Persistent effects of repeated adolescent and adult heroin vapor inhalation in female Wistar rats.

Adolescent drug exposure has been associated with more severe mental health outcomes related to substance abuse and anxiety disorders. The aim of the present study was to contrast the long-term effects of repeated heroin vapor inhalation during adolescence with similar heroin exposure in adulthood. Groups of female Wistar rats underwent twice daily 30-minute sessions of heroin or propylene glycol (control) vapor inhalation from postnatal days (PND) 36-45 or PND 85-94, respectively. Nociception was assessed after vapor inhalation sessions and forty days later, for the Adolescent-Exposed and Adult-Exposed groups. Anxiety-like behavior was assessed with an elevated plus-maze (EPM) and spatial learning was assessed with a Barnes maze. Acute effects of naloxone (0.3 mg/kg, i.p.) and heroin (0.5 and 1.0 mg/kg, s.c.) on thermal nociception were determined on PND 140/189 and PND 149/198, respectively. Repeated heroin vapor inhalation produced anti-nociceptive tolerance across sessions in both adolescent and adult rats, with the adolescents exhibiting more complete tolerance. Heroin vapor inhalation produced anxiolytic effects, regardless of age of exposure. There were no effects of heroin on spatial learning. Naloxone produced acute hyperalgesia in all but the Adolescent-Exposed heroin group, and heroin anti-nociception was blunted in both heroin-exposed groups at the highest heroin dose. Repeated heroin vapor inhalation can produce lasting effects on nociception and anxiety-like behavior that persist for months after the exposure. Importantly, these findings suggest that adolescent exposure to heroin vapor produces specific effects on nociception that are not observed when exposure occurs in adulthood.

Hyperactivity Induced By Vapor Inhalation of Nicotine in Male and Female Rats.

Rationale: Preclinical models of electronic nicotine delivery system (ENDS; "e-cigarette") use have been rare, so there is an urgent need to develop experimental approaches to evaluate their effects. Objective: To contrast the impact of inhaled nicotine across sex. Methods: Male and female Wistar rats were exposed to vapor from a propylene glycol vehicle (PG), nicotine (NIC; 1-30 mg/mL in PG), or were injected with NIC (0.1-0.8 mg/kg, s.c.), and then assessed for changes in temperature and activity. The antagonist mecamylamine (2 mg/kg) was administered prior to NIC to verify pharmacological specificity. Plasma levels of nicotine and cotinine were determined after inhalation and injection. Results: Activity increased in females for ~60 minutes after nicotine inhalation, and this was blocked by mecamylamine. A similar magnitude of hyperlocomotion was observed after s.c. administration. Body temperature was reduced after nicotine inhalation by female rats but mecamylamine increased this hypothermia. Increased locomotor activity was observed in male rats if inhalation was extended to 40 minutes or when multiple inhalation epochs were used per session. The temperature of male rats was not altered by nicotine. Plasma nicotine concentrations were slightly lower in male rats than in female rats after 30-minute nicotine vapor inhalation and slightly higher after nicotine injection (1.0 mg/kg, s.c.). Conclusions: Nicotine inhalation increases locomotor activity in male and female rats to a similar or greater extent than by subcutaneous injection. Sex differences were observed, which may be related to lower nicotine plasma levels, lower baseline activity and/or a higher vehicle response in males.

Adult consequences of repeated nicotine and Δ9-tetrahydrocannabinol (THC) vapor inhalation in adolescent rats.

