Revisiting dezocine for opioid use disorder: A narrative review of its potential abuse liability.

AIMS: Opioid use disorder (OUD) remains a serious public health problem. Opioid maintenance treatment is effective but under-utilized, hard to access under existing federal regulations, and, once patients achieve OUD stability, challenging to discontinue. Fewer than 2% of persons with OUD stop using opioids completely. There have been calls from public advocacy groups, governmental agencies, and public health officials for new treatments for OUD. Dezocine, a non-scheduled opioid previously used in the United States and currently widely prescribed in China for pain management, could be a candidate for a novel OUD treatment medication in the U.S. Nonetheless, to date, there have been no reviews of the clinical and preclinical literature detailing dezocine's abuse potential, a key consideration in assessing its clinical utility. DISCUSSION: There are no English language reports of human abuse, dependence, or overdose of dezocine, despite years of extensive clinical use. There are a few case reports of dezocine abuse in the Chinese literature, but there are no reports of overdose deaths. Dezocine is perceived as an opioid and is "liked" by opioid-experienced human and non-human primates, properties that are not dose-dependent and are mitigated by ceiling effects-higher doses do not result in more "liking." There is little withdrawal, spontaneous or precipitated, in humans, monkeys, rats, or mice treated chronically with dezocine alone. However, at some doses, dezocine can precipitate withdrawal in humans and monkeys dependent on other opioids. In rodents, dezocine reduces the severity of morphine withdrawal and the rewarding properties of other opioids. CONCLUSIONS: Although dezocine is reinforcing in humans and monkeys with prior or concurrent opioid use within a restricted dose range, there are only a few anecdotal reports of dezocine abuse despite of the long history of use in humans. Given the evidence of dezocine's limited abuse potential, it could be useful both as a treatment for OUD. However, in-depth studies would be required for dezocine to be re-considered for clinical use.

Effects of self- and experimenter-administered cocaine on subsequent ethanol drinking in rhesus monkeys.

BACKGROUND: One possible reason for the lack of FDA-approved pharmacotherapies to treat cocaine use disorder (CUD) is that, although cocaine is typically used in combination with alcohol, it is studied in isolation in preclinical studies. A better understanding of the cocaine-alcohol interactions that promote polysubstance use (PSU) will improve animal models of CUD and hasten pharmacotherapy development. We used a rhesus monkey model of cocaine-alcohol PSU to investigate one possible mechanism: that alcohol is used to mitigate negative effects associated with termination of cocaine use. METHODS: In 6 adult male rhesus monkeys, the relationship between self-administered cocaine intake and oral ethanol intake 2hours later was examined during self-administration of cocaine (0.0003-0.3mg/kg per injection, i.v.) under a fixed-ratio 30 schedule (FR30) or a progressive-ratio (PR) schedule. Next, ethanol consumption was measured 0-120minutes after experimenter-administered cocaine (0.3-1.7mg/kg, i.v.). RESULTS: Self-administered cocaine intake under both FR30 and PR schedules was unrelated to oral ethanol intakes 2hours later. When cocaine was administered non-contingently, cocaine decreased ethanol intake as well as intake of a non-alcoholic solution in monkeys who never consumed ethanol (n=4) in a time- and dose-dependent manner. CONCLUSIONS: Taken together, the results do not provide evidence for cocaine-induced increases in ethanol consumption. By extension, the results do not support the hypothesis that cocaine users drink alcohol to counteract negative effects that occur after terminating use. This finding implies either that such effects do not exist or that such effects exist but are unaffected by ethanol.

ß-caryophyllene inhibits heroin self-administration, but does not alter opioid-induced antinociception in rodents.

