Chronic inflammatory pain promotes place preference for fentanyl in male rats but does not change fentanyl self-administration in male and female rats.

The current opioid epidemic is a national health crisis marked by skyrocketing reports of opioid misuse and overdose deaths. Despite the risks involved, prescription opioid analgesics are the most powerful and effective medications for treating pain. There is a clear need to investigate the risk of opioid misuse liability in male and female adults experiencing chronic pain. In the present study, we tested the hypothesis that chronic inflammatory pain would increase fentanyl intake, motivation to acquire fentanyl, and drug seeking in the absence of fentanyl in rats. Fentanyl intake, motivation for fentanyl, and drug seeking were tested under limited and extended access conditions using intravenous fentanyl self-administration. Fos activity in ventral tegmental area (VTA) dopamine neurons following intravenous fentanyl challenge (35 µg/kg) was examined using immunohistochemistry. Finally, we tested whether low-dose fentanyl supports development of conditioned place preference under an inflammatory pain state in rats. Contrary to our hypothesis, fentanyl self-administration and VTA Fos activity were unaffected by inflammatory pain status. During acquisition, males exhibited increased fentanyl intake compared to females. Animals given extended access to fentanyl escalated fentanyl intake over time, while animals given limited access did not. Males given extended access to fentanyl demonstrated a greater increase in fentanyl intake over time compared to females. During the dose-response test, females given limited access to fentanyl demonstrated increased motivation to acquire fentanyl compared to males. Both sexes displayed significant increases in responding for fentanyl as unit fentanyl doses were lowered. Following fentanyl challenge, females exhibited higher numbers of Fos-positive non-dopaminergic VTA neurons compared to males. Using conditioned place preference, we found that chronic inflammatory pain promotes fentanyl preference in males, but not females. These findings suggest that established fentanyl self-administration is resistant to change by inflammatory pain manipulation in both sexes, but chronic inflammatory pain increases the rewarding properties of low-dose fentanyl in males.

Peer presence and familiarity as key factors to reduce cocaine intake in both rats and humans: an effect mediated by the subthalamic nucleus.

RATIONALE: Stimulant use, including cocaine, often occurs in a social context whose influence is important to understand to decrease intake and reduce associated harms. Although the importance of social influence in the context of drug addiction is known, there is a need for studies assessing its neurobiological substrate and for translational research. OBJECTIVES: Here, we explored the influence of peer presence and familiarity on cocaine intake and its neurobiological basis. Given the regulatory role of the subthalamic nucleus (STN) on cocaine intake and emotions, we investigated its role on such influence of social context on cocaine intake. METHODS: We first compared cocaine consumption in various conditions (with no peer present or with peers with different characteristics: abstinent peer or drug-taking peer, familiar or not, cocaine-naive or not, dominant or subordinate) in rats (n = 90). Then, with a translational approach, we assessed the influence of the social context (alone, in the group, in a dyad with familiar or non-familiar peers) on drug intake in human drug users (n = 77). RESULTS: The drug consumption was reduced when a peer was present, abstinent, or drug-taking as well, and further diminished when the peer was non-familiar. The presence of a non-familiar and drug-naive peer represents key conditions to diminish cocaine intake. The STN lesion by itself reduced cocaine intake to the level reached in presence of a non-familiar naive peer and affected social cognition, positioning the STN as one neurobiological substrate of social influence on drug intake. Then, the human study confirmed the beneficial effect of social presence, especially of non-familiar peers. CONCLUSION: Our results indirectly support the use of social interventions and harm reduction strategies and position the STN as a key cerebral structure to mediate these effects.

Evidence for a vocal signature in the rat and its reinforcing effects: a key role for the subthalamic nucleus.

Although rodents have a well-structured vocal form of communication, like humans and non-human primates, there is, to date, no evidence for a vocal signature in the well-known 50- and 22-kHz ultrasonic vocalizations (USVs) emitted by rats. Here, we show that rats can recognize the identity of the USV emitter since they choose to preferentially self-administer playback of 50-kHz USVs emitted by a stranger rat over those of their cagemate. In a second experiment, we show that only stranger, but not familiar, 50-kHz USVs reduce cocaine self-administration. Finally, to study the neurobiological substrate of these processes, we have shown that subthalamic nucleus (STN)-lesioned rats did not lever press much for any USV playback, whatever their emotional valence, nor did they seem able to differentiate familiar from stranger peer. Advocating for the existence of a vocal signature in rats, these results highlight the importance of ultrasonic communication in the socio-affective influence of behaviour, such as the influence of proximal social factors on drug consumption and confirm the role of the STN on this influence.

Repeated cocaine exposure prior to fear conditioning induces persistency of PTSD-like symptoms and enhancement of hippocampal and amygdala cell density in male rats.

