Effects of Δ⁹-tetrahydrocannabinol (THC) vapor inhalation in Sprague-Dawley and Wistar rats.

An inhalation system based on e-cigarette technology produces hypothermic and antinociceptive effects of Δ⁹-tetrahydrocannabinol (THC) in rats. Indirect comparison of some prior investigations suggested differential impact of inhaled THC between Wistar (WI) and Sprague-Dawley (SD) rats; thus, this study was conducted to directly compare the strains across inhaled and injected routes of administration. Groups (N = 8 per strain) of age-matched male SD and WI rats were prepared with radiotelemetry devices to measure temperature and then exposed to vapor from the propylene glycol (PG) vehicle or THC (25-200 mg/mL of PG) for 30 or 40 min. Additional studies evaluated effects of THC inhalation on plasma THC (50-200 mg/mL) and nociception (100-200 mg/mL) as well as the thermoregulatory effect of intraperitoneal injection of THC (5-30 mg/kg). Hypothermic effects of THC were more pronounced in SD rats, where plasma levels of THC were identical across strains, under either fixed inhalation conditions or injection of a mg/kg equivalent dose. Strain differences in hypothermia were largest after i.p. injection of THC, with SD rats exhibiting dose-dependent temperature reduction after 5 or 10 mg/kg, i.p. and the WI rats only exhibiting significant hypothermia after 20 mg/kg, i.p. The antinociceptive effects of inhaled THC (100, 200 mg/mL) did not differ significantly across the strains. These studies confirm an insensitivity of WI rats, compared with SD rats, to hypothermia induced by THC following inhalation conditions that produced identical plasma THC and antinociception. Thus, quantitative, albeit not qualitative, strain differences may be obtained when studying thermoregulatory effects of THC. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Intravenous self-administration of mephedrone, methylone and MDMA in female rats

Male rats will intravenously self-administer (IVSA) the substituted cathinone stimulants ("bath salts") mephedrone (4-methylmethcathione) and methylone (3,4-methylenedioxymethcathinone) robustly, whereas the IVSA of 3,4-methylenedioxymethamphetamine (MDMA) is inconsistent in many rat models. There are no data available on the self-administration of these drugs in female rats, thus a study was undertaken to contrast them directly. Groups of female Wistar rats were trained to self-administer mephedrone, methylone or MDMA (0.5 mg/kg/inf) under a Fixed-Ratio (FR) 1 schedule of reinforcement for 14 sessions. Following the acquisition interval, animals were evaluated in FR (0.0, 0.125, 0.25, 0.5, 1.0, 2.5 mg/kg/inf) and PR (0.125, 1.0 mg/kg/inf) dose-substitution procedures. The results show that female rats acquired the self-administration of all three compounds with intakes in mephedrone-trained rats that were significantly higher than that of methylone-trained or MDMA-trained rats. In dose-substitution under either FR or PR contingencies, however, the potencies of all three drugs were similar within the original training groups. The mephedrone-trained animals exhibited higher intakes of all drugs during dose-substitution, indicating lasting consequences of the training drug. Abuse liability of these three compounds is therefore predicted to be similar in established stimulant users but may differ in liability if they are primary drugs of initiation

A vapor exposure method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats

BackgroundThe ongoing crisis related to non-medical use of opioids makes it of continued importance to understand the risk factors for opioid addiction, the behavioral and neurobiological consequences of opioid exposure and to seek potential avenues for therapy. Pre-clinical rodent models have been critical to advancing understanding of opioid consequences for decades, but have been mostly limited to drug delivery by injection or by oral dosing. Inhalation, a significant route for many human users, has not been as well-established.MethodWe adapted an e-cigarette based exposure system, previously shown efficacious for delivery of other drugs to rats, to deliver heroin vapor. Effectsin vivo were assessed in male and female Sprague-Dawley rats using a warm-water assay for anti-nociception and an implanted radiotelemetry system for evaluating changes in body temperature and spontaneous activity rate.ResultsInhalation of vapor created by heroin 100 mg/mL in the propylene glycol (PG) vehicle significantly slowed tail-withdrawal from a 52 °C water bath, bi-phasically altered activity, and increased temperature in male and female rats. Inhalation of heroin 50 mg/mL for 15 min produced significant effects, as the lower bound on efficacy, whereas inhalation of heroin 100 mg/mL for 30 min produced robust effects across all endpoints and groups.ConclusionsThis work shows that e-cigarette devices deliver psychoactive doses of heroin to rats, using concentrations of ∼50-100 mg/mL and inhalation durations of 15-30 min. This technique may be useful to assess the health consequences of inhaled heroin and other opioid drugs