A growing body of research indicates that ß-caryophyllene (BCP), a constituent present in a large number of plants, possesses significant therapeutic properties against CNS disorders, including alcohol and psychostimulant use disorders. However, it is unknown whether BCP has similar therapeutic potential for opioid use disorders. In this study, we found that systemic administration of BCP dose-dependently reduced heroin self-administration in rats under an FR2 schedule of reinforcement and partially blocked heroin-enhanced brain stimulation reward in DAT-cre mice, maintained by optical stimulation of midbrain dopamine neurons at high frequencies. Acute administration of BCP failed to block heroin conditioned place preference (CPP) in male mice, but attenuated heroin-induced CPP in females. Furthermore, repeated dosing with BCP for 5 days facilitated the extinction of CPP in female but not male mice. In the hot plate assay, pretreatment with the same doses of BCP failed to enhance or prolong opioid antinociception. Lastly, in a substitution test, BCP replacement for heroin failed to maintain intravenous BCP self-administration, suggesting that BCP itself has no reinforcing properties. These findings suggest that BCP may have certain therapeutic effects against opioid use disorders with fewer unwanted side-effects by itself.

Xylazine does not enhance fentanyl reinforcement in rats: A behavioral economic analysis.

The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacodynamic and pharmacokinetic interactions in male and female rats using drug self-administration behavioral economic methods. Fentanyl, but not xylazine, functioned as a reinforcer under both fixed-ratio and progressive-ratio drug self-administration procedures. Xylazine combined with fentanyl at three fixed dose-proportion mixtures did not significantly alter fentanyl reinforcement as measured using behavioral economic analyses. Xylazine produced a proportion-dependent decrease in the behavioral economic Q0 endpoint compared to fentanyl alone. However, xylazine did not significantly alter fentanyl self-administration at FR1. Fentanyl and xylazine co-administration did not result in changes to pharmacokinetic endpoints. The present results demonstrate that xylazine does not enhance the addictive effects of fentanyl or alter fentanyl plasma concentrations. The premise for why illicitly manufacture fentanyl has been adulterated with xylazine remains to be determined.

A multivariate regressor of patterned dopamine release predicts relapse to cocaine.

Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is essential to inform prognostic tools for effective treatment strategies. However, technical limitations have hindered the direct measurement of sub-second dopamine release in vivo for prolonged periods of time, making it difficult to gauge the weight that these dopamine abnormalities have in determining future relapse incidence. Here, we use the fluorescent sensor GrabDA to record, with millisecond resolution, every single cocaine-evoked dopamine transient in the nucleus accumbens (NAc) of freely moving mice during self-administration. We reveal low-dimensional features of patterned dopamine release that are strong predictors of cue-induced reinstatement of cocaine seeking. Additionally, we report sex-specific differences in cocaine-related dopamine responses related to a greater resistance to extinction in males compared with females. These findings provide important insights into the sufficiency of NAc dopamine signaling dynamics-in interaction with sex-for recapitulating persistent cocaine seeking and future relapse vulnerability.

Towards neuromarkers for tailored smoking cessation treatments.

Vulnerability to compulsive drug use stems from dysregulated activity within the neural networks that underlie reward and executive functions. Empirical evidence suggests that a) attributing high motivational salience to drug-related stimuli leads to compulsive drug seeking and b) cognitive control deficits lead to compulsive drug taking. Noninvasive neuroimaging techniques enable brain activity monitoring during affective and cognitive processing and are paving the way to precision medicine for substance use disorders. Identifying robust neuromarkers of affective and cognitive dysregulation would allow clinicians to personalize treatments by targeting individual psychophysiological vulnerabilities. However, methodological choices have biased the field toward experimental paradigms that cannot optimally assess individual differences in the motivational salience of drug-related cues and in the ability to control drug-related decisions, choices which have hindered the identification of clinically relevant neuromarkers. Here, we show that once these shortcomings are amended, replicable neuromarkers of the tendency to attribute motivational salience to drug-related cues and the ability to control drug-related decisions emerge. While we use tobacco use disorder as a model, we also show that the methodological issues highlighted here are relevant to other disorders characterized by maladaptive appetitive behaviors.

Association of dopamine D2-like and D3 receptor function with initial sensitivity to cocaine reinforcement in male rhesus monkeys.

Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [11C]raclopride PET imaging and dopamine D3 receptor (D3R) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED50 of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between D3R sensitivity, represented by the ED50 of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of D3R sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure.