Pre- and post-trauma drug use can interfere with recovery from post-traumatic stress disorder (PTSD). However, the biological underpinnings of this interference are poorly understood. Here we examined the effect of pre-fear conditioning cocaine self-administration on PTSD-like symptoms in male rats, and defined impairment of fear extinction as difficulty to recover from PTSD. We also examined cell density changes in brain regions suspected of being involved in resistance to PTSD recovery. Before footshock stress testing, rats were trained to self-administer cocaine during 20 consecutive days, after which they were exposed to footshocks, while other rats continued to self-administer cocaine until the end of the experiment. Upon assessment of three PTSD-like symptoms (fear during situational reminders, anxiety-like behavior, and impairment of recognition memory) and fear extinction learning and memory, changes in cell density were measured in the medial prefrontal cortex, hippocampus, and amygdala. Results show that pre-footshock cocaine exposure did not affect fear during situational reminders. Fear conditioning did not lead to an increase in cocaine consumption. However, in footshock stressed rats, cocaine induced a reduction of anxiety-like behavior, an aggravation of recognition memory decline, and an impairment of extinction memory. These behavioral alterations were associated with increased cell density in the hippocampal CA1, CA2, and CA3 regions and basolateral amygdala, but not in the medial prefrontal cortex. Our findings suggest that enhancement of cell density in the hippocampus and amygdala may be changes associated with drug use, interfering with PTSD recovery.

Chronic nicotine increases alcohol self-administration in adult male Wistar rats.

RATIONALE: Alcohol and nicotine co-dependence is common in humans, and nicotine increases alcohol drinking in humans without alcohol use disorder (AUD). Nevertheless, there is little basic research on the interactions between the reinforcing effects of these two drugs. OBJECTIVES: The aim of this study was to investigate the effects of chronic nicotine injections on oral alcohol self-administration in alcohol non-dependent rats. METHODS: After stable alcohol self-administration was reached (baseline) and a period without alcohol access, adult male rats were treated with chronic nicotine or saline injections for 105 days during which time they were tested intermittently for alcohol self-administration. There were 3 experimental groups: (1) saline, rats treated with saline for 105 days; (2) early nicotine, rats treated with nicotine for 70 days, and then with saline for 35 days; and (3) late nicotine: rats treated with saline for 35 days, and then with nicotine for 70 days. RESULTS: Our results indicate that (1) chronic nicotine increases alcohol consumption regardless of whether exposure to alcohol was interrupted (early nicotine) or not (late nicotine) before the start of nicotine treatment, (2) the number of alcohol reinforcements correlates to blood-alcohol levels, and (3) alcohol self-administration rapidly decreases when nicotine is no longer available (early nicotine). CONCLUSIONS: These discoveries may have clinical implications in social drinkers that use nicotine products, in that chronic nicotine can escalate alcohol drinking and cessation of nicotine exposure may decrease alcohol use.

Subthalamic nucleus mediates the modulation on cocaine self-administration induced by ultrasonic vocalization playback in rats.

Drug intake is known to be under the influence of social context. We have recently shown that presence of a peer influences drug intake in both rats and humans. Whether or not social acoustic communications between the peers play a role during cocaine or sucrose self-administration (SA) was investigated here using playback of ultrasonic vocalizations (USVs) at 50 and 22 kHz, conveying, respectively, positive and negative internal affective states in adult rats. To assess the neurobiological substrate of a potential USV influence on drug and food intake, we tested the effects of subthalamic nucleus (STN) lesions, given its role in emotional and motivational processes. In sham-control rats, playback of USV associated with positive affective states induced long-term decreased cocaine consumption, while USV associated with negative affective states induced short-term increase. Interestingly, no effect of USV playback was observed on sucrose intake, whatever the frequency. STN lesions abolished the influence of USV on cocaine intake, highlighting the influence of STN in emotional processes induced by USV emitted by a peer. These results show how acoustic social communication is important to regulate drug intake in rats and how STN modulation could interfere with addiction processes.

Nicotine e-cigarette vapor inhalation effects on nicotine & cotinine plasma levels and somatic withdrawal signs in adult male Wistar rats.