RATIONALE: Use of electronic drug delivery systems (EDDS, "e-cigarettes") to ingest nicotine and Δ9-tetrahydrocannabinol (THC) has surged in adolescents in the USA; five times as many high-school seniors vape nicotine daily using tobacco. At the same time, 19.5% of seniors use cannabis at least monthly, with 12% using EDDS to deliver it. OBJECTIVES: This study was conducted to examine the impact of repeated adolescent vapor inhalation of nicotine and THC in rats. METHODS: Female Sprague-Dawley rats were exposed to 30-min sessions of vapor inhalation, twice daily, from post-natal day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle, nicotine (60 mg/mL in the PG), THC (100 mg/mL in the PG), or the combination of nicotine (60 mg/mL) and THC (100 mg/mL). Rats were assessed on wheel activity, heroin anti-nociception and nicotine and heroin vapor volitional exposure during adulthood. RESULTS: Nicotine-exposed rats exhibited few differences as adults, but were less sensitive to anti-nociceptive effects of heroin (1 mg/kg, s.c.). THC- and THC + nicotine-exposed rats were less spontaneously active, and obtained fewer nicotine vapor deliveries as adults. In contrast, THC-exposed rats obtained volitional heroin vapor at rates indistinguishable from the non-THC-exposed groups. Repeated THC exposure also caused tolerance to temperature-disrupting effects of THC (5 mg/kg, i.p.). CONCLUSIONS: These studies further confirm that the effects of repeated vapor exposure to THC in adolescence last into early to middle adulthood, including decreased volitional consumption of nicotine. Effects of repeated nicotine in adolescence were comparatively minor.

Rats chasing the dragon: A new heroin inhalation method.

BACKGROUND: Despite extensive human use of inhalation for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; "e-cigarettes") have shown efficacy in rodent models but these do not faithfully mimic the most popular human inhalation method of heating heroin to the point of vaporization. NEW METHOD: Middle aged rats were exposed to vapor created by direct heating of heroin HCl powder in a ceramic e-cigarette type atomizer. Efficacy was determined with a warm water tail withdrawal nociception assay, rectal temperature and self-administration. RESULTS: Ten minutes of inhalation of vaporized heroin slowed response latency in a warm water tail withdrawal assay and increased rectal temperature in male rats, in a dose-dependent manner. Similar antinociceptive effects in female rats were attenuated by the opioid antagonist naloxone (1.0 mg/kg, s.c.). Female rats made operant responses for heroin vapor in 15-minute sessions, increased their response rate when the reinforcement ratio increased from FR1 to FR5, and further increased their responding when vapor delivery was omitted. Anti-nociceptive effects of self-administered volatilized heroin were of a similar magnitude as those produced by the 10-minute non-contingent exposure. COMPARISON WITH EXISTING METHODS: Inhalation of directly volatilized heroin successfully produces heroin-typical effects, comparable to EDDS inhalation delivery. CONCLUSIONS: This study shows that "chasing the dragon" methods of inhalation of heroin can be modeled successfully in the rat. Inhalation techniques may be particularly useful for longer term studies deep into the middle age of rats.

Adult consequences of repeated nicotine vapor inhalation in adolescent rats.

INTRODUCTION: There has been a resurgence in nicotine inhalation in adolescents due to the popularity and availability of Electronic Nicotine Delivery Systems (ENDS). Almost five times as many US high-school seniors inhale nicotine vapor daily compared with those who smoke tobacco. This study was conducted to determine the impact of repeated adolescent vapor inhalation of nicotine on behavior in adulthood. METHODS: Male and female Sprague-Dawley rats were exposed to 30-minute sessions of ENDS vapor inhalation, twice daily, from Post-Natal Day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle or nicotine (30 mg/mL in the PG). Animals were assessed for effects of nicotine on open field (PND 74-105) and wheel activity (PND 126-180) and for volitional exposure to nicotine vapor (PND 285-395). Plasma nicotine and cotinine were assessed in separate groups of male and female Wistar and Sprague-Dawley rats after a single nicotine inhalation session. RESULTS: Group mean plasma nicotine ranged from 39 to 59 ng/mL post-session with minimal strain differences detected. Adolescent nicotine exposure enhanced sensitivity to the locomotor stimulating effects of nicotine (0.1-0.8 mg/kg, s.c.) in an open field in female rats, but didn't change effects of nicotine on wheel activity. Female rats exposed to nicotine (30 mg/mL) vapor as adolescents responded more vigorously than PG exposed females for nicotine vapor in a FR5 challenge. CONCLUSIONS: Repeated adolescent nicotine vapor inhalation leads to enhanced liability for volitional exposure to nicotine vapor in adulthood in female rats, but minimal change in spontaneous locomotor behavior. IMPLICATIONS: These results show that adolescent vaping of nicotine can lead to lasting sensitization to the effects of nicotine in adulthood, including volitional responding for nicotine vapor. Demonstration of this in a controlled animal model establishes causality in a manner not possible from longitudinal evidence in human populations. These findings further highlight the importance of decreasing adolescent nicotine exposure by e-cigarettes to reduce consumption in adulthood.

