Withdrawal Signs Research Articles

Cannabidiol Modulates Behavioural and Gene Expression Alterations Induced by Spontaneous Cocaine Withdrawal.

The aim of this study was to evaluate the effects of cannabidiol (CBD) on the behavioural and gene expression changes in a new animal model of spontaneous cocaine withdrawal. For this purpose, male CD-1 mice were exposed to progressive increasing doses of cocaine for 12days (15 to 60mg/kg/day, i.p.), evaluating spontaneous cocaine withdrawal 6h after the last cocaine administration. The effects of CBD (10, 20, and 40mg/kg, i.p.) were evaluated on cocaine withdrawal-induced alterations in motor activity, somatic signs, and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens, were analysed by real-time PCR. The results obtained in the study showed that mice exposed to the spontaneous cocaine withdrawal model presented increased motor activity, somatic withdrawal signs, and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal, regulated the decrease of CNR1 and induced an additional upregulation of CNR2 gene expression. Thus, this model of spontaneous cocaine withdrawal induces clear behavioural and gene expression changes in mice. Interestingly, CBD alleviates these behavioural and gene expression alterations suggesting its potential for the management of cocaine withdrawal.

The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice

Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive alcohol intake, loss of control over alcohol intake, and a negative emotional state when access to alcohol is prevented. AUD is also closely tied to pain, as repeated alcohol drinking leads to increased pain sensitivity during withdrawal. The sigma-2 receptor, recently identified as transmembrane protein 97 (σ2R/TMEM97), is an integral membrane protein involved in cholesterol homeostasis and lipid metabolism. Selective σ2R/Tmem97 modulators have been recently shown to relieve mechanical hypersensitivity in animal models of neuropathic pain as well as to attenuate alcohol withdrawal signs in C. elegans and to reduce alcohol drinking in rats, suggesting a potential key role for this protein in alcohol-related behaviors. In this study, we tested the effects of a potent and selective σ2R/TMEM97 ligand, JVW-1034, on heavy alcohol drinking and alcohol-induced heightened pain states in mice using an intermittent access model. Administration of JVW-1034 decreased both ethanol intake and preference for ethanol, without affecting water intake, total fluid intake, or food intake. Notably, this effect was specific for alcohol, as JVW-1034 had no effect on sucrose intake. Furthermore, JVW-1034 reduced both thermal hyperalgesia and mechanical hypersensitivity in ethanol withdrawn mice. Our data provide important evidence that modulation of σ2R/TMEM97 with small molecules can mediate heavy alcohol drinking as well as chronic alcohol-induced heightened pain sensitivity, thereby identifying a promising novel pharmacological target for AUD and associated pain states.

Effect of Afghan Saffron (Crocus sativus L.) Aqueous Extract on Withdrawal Signs in Morphine-Dependent Rats

Introduction: Opioid dependency, as a global problem is accompanied with serious personal, economic, social and hygienic disorders. Synthetic drugs beside their efficacies, have numerous adverse effects. As the medicinal plants have low costs and adverse effects, and they are also affective on different stages of dependency treatment, they attracted the attention of the researchers in the field of medicine. This study was aimed to investigate the effect of the aqueous extract of Afghan saffron on the withdrawal signs in morphine-dependent rats. Methods: Rats divided into 5 groups (1 Normal Saline, 1 Morphine, and 3 Extract groups). The rats that received morphine and extract became morphine-dependent by subcutaneous (s.c.) administration of morphine hydrochloride for 7 days (2.5, 2.5, 5, 10, 20, 40 mg/kg doses twice daily on 1st to 6th days respectively, and a single dose of 50 mg/kg on 7th day). The extract groups received 100, 150 and 200 mg/kg doses of the saffron aqueous extract by intraperitoneal (i.p.) administration simultaneously with morphine. Two hours after the administration of the last dose of morphine, Naloxone (3 mg/kg, i.p.) was injected and withdrawal signs were noted for 30 minutes. Results: The results showed that the administration of the saffron aqueous extract (100, 150 and 200 mg/kg) significantly decreased most of the withdrawal signs in morphine-dependent rats (P<0.05). Conclusion: Afghan saffron aqueous extract can alleviate the withdrawal signs in morphine-dependent rats.

Addiction as a Coping Response: Hyperkatifeia, Deaths of Despair, and COVID-19.