Assessment of abuse potential of carfentanil.

Carfentanil, as a fentanyl analogue, is a potent synthetic opioid. It has been controlled in many countries, and its emergence has been highlighted by many recent reports. However, although discriminative stimulus effects of carfentanil in rats had been reported, its abuse potential has not been fully evaluated. In this study, we evaluated the abuse potential of carfentanil via the tests of conditioned place preference (CPP), drug self-administration and naloxone-precipitated opioid withdrawal assay, compared with fentanyl and heroin. Carfentanil exhibited significant place preference at a minimum dose of 1 µg/kg in mice, whereas fentanyl and heroin induced significant place preference at the minimum doses of 100 µg/kg and 1000 µg/kg, respectively. In the drug-substitution test in heroin self-administered rats (50 µg/kg/infusion), carfentanil and fentanyl acquired significant self-administrations above saline levels from 0.05-0.1 and 0.1-10.0 µg/kg/infusion, respectively. Carfentanil induced the maximum number of infusions at 0.1 µg/kg, whereas fentanyl and heroin at 1 and 25 µg/kg, respectively. In short, carfentanil showed the highest potency to induce CPP and self-administration. Furthermore, repeated treatment with escalating doses of carfentanil, fentanyl or heroin induced typical withdrawal symptoms in mice, including a greater number of jumping and weight loss than saline group. This indicated that carfentanil could produce physical dependence similar to fentanyl and heroin. Taken together, the present study demonstrated the higher abuse potential of carfentanil compared with fentanyl and heroin. The rank order of abuse potential for these compounds is carfentanil > fentanyl > heroin.

Daily, limited access to methamphetamine self-administration during pregnancy leads to increased methamphetamine sensitivity in adult offspring.

Methamphetamine use by women, even throughout pregnancy, is common. But there is limited knowledge about the effects in prenatally methamphetamine-exposed children. This study investigated how prenatal methamphetamine exposure in rats, via maternal i.v. self-administration, affected the sensitivity of adult offspring to methamphetamine in comparison with controls. The offspring were generated from dams either self-administering methamphetamine daily under limited-access conditions prior to and throughout pregnancy, or their respective saline-yoked control dams. Spontaneous and methamphetamine-induced locomotor activity was assessed in male and female offspring of both exposure groups after a range of methamphetamine doses. In a separate group of offspring, acquisition of i.v. methamphetamine self-administration, responding under fixed and progressive ratio schedules of methamphetamine reinforcement, and reinstatement of extinguished drug-seeking behavior were assessed. Methamphetamine dose-dependently increased locomotor activity in both exposure groups. However, methamphetamine-exposed males showed significantly enhanced locomotor activity compared with controls at 1 mg/kg, and methamphetamine-exposed females showed significantly enhanced locomotor activity compared with controls at 3.2 mg/kg. Methamphetamine-exposed offspring of both sexes acquired methamphetamine self-administration faster and showed overall higher levels of methamphetamine-induced reinstatement compared with controls. Taken together, these results indicate that prenatal methamphetamine exposure to relatively low levels alters methamphetamine sensitivity in male and female adult offspring.

Effects of chronic cocaine and ethanol self-administration on brain dopamine receptors in a rhesus monkey model of polysubstance abuse.

Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group). Specifically, all monkeys self-administered cocaine (0.1 mg/kg per injection) 5 days per week in the morning. In the afternoon, six monkeys consumed 2.0 g/kg ethanol over 1 h to model binge drinking and six monkeys drank an ethanol-free solution. Assessment of D2R availability using positron emission tomography (PET) and [11 C]raclopride occurred when monkeys were drug-naïve and again when monkeys had self-administered approximately 400-mg/kg cocaine. D3 R function was assessed at the same time points by determining the potency of the D3 R-preferring agonist quinpirole to elicit yawns. Chronic cocaine self-administration decreased D2R availability in subregions of the basal ganglia in control monkeys, but not those that also drank ethanol. In contrast, D3 R sensitivity increased significantly after chronic cocaine self-administration in ethanol-drinking monkeys but not controls. These results suggest that co-use of ethanol substantially changes the effects of chronic cocaine self-administration on dopamine receptors, specifically implicating D3 R as a target for medications in these individuals.