Oxycodone Self-Administration in Female Rats is Enhanced by ∆9-tetrahydrocannabinol, but not by Cannabidiol, in a Progressive Ratio Procedure.

Epidemiological evidence suggests that the legalization of cannabis may reduce opioid-related harms. Preclinical evidence of neuropharmacological interactions of endogenous cannabinoid and opioid systems prompts further investigation of cannabinoids as potential therapeutics for the non-medical use of opioids. In these studies female rats, previously trained to self-administer oxycodone (0.15 mg/kg/infusion) intravenously in 6 h sessions, were allowed to self-administer oxycodone after exposure to cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) by vapor inhalation and THC by injection (5.0-20 mg/kg, i.p.). Self-administration was characterized under Progressive Ratio (PR) and Fixed Ratio (FR) 1 schedules of reinforcement in 3 h sessions. THC decreased IVSA of oxycodone in a FR procedure but increased reward seeking in a PR procedure. CBD decreased the IVSA of oxycodone in the FR but not the PR procedure. The results are consistent with an anti-reward effect of CBD but suggest THC acts to increase the reinforcing efficacy of oxycodone in this procedure.

Nicotine, THC, and Dolutegravir Modulate E-Cigarette-Induced Changes in Addiction- and Inflammation-Associated Genes in Rat Brains and Astrocytes.

E-cigarette use has been marketed as a safer alternative to traditional cigarettes, as a means of smoking cessation, and are used at a higher rate than the general population in people with HIV (PWH). Early growth receptor 2 (EGR2) and Activity-Regulated Cytoskeleton-Associated Protein (ARC) have a role in addiction, synaptic plasticity, inflammation, and neurodegeneration. This study showed that 10 days of exposure to e-cigarette vapor altered gene expression in the brains of 6-month-old, male, Sprague Dawley rats. Specifically, the e-cigarette solvent vapor propylene glycol (PG) downregulated EGR2 and ARC mRNA expression in frontal cortex, an effect which was reversed by nicotine (NIC) and THC, suggesting that PG could have a protective role against NIC and cannabis dependence. However, in vitro, PG upregulated EGR2 and ARC mRNA expression at 18 h in cultured C6 rat astrocytes suggesting that PG may have neuroinflammatory effects. PG-induced upregulation of EGR2 and ARC mRNA was reversed by NIC but not THC. The HIV antiretroviral DTG reversed the effect NIC had on decreasing PG-induced upregulation of EGR2, which is concerning because EGR2 has been implicated in HIV latency reversal, T-cell apoptosis, and neuroinflammation, a process that underlies the development of HIV-associated neurocognitive disorders.

Rats Chasing the Dragon: A new heroin inhalation method.

Rationale: Despite extensive human use of the inhalation route for ingesting opioids, models in rodents have mostly been limited to parenteral injection and oral dosing. Methods using electronic drug delivery systems (EDDS; "e-cigarettes") have shown efficacy in rodent models but these do not faithfully mimic the most popular human inhalation method of heating heroin to the point of vaporization. Objective: This study was designed to determine if direct volatilization of heroin hydrochloride delivers effective heroin doses to rodents. Methods: Middle aged rats were exposed to vapor created by direct heating of heroin HCl powder in a ceramic e-cigarette type atomizer. Efficacy was determined with a warm water tail withdrawal nociception assay, rectal temperature and self-administration. Results: Ten minutes of inhalation of vaporized heroin slowed response latency in a warm water tail withdrawal assay and increased rectal temperature in male rats, in a dose-dependent manner. Similar antinociceptive effects in female rats were attenuated by the opioid antagonist naloxone (1.0 mg/kg, s.c.). Female rats made operant responses for heroin vapor in 15-minute sessions, increased their response rate when the reinforcement ratio increased from FR1 to FR5, and further increased their responding when vapor delivery was omitted. Anti-nociceptive effects of self-administered volatilized heroin were of a similar magnitude as those produced by the 10-minute non-contingent exposure. Conclusions: This study shows that "chasing the dragon" methods of inhalation of heroin can be modeled successfully in the rat. Inhalation techniques may be particularly useful for longer term studies deep into middle age of rat species.