Intravenous self-administration of entactogen-class stimulants in male rats.

The intravenous self-administration (IVSA) of 3,4-methylenedioxymethamphetamine (MDMA) is inconsistent in rats, with up to half of subjects failing to acquire reliable drug intake. It is unknown if this changes under long-access conditions (6 h sessions) under which the IVSA of cocaine and methamphetamine escalates. The entactogen class cathinone stimulants which exhibit MDMA-like monoamine effects in the nucleus accumbens, mephedrone (4-methylmethcathinone) and methylone (3,4-methylenedioxymethcathinone), may support more reliable IVSA but results have been mixed. This study was designed to directly compare the IVSA of these three compounds. Groups of male Wistar rats were trained to self-administer mephedrone, methylone or MDMA (0.5 mg/kg/inf) under a Fixed-Ratio (FR) 1 schedule of reinforcement for 14 sessions. Following the acquisition interval, animals were evaluated in FR (0.0, 0.125, 0.25, 0.5, 1.0, 2.5 mg/kg/inf) and Progressive Ratio (PR; 0.125, 1.0 mg/kg/inf) dose-substitution procedures. Long access conditions escalated MDMA intake over the 6 h session but not in the first 2 h. In short access, drug intake was significantly higher in mephedrone-trained rats compared with either the methylone-trained or MDMA-trained groups during acquisition. Mephedrone resulted in the highest intakes during FR and PR dose-substitution in MDMA- and mephedrone-trained groups. Overall it was found that mephedrone is a more effective reinforcer than methylone or MDMA and represents a higher risk for compulsive use

Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Δ(9) -tetrahydrocannabinol in Sprague-Dawley rats.

Background and purposeGrowing evidence shows cannabidiol (CBD) modulates some of the effects of Δ(9) -tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats.Experimental approachesMale Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10-30 mg·kg(-1) , i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant).Key resultsCBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model.Conclusions and implicationsThere is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats

Vapor inhalation of cannabidiol (CBD) in rats.

RATIONALE:Cannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. OBJECTIVE:To further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. METHODS:Blood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. RESULTS:Vapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. CONCLUSIONS:The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels

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

RationaleUse 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.ObjectivesThis study was conducted to examine the impact of repeated adolescent vapor inhalation of nicotine and THC in rats.MethodsFemale 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.ResultsNicotine-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.).ConclusionsThese 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

Lasting effects of repeated ∆9 -tetrahydrocannabinol vapour inhalation during adolescence in male and female rats.

Background and purposeAdolescents are regularly exposed to ∆9 -tetrahydrocannabinol (THC) via smoking and, more recently, vaping cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response to THC.Experimental approachesMale and female rats inhaled THC vapour, or that from the propylene glycol (PG) vehicle, twice daily for 30 min from postnatal day (PND) 35-39 and PND 42-46 using an e-cigarette system. Thermoregulatory responses to vapour inhalation were assessed by radio-telemetry during adolescence and from PND 86-94. Chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after 4 days of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults.Key resultsFemale, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC. However, enhanced potency was found in females. Repeated THC male rats consumed more food than their PG-treated control group, without significant bodyweight differences. Adolescent THC did not alter oxycodone self-administration in either sex but increased fentanyl self-administration in females.Conclusions and implicationsRepeated THC vapour inhalation in adolescent rats has lasting consequences observable in adulthood

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

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. 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. 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. 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. The present study demonstrates that heroin vapor inhalation during adolescence produces behavioral and physiological consequences in rats that persist well into adulthood