Placenta-Derived Mesenchymal-like Adherent Stromal Cells as an Effective Cell Therapy for Cocaine Addiction in a Rat Model.

Recent research points to mesenchymal stem cells' potential for treating neurological disorders, especially drug addiction. We examined the longitudinal effect of placenta-derived mesenchymal stromal-like cells (PLX-PAD) in a rat model for cocaine addiction. Sprague-Dawley male rats were trained to self-administer cocaine or saline daily until stable maintenance. Before the extinction phase, PLX-PAD cells were administered by intracerebroventricular or intranasal routes. Neurogenesis was evaluated, as was behavioral monitoring for craving. We labeled the PLX-PAD cells with gold nanoparticles and followed their longitudinal migration in the brain parallel to their infiltration of essential peripheral organs both by micro-CT and by inductively coupled plasma-optical emission spectrometry. Cell locations in the brain were confirmed by immunohistochemistry. We found that PLX-PAD cells attenuated cocaine-seeking behavior through their capacity to migrate to specific mesolimbic regions, homed on the parenchyma in the dentate gyrus of the hippocampus, and restored neurogenesis. We believe that intranasal cell therapy is a safe and effective approach to treating addiction and may offer a novel and efficient approach to rehabilitation.

2-Fluorodeschloroketamine has similar abuse potential as ketamine.

2-Fluorodeschloroketamine (2-FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2-FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2-FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self-administration and drug discrimination using ketamine as a reference. 2-FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2-FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2-FDCK and ketamine induced locomotor sensitization after withdrawal. 2-FDCK readily induced self-administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2-FDCK dose-dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2-FDCK has an abuse potential comparable with ketamine.

A novel approach to treating opioid use disorders: Dual agonists of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors.

The widespread misuse of opioids and opioid use disorder (OUD) together constitute a major public health crisis in the United States. The greatest challenge for successfully treating OUD is preventing relapse. Unfortunately, there are few FDA-approved medications to treat OUD and, while effective, these pharmacotherapies are limited by high relapse rates. Thus, there is a critical need for conceptually new approaches to developing novel medications to treat OUD. Here, we review an emerging preclinical literature that suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists could be re-purposed for treating OUD. Potential limitations of this approach are also discussed along with an alternative strategy that involves simultaneously targeting and activating GLP-1Rs and neuropeptide Y2 receptors (Y2Rs) in the brain using a novel monomeric dual agonist peptide. Recent studies indicate that this combinatorial pharmacotherapy approach attenuates voluntary fentanyl taking and seeking in rats without producing adverse effects associated with GLP-1R agonist monotherapy alone. While future studies are required to comprehensively determine the behavioral effects of GLP-1R agonists and dual agonists of GLP-1Rs and Y2Rs in rodent models of OUD, these provocative preclinical findings highlight a potential new GLP-1R-based approach to preventing relapse in humans with OUD.

Ventral pallidum DRD3 potentiates a pallido-habenular circuit driving accumbal dopamine release and cocaine seeking.

Drugs of abuse induce persistent remodeling of reward circuit function, a process thought to underlie the emergence of drug craving and relapse to drug use. However, how circuit-specific, drug-induced molecular and cellular plasticity can have distributed effects on the mesolimbic dopamine reward system to facilitate relapse to drug use is not fully elucidated. Here, we demonstrate that dopamine receptor D3 (DRD3)-dependent plasticity in the ventral pallidum (VP) drives potentiation of dopamine release in the nucleus accumbens during relapse to cocaine seeking after abstinence. We show that two distinct VP DRD3+ neuronal populations projecting to either the lateral habenula (LHb) or the ventral tegmental area (VTA) display different patterns of activity during drug seeking following abstinence from cocaine self-administration and that selective suppression of elevated activity or DRD3 signaling in the LHb-projecting population reduces drug seeking. Together, our results uncover how circuit-specific DRD3-mediated plasticity contributes to the process of drug relapse.