Adult consequences of repeated nicotine and Δ 9 -tetrahydrocannabinol (THC) vapor inhalation in adolescent rats.

The use of Electronic Drug Delivery Systems (EDDS, "e-cigarettes") to ingest nicotine and Δ 9 -tetrahydrocannabinol (THC) has surged in adolescent populations in the United States, as five times as many high-school seniors vape nicotine daily as use tobacco. At the same time 19.5% of seniors use cannabis at least monthly, with 12% using EDDS to deliver it. This study was conducted to examine the impact of repeated adolescent vapor inhalation of nicotine and THC in rats. Female Sprague-Dawley rats were exposed to 30-minute sessions of vapor inhalation, twice daily, from Post-Natal Day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle, Nicotine (60 mg/mL in the PG), THC (100 mg/mL in the PG) or the combination of Nicotine (60 mg/mL) and THC (100 mg/mL). Rats were assessed on wheel activity, heroin anti-nociception and nicotine and heroin vapor volitional exposure during adulthood. Nicotine exposed rats exhibited few differences as adults, but were less sensitive to anti-nociceptive effects of heroin (1 mg/kg, s.c.). THC- and THC+Nicotine-exposed rats were less spontaneously active, and obtained fewer nicotine vapor deliveries as adults. In contrast, THC exposed rats obtained volitional heroin vapor at rates indistinguishable from the non-THC-exposed groups. Repeated THC exposure also caused tolerance to temperature-disrupting effects of THC (5 mg/kg, i.p.). These studies further confirm that the effects of repeated vapor exposure to THC in adolescence last into early to middle adulthood, including decreased volitional consumption of nicotine. Effects of repeated nicotine in adolescence were comparatively minor.

The long-term effects of repeated heroin vapor inhalation during adolescence on measures of nociception and anxiety-like behavior in adult Wistar rats.

RATIONALE: Adolescents represent a vulnerable group due to increased experimentation with illicit substances that is often associated with the adolescent period, and because adolescent drug use can result in long-term effects that differ from those caused by drug use initiated during adulthood. OBJECTIVES: The purpose of the present study was to determine the effects of repeated heroin vapor inhalation during adolescence on measures of nociception, and anxiety-like behavior during adulthood in female and male Wistar rats. METHODS: Rats were exposed twice daily to 30 min of heroin vapor from post-natal day (PND) 36 to PND 45. At 12 weeks of age, baseline thermal nociception was assessed across a range of temperatures with a warm-water tail-withdrawal assay. Anxiety-like behavior was assessed in an elevated plus-maze (EPM) and activity was measured in an open-field arena. Starting at 23 weeks of age, baseline thermal nociception was re-assessed, nociception was determined after acute heroin or naloxone injection, and anxiety-like behavior was redetermined in the EPM. RESULTS: Adolescent heroin inhalation altered baseline thermal nociception in female rats at 12 weeks of age and in both female and male rats at ~ 23 weeks. Heroin-treated animals exhibited anxiety-like behavior when tested in the elevated plus-maze, showed blunted heroin-induced analgesia, but exhibited no effect on naloxone-induced hyperalgesia. CONCLUSIONS: The present study demonstrates that heroin vapor inhalation during adolescence produces behavioral and physiological consequences in rats that persist well into adulthood.

Behavioral effects of ethanol in the Red Swamp Crayfish (Procambarus clarkii).

