0.3, 1, 3 and-10 mg/kg, s. c.) to decrease self-administration was tested. The rats then underwent extinction training, during which oxycodone, SCM, and the S D were withheld. After extinction, the ability of ADX106772 to prevent S D -induced conditioned reinstatement of oxycodone and SCM seeking was tested. ADX106772 reduced oxycodone self-administration and conditioned reinstatement without affecting SCM self-administration or conditioned reinstatement. ADX106772 reduced oxycodone taking and seeking and did not affect the motivation for the palatable conventional reinforcer, SCM, suggesting that activating mGlu2 receptors with a positive allosteric modulator is a potential approach for prescription OUD treatment., Competing Interests: Declaration of competing interest None, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest This work was supported by the National Institute on Drug Abuse [DA051972 and DA056602 to FT, CB and GdG, DA044451 to OG and DA053443 to RM-F], by the National Institute on Alcohol Abuse and Alcoholism [T32 AA007456 to MRD, AA026999, AA028549 and AA006420 to RM-F] by the Brain & Behavior Research Foundation [2020 NARSAD Young Investigator Award to GdG] and from the Preclinical Addiction Research Consortium (PARC) at the University of California San Diego. The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 by Elsevier Ltd.)