Addiction as a Coping Response: Hyperkatifeia, Deaths of Despair, and COVID-19.

Female rats self-administer heroin by vapor inhalation

Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of prescription opioids around 2002, followed later by increased heroin use and then most recently fentanyl. Inhalation is a common route of administration for opioids, with a documented history spanning back to Mediterranean antiquity and up through modern use with e-cigarette devices. Unfortunately, preclinical studies using inhalation as the route of administration remain relatively few. This study was conducted to determine the efficacy of e-cigarette vapor inhalation of heroin in rats. Non-contingent exposure to heroin or methadone vapor produced anti-nociceptive efficacy in male and female rats. Female rats were trained to self-administer heroin vapor; the most-preferring half of the distribution obtained more vapor reinforcers when the concentration of heroin was reduced in the vapor vehicle and when pre-treated with the opioid receptor antagonist naloxone. The anti-nociceptive effect of heroin self-administered by vapor was identical in magnitude to that produced by intravenous self-administration. Finally, anxiety-like behavior increased 24–48 h after last heroin vapor access, consistent with withdrawal signs observed after intravenous self-administration. In sum, these studies show that rewarding and anti-nociceptive effects of heroin are produced in rats by vapor inhalation using e-cigarette technology. Importantly, self-administration models by this route can be deployed to determine health effects of inhaled heroin or other opioids.

Sequence stratigraphy study of the Dariyan Formation in the Gadvan and Zana sections in the northeast and northwest of Shiraz, Zagros Basin, SW Iran

In the present paper, sequence stratigraphy and microfacies of the Dariyan Formation in the two sections of the Gadvan and Zana Mountains located were studied in NE and NW of Shiraz (Fars province, SW Iran). An area of 429.5 m of the Dariyan Formation sediments was studied through 187 thin sections. Also, the index microfacies were closely identified. Generally, index microfacies of the studied thin section were mudstone, wackestone, packstone, and grainstone microfacies. Received paleontological data confirm Aptian–lower Albian age of the Dariyan Formation. According to the lithostratigraphic aspect, the lower contact of Dariyan Formation with the Gadvan Formation in the Gadvan Mountain was described as a gradual type and in Zana Mountain; disconformity was found due to the sign of water withdrawal. Given the upper contact of the Dariyan Formation concerning the formation percentage, contact disconformity was observed due to the changes in the Allochem element and the situation of the entity from water and also according to the high percentage of iron nodules and Gluconate. According to the sequence, stratigraphic studies in the section of Gadvan Mountain, the lower border of the Dariyan Formation with Gadvan Formation was in the gradual form [type 2 Sequence Boundary (SB2)] and there was a disconformity in the upper border of this formation with Kazhdumi Formation [type 1 Sequence Boundary (SB1)]. Dariyan Formation included the system tracts (transgressive system tract, early highstand system tract, and late highstand system tract). There was a disconformity in its lower of the Gadvan Formation and disconformity in its upper boundary with the lower of the part Kazhdumi Formation (SB1) and it included the system tracts (highstand system tract, transgressive system tract, and lowstand system tract). Overall, lap sequence grade3 was seen in the two sections.

Chronic opioid exposure differentially modulates oxycodone self-administration in male and female rats.

Withdrawal from opioid painkillers can produce short‐lived physical symptoms and protracted psychological symptoms including anxiety and depressive‐like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self‐administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self‐medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating‐dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating‐dose morphine (5–30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2‐week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females.

Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ1 Receptor Antagonist Clinical Candidate for the Treatment of Pain.

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

Paternal exposure to morphine during adolescence potentiates morphine withdrawal in male offspring: Involvement of the lateral paragigantocellularis nucleus.