RATIONALE: Non-contingent chronic nicotine exposure procedures have evolved rapidly in recent years, culminating in electronic nicotine delivery systems (ENDS or e-cigarettes) to deliver vaporized drugs to rodents in standard housing chambers. OBJECTIVES: The aim of the current work was to use ENDS to test concentration-dependent effects of nicotine e-cigarette vapor inhalation on blood-nicotine concentrations, blood-cotinine concentrations, and somatic withdrawal signs over time in rats. METHODS: Male Wistar rats were exposed to vapor containing various concentrations of nicotine (20, 40, 80 mg/mL) for 11 days through ENDS, and blood concentrations of nicotine and cotinine, the major proximate metabolite of nicotine, as well as spontaneous and precipitated somatic withdrawal signs, were measured over time (across days of exposure and over hours after termination of vapor exposure). RESULTS: Exposing male Wistar rats to non-contingent nicotine vapor inhalation through ENDS produces somatic withdrawal symptoms and measurable blood-nicotine and blood-cotinine levels that change according to (1) concentration of nicotine in vape solution, (2) number of days of nicotine vapor exposure, (3) time since termination of nicotine vapor exposure, and (4) relative to the withdrawal signs, whether withdrawal was spontaneous or precipitated (by mecamylamine). CONCLUSIONS: The data presented here provide parameters that can be used as a reasonable starting point for future work that employs ENDS to deliver non-contingent nicotine vapor in rats, although many parameters can and should be altered to match the specific goals of future work.

Social modulation of drug use and drug addiction.

This review aims to demonstrate how social science and behavioral neurosciences have highlighted the influence of social interactions on drug use in animal models. In neurosciences, the effect of global social context that are distal from drug use has been widely studied. For human and other social animals such as monkeys and rodents, positive social interactions are rewarding, can overcome drug reward and, in all, protect from drug use. In contrast, as other types of stress, negative social experiences facilitate the development and maintenance of drug abuse. However, interest recently emerged in the effect of so-called "proximal" social factors, that is, social interactions during drug-taking. These recent studies have characterized the role of the drug considered, the sharing of drug experience and the familiarity of the peer which interaction are made with. We also examine the few studies regarding the sensorial mediator of social behaviors and critically review the neural mediation of social factors on drug use. However, despite considerable characterization of the factors modulating distal influences, the mechanisms for proximal influences on drug use remain largely unknown. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Heroin versus cocaine: opposite choice as a function of context but not of drug history in the rat.

RATIONALE: Previous studies have shown that rats trained to self-administer heroin and cocaine exhibit opposite preferences, as a function of setting, when tested in a choice paradigm. Rats tested at home prefer heroin to cocaine, whereas rats tested outside the home prefer cocaine to heroin. Here, we investigated whether drug history would influence subsequent drug preference in distinct settings. Based on a theoretical model of drug-setting interaction, we predicted that regardless of drug history rats would prefer heroin at home and cocaine outside the home. METHODS: Rats with double-lumen catheters were first trained to self-administer either heroin (25 µg/kg) or cocaine (400 µg/kg) for 12 consecutive sessions. Twenty-six rats were housed in the self-administration chambers (thus, they were tested at home), whereas 30 rats lived in distinct home cages and were transferred to self-administration chambers only for the self-administration session (thus, they were tested outside the home). The rats were then allowed to choose repeatedly between heroin and cocaine within the same session for seven sessions. RESULTS: Regardless of the training drug, the rats tested outside the home preferred cocaine to heroin, whereas the rats tested at home preferred heroin to cocaine. There was no correlation between drug preference and drug intake during the training phase. CONCLUSION: Drug preferences were powerfully influenced by the setting but, quite surprisingly, not by drug history. This suggests that, under certain conditions, associative learning processes and drug-induced neuroplastic adaptations play a minor role in shaping individual preferences for one drug or the other.

Ultrasonic vocalization in rats self-administering heroin and cocaine in different settings: evidence of substance-specific interactions between drug and setting.

RATIONALE: Clinical and preclinical evidence indicates that the setting of drug use affects drug reward in a substance-specific manner. Heroin and cocaine co-abusers, for example, indicated distinct settings for the two drugs: heroin being used preferentially at home and cocaine preferentially outside the home. Similar results were obtained in rats that were given the opportunity to self-administer intravenously both heroin and cocaine. OBJECTIVES: The goal of the present study was to investigate the possibility that the positive affective state induced by cocaine is enhanced when the drug is taken at home relative to a non-home environment, and vice versa for heroin. METHODS: To test this hypothesis, we trained male rats to self-administer both heroin and cocaine on alternate days and simultaneously recorded the emission of ultrasonic vocalizations (USVs), as it has been reported that rats emit 50-kHz USVs when exposed to rewarding stimuli, suggesting that these USVs reflect positive affective states. RESULTS: We found that Non-Resident rats emitted more 50-kHz USVs when they self-administered cocaine than when self-administered heroin whereas Resident rats emitted more 50-kHz USVs when self-administering heroin than when self-administering cocaine. Differences in USVs in Non-Resident rats were more pronounced during the first self-administration (SA) session, when the SA chambers were completely novel to them. In contrast, the differences in USVs in Resident rats were more pronounced during the last SA sessions. CONCLUSION: These findings indicate that the setting of drug taking exerts a substance-specific influence on the ability of drugs to induce positive affective states.

Differential vulnerability to relapse into heroin versus cocaine-seeking as a function of setting.