Alcohol abuse remains one of the primary preventable sources of mortality in the United States. Model species can be used to evaluate behavioral and other biological changes associated with alcohol and to identify novel treatments. This report describes methods for evaluating the behavioral effects of ethanol (EtOH) in crayfish. Crayfish (Procambarus clarkii) were immersed in ethanol concentrations ranging from 0.1 to 1.0 molar, for 10-30 min. Studies evaluated hemolymph alcohol concentration, locomotion in an open field and anxiety-like behavior using a Light/Dark transfer approach. EtOH immersion produced dose-dependent increases in hemolymph EtOH (up to 249 mg/dL) and reductions in open field locomotion that depended on EtOH concentration or exposure duration. Untreated crayfish exhibit avoidance of the open parts of the locomotor arena and a preference for a covered portion. Acute EtOH immersion decreased time spent in the covered portion of the Light/Dark arena, consistent with a decrease in anxiety-like behavior. Daily EtOH immersion for 5 days did not alter locomotor responses, however, activity was increased 3 days after the repeated EtOH regimen. Overall, this study shows that this inexpensive, easily maintained species can be used for behavioral pharmacological experiments designed to assess the acute and repeated effects of EtOH.

Effects of combined THC and heroin vapor inhalation in rats.

RATIONALE: Opioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use, and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms. OBJECTIVES: To determine if heroin and Δ9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature, and spontaneous locomotor activity when inhaled or injected. METHODS: Groups of female and male rats, implanted with radiotelemetry transmitters, were exposed to vapor generated from heroin (50 mg/mL in propylene glycol vehicle; PG), THC (50 mg/mL), or the combination for assessment of effects on temperature and activity. Thermal nociception was assessed with a warm water tail-withdrawal assay. RESULTS: Heroin inhalation increased temperature and activity whereas THC inhalation decreased temperature and activity in both female and male Sprague-Dawley rats. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of heroin and THC by either inhalation or injection produced additive effects on thermal nociception in both male and female Sprague-Dawley and Wistar rats. CONCLUSIONS: This study shows that additive effects of THC with an opioid on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.

Blinding peer review.

Concealing the identity of the principal investigator only partially closes the success gap between white and African American or Black researchers in NIH grant applications.

Toward an Anti-Racist Approach to Biomedical and Neuroscience Research.

Racism is a threat to public health. Race is a sociopolitical construct that has been used for generations to create disparities in educational access, housing conditions, exposure to environmental contaminants, and access to health care. Collectively, these disparities have a negative impact on the health of non-white Americans. The National Institutes of Health (NIH) funds biomedical research, including basic neuroscience research, aimed at understanding the mechanisms and consequences of health and disease in Americans. NIH has recently acknowledged its own structural racism, the disadvantage this perpetuates in the biomedical research enterprise, and has announced its commitment to eliminating these disparities. Here, we discuss different rates of disease in U.S. citizens from different racial backgrounds. We next describe ways in which the biomedical research enterprise (1) has contributed to health disparities and (2) can contribute to the solving this problem. Based on our own scientific expertise, we use neuroscience in general and mental health/addiction disorders more specifically as examples of a broader issue. The NIH, including its neuroscience-focused Institutes, and NIH-funded scientists, including neuroscientists, should prioritize research topics that reflect the health conditions that affect all Americans, not just white Americans.

Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors. Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

Vapor exposure to Δ9-tetrahydrocannabinol (THC) slows locomotion of the Maine lobster (Homarus americanus).

RATIONALE: Despite a long history of use in synaptic physiology, the lobster has been a neglected model for behavioral pharmacology. A restaurateur proposed that exposing lobster to cannabis smoke reduces anxiety and pain during the cooking process. It is unknown if lobster gill respiration in air would result in significant Δ9-tetrahydrocannabinol (THC) uptake and whether this would have any detectable behavioral effects. OBJECTIVE: The primary goal was to determine tissue THC levels in the lobster after exposure to THC vapor. Secondary goals were to determine if THC vapor altered locomotor behavior or nociception. METHODS: Tissue samples were collected (including muscle, brain and hemolymph) from Homarus americanus (N = 3 per group) following 30 or 60 min of exposure to vapor generated by an e-cigarette device using THC (100 mg/mL in a propylene glycol vehicle). Separate experiments assessed locomotor behavior and hot water nociceptive responses following THC vapor exposure. RESULTS: THC vapor produced duration-related THC levels in all tissues examined. Locomotor activity was decreased (distance, speed, time-mobile) by 30 min inhalation of THC. Lobsters exhibit a temperature-dependent withdrawal response to immersion of tail, antennae or claws in warm water; this is novel evidence of thermal nociception for this species. THC exposure for 60 min had only marginal effect on nociception under the conditions assessed. CONCLUSIONS: Vapor exposure of lobsters, using an e-cigarette based model, produces dose-dependent THC levels in all tissues and reduces locomotor activity. Hot water nociception was temperature dependent, but only minimal anti-nociceptive effect of THC exposure was confirmed.