Opiate exposure during adolescence perturbs the brain's maturation process and potentially confers long-term adverse consequences, not only in exposed individuals but also in their posterity. Here, we investigate the outcomes of adolescent paternal morphine exposure on morphine withdrawal profile in male offspring. Male Wistar rats were chronically subjected to 10 days of an escalating regimen of morphine during adolescence. After a 20-day washout period, adult males were allowed to copulate with naïve females. The adult male offspring were tested for somatic and affective components of naloxone-precipitated morphine withdrawal using conditioned place aversion. Moreover, electrical activity of the lateral paragigantocellularis (LPGi) nucleus, which is involved in development of opiate dependence, was recorded in response to a challenge dose of morphine via extracellular single-unit recordings. Morphine-sired offspring exhibited augmented expression of naloxone-induced somatic and affective signs of opiate withdrawal compared to the control saline-sired counterparts. In vivo recording revealed that LPGi neurons displayed heterogeneous responses (inhibitory, excitatory, and no change) to acute morphine administration in both morphine- and saline-sired animals. The morphine-induced discharge inhibition was potentiated in morphine-sired offspring. However, the extent of discharge excitation in response to morphine did not reach significance in these subjects. Moreover, the lack of alteration in maternal behavior toward morphine-sired offspring indicates that this is due to germline-dependent transmission of epigenetic traits across generations. Preconception paternal exposure to morphine during adolescence potentiates opiate withdrawal signs in male offspring which is mediated, at least in part, by epigenetic alteration of LPGi-related brain circuitry.

Hospital Outcomes of Infants with Neonatal Opioid Withdrawal Syndrome at a Tertiary Care Hospital with High Rates of Concurrent Nonopioid (Polysubstance) Exposure.

Neonatal opioid withdrawal syndrome (NOWS) describes infants' withdrawal signs and symptoms after birth due to an interruption of prenatal opioid exposure. Many infants with NOWS are also exposed to nonopioids, however. This study was to determine hospital outcomes of infants exposed to opioids alone or coexposed with nonopioid substances (polysubstance). We reviewed infants of ≥34 weeks of gestation with prenatal opioid exposure from April 2015 to May 2018. We compared the median lengths of stay (LOS) and treatment (LOT) and the percentages of infants requiring pharmacologic and adjunctive treatment in infants exposed to opioids alone or polysubstance. We used Wilcoxon's test for continuous outcomes or Chi-squared test for categorical outcomes to determine statistical significance. We used multivariable regression model to calculate each drug category's estimates of adjusted mean ratios for LOS and LOT plus estimates of adjusted odds ratios for pharmacologic/adjunctive treatments. Of the 175 infants, 33 (19%) infants had opioid exposure alone. Opioid exposure included short- and/or long-acting opioids. A total of 142 (81%) had polysubstance exposure with 47% of mothers using nicotine products. We saw similar hospital outcomes between infants exposed to opioids alone or polysubstance; however, a higher percentage of infants with both short- and long-acting opioid exposure required pharmacologic treatment compared with either opioid alone. Focusing on individual drug categories, we detected differential hospital outcomes in which short-acting opioids decreased LOT, whereas long-acting opioids increased LOS, LOT, and need for pharmacologic and adjunctive treatment. Coexposure of opioids with stimulants decreased LOT and reduced need for adjunctive treatment. Coexposures with antidepressants increased LOT, while with antiepilepetics increased LOS. Because infants with NOWS often have coexposures to other nonopioid substances, appreciating the associated risks of individual or combination of drugs in modulating hospital outcomes may help counsel families on their infants' expected hospital course. · Hospital outcomes were similar between infants exposed to opioids alone or polysubstance including opioids.. · Infants with short- and long-acting opioids required pharmacologic treatment more often than either opioid alone.. · Differential hospital outcomes exist for various co-exposures of opioids with nonopioids..

BDNF receptor antagonism during the induction of morphine dependence exacerbates the severity of physical dependence and ameliorates psychological dependence in rats

This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) during induction of morphine dependence on the severity of physical and psychological dependence and the cerebrospinal fluid (CSF) BDNF levels in morphine-dependent and withdrawn rats. Rats became morphine-dependent by increasing daily doses of morphine for 7 days, along with ANA-12 injection. Then, rats were tested for the severity of physical dependence on morphine (spontaneous withdrawal signs), anxiety-like (the elevated plus maze), depressive-like (sucrose preference test) behaviors after spontaneous morphine withdrawal. Also, the CSF BDNF levels were assessed 2 h after the last dose of morphine and day 13 after morphine withdrawal in morphine-dependent and withdrawn rats. We found that the morphine withdrawal signs were significantly higher in morphine dependent rats receiving ANA-12 on days of 5–7 after morphine withdrawal, also ANA-12 exacerbated overall dependence severity. While, the percentage of time spent in the open arms and sucrose preference were higher in morphine-dependent rats receiving ANA-12 than morphine-dependent rats receiving saline. Also, the ANA-12 injection decreased the CSF BDNF levels following morphine dependence, while increased it after morphine withdrawal. We conclude that the ANA-12 exacerbated the severity of physical morphine dependence but attenuated the anxiety/depressive-like behaviors in morphine-dependent and withdrawn rats. Also, ANA-12 injection was able to reverse the changes in the CSF BDNF levels. Therefore, ANA-12 is not more likely to complete treatment for opiate addiction.