RATIONALE: Previous studies have shown that the effect of setting on drug-taking is substance specific in both humans and rats. In particular, we have shown that when the setting of drug self-administration (SA) coincides with the home environment of the rats (resident rats), the rats tend to prefer heroin to cocaine. The opposite was found in nonresident rats, for which the SA chambers represented a distinct environment. OBJECTIVES: The aim of the present study was to investigate the influence of setting on the ability of different doses of cocaine and heroin to prime cocaine- versus heroin-seeking in rats that had been trained to self-administer both drugs and had then undergone an extinction procedure. METHODS: Resident (N = 62) and nonresident (N = 63) rats with double-lumen intra-jugular catheters were trained to self-administer cocaine (400 µg/kg/infusion) and heroin (25 µg/kg/infusion) on alternate days for 10 consecutive daily sessions (3 h each). After the extinction phase, independent groups of rats were given a noncontingent intravenous infusion of heroin (25, 50, or 100 µg/kg) or cocaine (400, 800, or 1600 µg/kg), and drug-seeking was quantified by counting nonreinforced lever presses. RESULTS: All resident and nonresident rats acquired heroin and cocaine SA. However, cocaine primings reinstated cocaine-seeking only in nonresident rats, whereas heroin primings reinstated heroin-seeking only in resident rats. CONCLUSIONS: We report here that the susceptibility to relapse into drug-seeking behavior is drug-specific and setting-specific, confirming the crucial role played by drug, set, and setting interactions in drug addiction.

Partial extinction of a conditioned context enhances preference for elements previously associated with cocaine but not with chocolate.

Drug-associated stimuli are crucial to reinstatement of drug-seeking after periods of abstinence, representing a central problem in treatment of addiction. The present study investigated the influence of partial extinction of the conditioned context on the expression of conditioned place preference (CPP). Mice of the inbred DBA/2J strain were conditioned with cocaine or chocolate in a context identified by multiple elements (A+B) and subsequently CPP expression was evaluated in a context containing only one element (A or B) or both (A+B). Cocaine- and chocolate-conditioned mice showed CPP in presence of the original compound stimulus. However, cocaine-conditioned mice did not show CPP when tested in A or B context, while chocolate-conditioned mice did show CPP to single element context. After conditioning mice were exposed to extinction training of the context A or B and then tested for CPP 1 and 9 days after the end of the extinction (days 9 and 18). Cocaine-conditioned mice showed CPP 9 days after extinction while chocolate-conditioned mice were relatively insensitive to the extinction procedure on day 1 after extinction, but they did not show CPP for the partial or the original compound 9 days after extinction. Cocaine-conditioned mice not submitted to the extinction training (simple passage of time) or submitted to a Sham-extinction procedure (saline injections and confinement in a new environment) did not show CPP on day 9 or 18. Cocaine-conditioned mice exposed to extinction training showed increased c-Fos expression in several brain areas in comparison to mice exposed to Sham-extinction. The extinction procedure did not specifically reduce behavioral sensitization. The results suggest that extinction training involving only elements of a drug-associated context can result in increased associative strength of those elements.

Induction of morphine-6-glucuronide synthesis by heroin self-administration in the rat.

RATIONALE: Heroin is rapidly metabolized to morphine that in turn is transformed into morphine-3-glucuronide (M3G), an inactive metabolite at mu-opioid receptor (MOR), and morphine-6-glucuronide (M6G), a potent MOR agonist. We have found that rats that had received repeated intraperitoneal injections of heroin exhibit measurable levels of M6G (which is usually undetectable in this species). OBJECTIVE: The goal of the present study was to investigate whether M6G synthesis can be induced by intravenous (i.v.) heroin self-administration (SA). MATERIALS AND METHODS: Rats were trained to self-administer either heroin (50 µg/kg per infusion) or saline for 20 consecutive 6-h sessions and then challenged with an intraperitoneal challenge of 10 mg/kg of heroin. Plasma levels of heroin, morphine, 6-mono-acetyl morphine, M3G, and M6G were quantified 2 h after the challenge. In vitro morphine glucuronidation was studied in microsomal preparations obtained from the liver of the same rats. RESULTS: Heroin SA induced the synthesis of M6G, as indicated by detectable plasma levels of M6G (89.7 ± 37.0 ng/ml vs. 7.35 ± 7.35 ng/ml after saline SA). Most important, the in vitro V (max) for M6G synthesis was correlated with plasma levels of M6G (r (2) = 0.78). Microsomal preparations from saline SA rats produced negligible amounts of M6G. CONCLUSION: Both in vivo and in vitro data indicate that i.v. heroin SA induces the synthesis of M6G. These data are discussed in the light of previous studies conducted in heroin addicts indicating that in humans heroin enhances the synthesis of the active metabolite of heroin and morphine.