Effects of α-pyrrolidino-phenone cathinone stimulants on locomotor behavior in female rats.

The α-pyrrolidino-phenone cathinone stimulants first came to widespread attention because of bizarre behavior consequent to the use of α-pyrrolidinopentiophenone (α-PVP, "flakka") reported in popular press. As with other designer drugs, diversification of cathinones has been driven by desirable subjective effects, but also by attempts to stay ahead of legal controls of specific molecules. The α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinopropiophenone (α-PPP) compounds have been relatively under-investigated relative to α-PVP and provide a key opportunity to also investigate structure-activity relationships, i.e., how the extension of the alpha carbon chain may affect potency or efficacy. Female rats were used to contrast the effects of α-PHP and α-PPP with those of α-PVP in altering wheel activity and effects on spontaneous locomotion, temperature and intracranial self-stimulation reward. The α-PPP, α-PHP and α-PVP compounds (5, 10 mg/kg, i.p.) suppressed wheel activity. Inhalation of α-PHP or α-PVP also suppressed wheel activity, but for an abbreviated duration compared with the injection route. Spontaneous activity was increased, and brain reward thresholds decreased, in a dose-dependent manner by all three compounds; only small decrements in body temperature were observed. These data show that all three of the α-pyrrolidino-phenone cathinones exhibit significant stimulant-like activity in female rats. Differences were minor and abuse liability is therefore likely to be equivalent for all three α-pyrrolidino-phenones.

Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis.

BACKGROUND AND PURPOSE: The extra medical use of, and addiction to, prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self-stimulation (ICSS) reward and oxycodone intravenous self-administration (IVSA) models. EXPERIMENTAL APPROACH: Male Wistar rats were given access to oxycodone IVSA (0.15 mg·kg-1 per infusion, i.v.) in short-access (ShA; 1 h) or long-access (LgA; 12 h) sessions for five sessions per week followed by intermittent 60-h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. Separate groups were first trained in the ICSS procedure and then in oxycodone IVSA in 11-h LgA sessions. KEY RESULTS: Rats given LgA to oxycodone escalated their responding more than ShA rats, with further significant increases observed following each 60-h discontinuation. Presession brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1-h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60-h weekend abstinence. The increase in ICSS thresholds was attenuated in a group treated with the long-acting κ-opioid antagonist norbinaltorphimine prior to IVSA training. CONCLUSION AND IMPLICATIONS: Changes in brain reward function during escalation of oxycodone self-administration are driven by an interplay between κ-opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice.

Cannabis use is widespread among adolescents and has been associated with long-term negative outcomes on neurocognitive functions. However, the factors that contribute to the long-term detrimental effects of cannabis use remain poorly understood. Here, we studied how Reelin deficiency influences the behavior of mice exposed to cannabis during adolescence. Reelin is a gene implicated in the development of the brain and of psychiatric disorders. To this aim, heterozygous Reeler (HR) mice, that express reduced level of Reelin, were chronically injected during adolescence with high doses (10 mg/kg) of Δ9-tetrahydrocannabinol (THC), a major psychoactive component of cannabis. Two weeks after the last injection of THC, mice were tested with multiple behavioral assays, including working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition. Compared to wild-type (WT), HR mice treated with THC showed impaired social behaviors, elevated disinhibitory phenotypes and increased reactivity to aversive situations, in a sex-specific manner. Overall, these findings show that Reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence and suggest that elucidating Reelin signaling will improve our understanding of neurobiological mechanisms underlying behavioral traits relevant to the development of psychiatric conditions.