A Review of Feeding Practices in Infants With Neonatal Abstinence Syndrome.

There has been an increase in infants with neonatal abstinence syndrome (NAS) in neonatal intensive care units (NICUs) over the past several decades. Infants with NAS experience withdrawal as a result of the sudden termination at birth of substance exposure during pregnancy. A serious sign related to infants diagnosed with NAS is poor feeding. The prevalence of NAS urges researchers and clinicians to develop effective strategies and techniques to treat and manage the poor feeding of infants exposed to substances in utero. To synthesize current feeding methods and practices used for infants diagnosed with NAS. PubMed, CINAHL, and Scopus were searched for articles published within the last 20 years that focused on feeding practices or feeding schedules, were written in English, were peer-reviewed, and described human studies. The search terms utilized were "neonatal abstinence syndrome" OR "neonatal opioid withdrawal syndrome" AND "feeding." Three findings emerged regarding techniques and management of poor feeding in the NAS population. The findings included infants who received mother's own milk had decreased severity and later onset of clinical signs of withdrawal, demand feeding is recommended, and the infant's cues may be helpful to follow when feeding. Clinicians should encourage mother's own milk in this population unless contraindications are present. Caregivers and clinicians must be receptive to cues when feeding infants with NAS. Even with the clinical knowledge and experience that infants with NAS are difficult to feed, there is limited research assessing techniques and schedules that are effective in managing successful feeding. Future research should compare feeding schedules such as on-demand feeding versus regimented feeding schedules, as well as investigate techniques that mothers and nurses can utilize to encourage oral intake in this population.Video abstract available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?autoPlay=false&videoId=37.

Injection of minocycline into the periaqueductal gray attenuates morphine withdrawal signs

This study investigated the effects of minocycline microinjections, into the midbrain periaqueductal gray (PAG), on morphine withdrawal and the expression of pannexin-1 (panx1), phosphorylated mammalian target of rapamycin (p-mTOR), protein kinase A (PKA), and cAMP response element-binding protein (CREB). Rats were injected with morphine, intraperitoneally, at increasing doses, twice per day, to establish animal models of morphine exposure. Minocycline was administered into the PAG before the first intraperitoneal (i.p.) injection of morphine each day, on days 1–4. On the last day of the experiment, all rats were injected with naloxone, and morphine withdrawal was observed, and then changes in the expression levels of ionized calcium-binding adaptor molecule 1 (Iba1) and its downstream factors, panx1, p-mTOR, PKA, and CREB were evaluated by western blot and immunohistochemistry analyses. Morphine withdrawal increased microglial activation, whereas minocycline could inhibit microglial activation and withdrawal and the downregulation of panx1, p-mTOR, PKA, and CREB expression, reducing the effects of morphine withdrawal.

Behavioral changes in preterm children during nasogastric tube feeding. Comparative study of manual administration by parents versus mechanical administration via electric syringe pump

IntroductionManual feeding by parents using a syringe, a widespread practice in Sweden since the 1980s, favors parents' involvement in childcare tasks. This approach is used in our neonatal unity since 2007. ObjectiveTo study the behavioral changes of preterm children during nasogastric tube feeding: manual milk administration by parents (MAP) versus electric syringe administration (ESA) over a 30-minute period. MethodThis is a randomized, crossover study conducted in the neonatology unit of Toulouse. Preterm children under 33 weeks of age and over 7 days of life were included. A video recording was performed to assess the children's behavioral response, using the Dsilna score. The reviewer was blinded. Results15 preterm children with a median gestational age of 30.1 weeks and a median birth weight of 1.210 g were included from March to October 2012. The facility, environment, and state of alertness of children were similar in both groups. Signs of well-being were significantly more prevalent in the MAP group versus the ESA group (36.2 (±8.0) versus 30.7 (±9.5)), (p = 0.04), particularly “hand-to-mouth, mouth gestures, seeking suction and sucking”. Although not significant, motor withdrawal signs were more apparent and fluctuating in the ESA group. Qualitative analysis of NIDCAP observations confirms this data. ConclusionThere are behavior changes of preterm children during nasogastric tube feeding. This pilot study showed previously undescribed results: MAP is associated with more common well-being signs and could be more widely used in neonatal units.