Effect of chronic binge-like ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys.

BACKGROUND: Although most individuals with cocaine use disorder also abuse alcohol, little is known about the behavioral and pharmacological mechanisms that promote co-abuse. For example, it is unclear whether prior experience with alcohol renders individuals more sensitive to cocaine when it is subsequently experienced. METHODS: This study examined the effects of chronic ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys. Six monkeys consumed 2.0 g/kg ethanol in a binge-drinking paradigm and 6 monkeys drank a non-alcoholic solution 5 days per week. After 9 months, each monkey's sensitivity to acquiring cocaine self-administration was determined. Monkeys performed an operant response resulting in food pellet delivery under a fixed-ratio 30 schedule of reinforcement. Saline, then ascending doses of cocaine, were substituted for food pellets until a cocaine dose was reached at which the number of cocaine injections delivered differed significantly from saline injections delivered. Following acquisition, a complete cocaine dose-effect curve was generated to determine whether ethanol consumption altered the reinforcing potency of cocaine determined by calculating the ED50 of the ascending limb of each subject's curve. RESULTS: Although individual variability was observed, the cocaine dose which initially served as a reinforcer did not differ between ethanol-drinking and control groups and, within the ethanol-drinking group, was not related to the amount of ethanol consumed. Moreover, the reinforcing potency of cocaine did not differ between groups. CONCLUSION: Taken together, the data suggest that a history of binge-like alcohol consumption does not affect sensitivity to cocaine when it is subsequently first experienced.

A drug-vs-food "choice" self-administration procedure in rats to investigate pharmacological and environmental mechanisms of substance use disorders.

BACKGROUND: Preclinical drug self-administration procedures are commonly used to investigate expression, mechanisms, and treatment of substance use disorders. NEW METHOD: The aims were to back-translate an intravenous drug-vs-food choice procedure primarily utilized in monkeys to male and female rats and to develop a surgical method for sustained intravenous catheter patency suitable for long-term drug-choice studies. RESULTS: The surgical protocol resulted in a median intravenous jugular catheter patency in male and female rats of 126 days (range: 25-365 days). Drug-vs-food choice was established with opioids (fentanyl and heroin), psychostimulants (cocaine, methamphetamine, and amphetamine), and an opioid/psychostimulant mixture (fentanyl + methamphetamine). The average time from catheter implantation to stable choice behavior across all drugs was 27 sessions (range: 16-44 sessions). Choice behavior stabilized more quickly for cocaine and fentanyl than for other drugs. Manipulations of both environmental variables (e.g., response requirement or food reinforcer magnitude) and pharmacological variables (e.g., extended access drug self-administration or continuous buprenorphine treatment via osmotic pump) significantly shifted opioid-vs-food choice consistent with previous monkey studies. COMPARISON WITH EXISTING METHODS: Duration of intravenous catheter patency in rats was suitable for long-term, within-subject drug choice studies. Effects of environmental and pharmacological manipulations in rats confirmed and extended previous results from monkeys. CONCLUSIONS: The concordance of behavioral results between rats and monkeys using the present drug-vs-food choice procedure supports its utility to improve our basic understanding of the expression and mechanisms of substance use disorders towards to development of more effective therapeutics.

Samidorphan, an opioid receptor antagonist, attenuates drug-induced increases in extracellular dopamine concentrations and drug self-administration in male Wistar rats.

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (µ), kappa- (κ), and delta- (δ) opioid receptors and functions as a µ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DAext) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DAext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DAext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.

Peripheral nerve injury promotes morphine-seeking behavior in rats during extinction.