Effect of Essential Oil of Zhumeria majdae on Morphine Tolerance and Dependence in Mice.

To evaluate the effects of Zhumeria majdae essential oil (ZMEO) on morphine dependence and tolerance in mice. ZMEO (10, 20, and 40 mg/kg) and clonidine (0.1 mg/kg) as the positive control were injected intraperitoneally (i.p.). The effect of ZMEO and clonidine on the dependence were evaluated by counting the number of jumps induced by naloxone (5 mg/kg) while the tolerance was evaluated by the tail-flick test. ZMEO at the dose of 10 mg/kg during the development period led to a significant inhibition of morphine tolerance (P<0.01), while it led to reduced morphine dependence with the doses of 20 and 40 mg/kg. ZMEO at two dose levels of 20 and 40 mg/kg indicated significant antinociceptive activity (P>0.01), and significantly reduced the withdrawal signs (number of jumps) of mice (P>0.01). ZMEO had significant effects on morphine tolerance and dependence. The linalool rich essential oil of Z. majdae plays a major role in the reduction of tolerance and dependence induced by morphine.

The Effect of Dihydromyricetin, a Natural Flavonoid, on Morphine-induced Conditioned Place Preference and Physical Dependence in Mice.

Dihydromyricetin (DHM), a natural flavonoid, is used to reduce alcohol hangover. It has a modulatory role on GABAA receptors with significant effects on seizure and anxiety in animal models. We aimed to evaluate the effect of DHM on morphine conditioned place preference (CPP) and withdrawal sings following morphine dependence using animal models. The effect of DHM (1, 2 and 5 mg/kg, intraperitoneal; ip) on the acquisition and expression of morphine-induced CPP was evaluated in male mice. Administration of morphine for three consecutive days induced physical dependence. The withdrawal signs such as jumping and defecation were precipitated by administration of naloxone (8 mg/kg, ip). The effect of DHM on the development of physical dependence was assessed by injection of DHM before morphine administrations. DHM, at the dose of 5 mg/kg, reduced expression of morphine CPP with an increase in the locomotor activity. DHM, at the doses of 2 and 5 mg/kg, also reduced development of morphine CPP. DHM alleviated development of morphine-induced physical dependence at the dose of 1, 2, and 5 mg/kg by decreasing jumping and defecation. These results indicated that DHM decreased acquisition and expression of morphine CPP and inhibited development of morphine-induced physical dependence.

Exposure to smoke from high- but not low-nicotine cigarettes leads to signs of dependence in male rats and potentiates the effects of nicotine in female rats

Nicotine is only mildly rewarding, but after becoming dependent, it is difficult to quit smoking. The goal of these studies was to determine if low-nicotine cigarettes are less likely to cause dependence and enhance the reinforcing effects of nicotine than regular high-nicotine cigarettes. Male and female rats were exposed to tobacco smoke with a low or high nicotine level for 35 days. It was investigated if smoke exposure affects the development of dependence, anxiety- and depressive-like behavior, and nicotine-induced behavioral sensitization. Smoke exposure did not affect locomotor activity in a small open field or sucrose preference. Mecamylamine precipitated somatic withdrawal signs in male rats exposed to smoke with a high level of nicotine, but not in male rats exposed to smoke with a low level of nicotine or in females. After cessation of smoke exposure, there was a small decrease in sucrose preference in the male rats, which was not observed in the females. Cessation of smoke exposure did not affect anxiety-like behavior in the large open field or the elevated plus maze test. Female rats displayed less anxiety-like behavior in both these tests. Repeated treatment with nicotine increased locomotor activity, rearing, and stereotypies. Prior exposure to smoke with a high level of nicotine increased nicotine-induced rearing in the females. These findings indicate that exposure to smoke with a low level of nicotine does not lead to dependence and does not potentiate the effects of nicotine. Exposure to smoke with a high level of nicotine differently affects males and females.

The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice

BackgroundRecent years have seen a rise in the diversity and use of synthetic cannabinoids. The present study evaluated the behavioral effects of the third-generation indazole-3-carboxamide-type synthetic cannabinoid, AB-FUBINACA. MethodsAdult male and female C57BL/6J mice were treated with AB-FUBINACA (0−3 mg/kg, i.p.) and tested repeatedly in the tetrad battery measuring catalepsy, antinociception, hypothermia, and locomotor activity. Mice treated with AB-FUBINACA (≥2 mg/kg, i.p.) displayed classic cannabinoid effects in the tetrad that were blocked by the CB1 receptor selective antagonist rimonabant. To address tolerance and withdrawal effects, a second group of mice was injected with AB-FUBINACA (3 mg/kg, s.c.) or vehicle consisting of 5% ethanol, 5% Kolliphor EL, and 90 % saline every 12 h and tested daily in modified tetrad over the course of 5 days. On the 6th day, withdrawal was precipitated using rimonabant (3 mg/kg, s.c.), and somatic signs of withdrawal (i.e., head twitches and paw tremors) were quantified. ResultsAlthough mice did not develop tolerance to AB-FUBINACA or cross-tolerance to Δ9-tetrahydrocannabinol (THC; 50 mg/kg, i.p.), somatic precipitated withdrawal signs were observed. Repeated tetrad testing up to 48 h post injection indicated that AB-FUBINACA effects are relatively short-lived, as compared with THC. Brain levels of AB-FUBINACA, as quantified by UHPLC-MS/MS, were undetectable 4 h post injection. ConclusionsThese data indicate that the cannabinoid effects of AB-FUBINACA are relatively short-lived, yet sufficient to induce dependence in mice.

Opioid receptors and butorphanol dependence

Butorphanol, a mixed opioid agonist/antagonist, is considered to be a relatively safe drug when used within the therapeutic dose range. However, diversional uses of butorphanol involving high dose have been documented. In the present review, the relative involvement of μ, δ, and κ-opioid receptors in butorphanol physical dependence in rats is discussed. Physical dependence was produced by continuous intracerebroventricular (icv) infusion of butorphanol (26 nmol/h) for 72 h in male Sprague-Dawley rats. Multiple icv injections of β-funaltrexamine (β-FNA, a μ-antagonist, 12, 24, or 48 nmol/5 μl), naltrindole (NTI, a δ-antagonist, 0.1, 1, or 10 nmol/5 μl), or nor-binaltorphimine (nor-BNI, a κ-antagonist, 12, 24, or 48 nmol/5 μl) significantly attenuated the development of butorphanol dependence. Furthermore, icv administration of both NTI (24, 48, or 100 nmol/5 μl) and nor-BNI (3, 10, 20, 48 or 100 nmol/5 μl) precipitated withdrawal behaviors, whereas, β-FNA (12, 24, 48, or 100 nmol/5 μl) was unable to elicit withdrawal signs in butorphanol-dependent rats. The results indicate that the development of butorphanol dependence is due to effects of butorphanol on central μ-, δ-, and κ-opioid receptors.

Validation of a nicotine vapor self-administration model in rats with relevance to electronic cigarette use.

The debate about electronic cigarettes is dividing healthcare professionals, policymakers, manufacturers, and communities. A key limitation in our understanding of the cause and consequences of vaping is the lack of animal models of nicotine vapor self-administration. Here, we developed a novel model of voluntary electronic cigarette use in rats using operant behavior. We found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans. The level of responding on the active (nicotine) lever was similar to the inactive (air) lever and lower than the active lever that was associated with vehicle (polypropylene glycol/glycerol) vapor, suggesting low positive reinforcing effects and low nicotine vapor discrimination. Lever pressing behavior with nicotine vapor was pharmacologically prevented by the α4β2 nicotinic acetylcholine receptor partial agonist and α7 receptor full agonist varenicline in rats that self-administered nicotine but not vehicle vapor. Moreover, 3 weeks of daily (1 h) nicotine vapor self-administration produced addiction-like behaviors, including somatic signs of withdrawal, allodynia, anxiety-like behavior, and relapse-like behavior after 3 weeks of abstinence. Finally, 3 weeks of daily (1 h) nicotine vapor self-administration produced cardiopulmonary abnormalities and changes in α4, α3, and β2 nicotinic acetylcholine receptor subunit mRNA levels in the nucleus accumbens and medial prefrontal cortex. These findings validate a novel animal model of nicotine vapor self-administration in rodents with relevance to electronic cigarette use in humans and highlight the potential addictive properties and harmful effects of chronic nicotine vapor self-administration.