Chronic neuropathic pain and prescription opioid abuse represent highly interconnected societal problems. We used a rat model of spared nerve injury (SNI) and an intravenous drug self-administration paradigm to investigate the impact of a neuropathic pain state on morphine-seeking behavior in extinction (i.e. when morphine is withheld). SNI, sham-operated and naive groups exhibited similar levels of active lever presses for morphine infusions on a fixed ratio 1 (FR1) schedule. Self-administration of morphine, but not vehicle, attenuated nerve injury-induced mechanical allodynia in SNI rats. Under these same conditions, mechanical paw withdrawal thresholds in sham-operated and naive groups were largely unaltered. However, SNI rats showed higher levels of morphine-seeking behavior compared to sham-operated or naïve groups in extinction (i.e. when vehicle was substituted for morphine). Interestingly, the perseveration of morphine-seeking behavior observed during extinction was only present in the SNI group despite the fact that all groups had a similar history of morphine self-administration intake. Our results suggest that different motivational states associated with neuropathic pain promote morphine-seeking behavior in extinction. Drug self-administration paradigms may be useful for evaluating analgesic efficacy and motivational properties associated with opioid reinforcers in pathological pain states.

Female rats display higher methamphetamine-primed reinstatement and c-Fos immunoreactivity than male rats.

Methamphetamine (meth) dependence is often characterized by persistent and chronic relapse (i.e., return to drug use). Previous work suggests females may be at greater risk to relapse. In this study, we extended this limited evidence and identified sex-dependent neural substrates related to meth-triggered reinstatement. Male and female Sprague-Dawley rats were implanted with indwelling jugular catheters. Half of the rats were then trained to self-administer meth (0.05 mg/kg/inf); the other half self-administered saline during 21 daily sessions (2 h). Rats were then given 12 extinction sessions. Twenty-four hours after the last extinction session, rats received reinstatement testing. Half of the rats received a meth-prime (0.3 mg/kg, IP) injection and the remaining rats received a saline injection. This design resulted in 4 separate groups for each sex, allowing for careful investigation of brain regions related to meth-triggered reinstatement. Brains were harvested following the reinstatement session and c-Fos immunoreactivity was measured in multiple brain regions. Meth triggered reinstatement in both sexes and this effect was more robust in females compared to males. Significant sex differences were detected. Females showed greater c-Fos immunoreactivity in the cingulate cortex area 1, lateral orbitofrontal cortex, prelimbic cortex, caudate-putamen, nucleus accumbens core and shell, and central nucleus of the amygdala following meth-primed reinstatement.

A synthetic opioid vaccine attenuates fentanyl-vs-food choice in male and female rhesus monkeys.

AIM: Opioid-targeted vaccines are under consideration as candidate Opioid Use Disorder medications. We recently reported that a fentanyl-targeted vaccine produced a robust and long-lasting attenuation of fentanyl-vs-food choice in rats. In the current study, we evaluated an optimized fentanyl-targeted vaccine in rhesus monkeys to determine whether vaccine effectiveness to attenuate fentanyl choice translated to a species with greater phylogenetic similarity to humans. METHODS: Adult male (2) and female (3) rhesus monkeys were trained to respond under a concurrent schedule of food (1 g pellets) and intravenous fentanyl (0, 0.032-1 µg/kg/injection) reinforcement during daily 2 h sessions. Fentanyl choice dose-effect functions were determined daily and 7-day buprenorphine treatments (0.0032-0.032 mg/kg/h IV; n = 4-5) were determined for comparison to vaccine effects. Subsequently, a fentanyl-CRM197 conjugate vaccine was administered at week 0, 3, 8, 15 over a 29-week experimental period during which fentanyl choice dose-effect functions continued to be determined daily. RESULTS: Buprenorphine significantly decreased fentanyl choice and reciprocally increased food choice. Vaccination eliminated fentanyl choice and increased food choice in four-of-the-five monkeys. A transient and less robust vaccine effect was observed in the fifth monkey. Fentanyl-specific antibody concentrations peaked after the third vaccination to approximately 50 µg/mL while anti-fentanyl antibody affinity increased to a sustained low nanomolar level. CONCLUSION: These results translate fentanyl vaccine effectiveness from rats to rhesus monkeys to decrease fentanyl-vs-food choice, albeit with greater individual differences observed in monkeys. These results support the potential and further clinical evaluation of this fentanyl-targeted vaccine as a candidate Opioid Use Disorder medication.