Biology subjects

Taffe, M. A.

Publications and source records attributed to Taffe, M. A..

35 records · Page 2Linked to original sources

bioRxiv2020

Antinociceptive, hypothermic, and appetitive effects of vaped and injected Δ9-tetrahydrocannabinol (THC) in rats: exposure and dose-effect comparisons by strain and sex

Advances in drug vapor exposure systems utilizing e-cigarette technology have enabled evaluation of {Delta}-9-tetrahydrocannabinol (THC) vapor effects in laboratory animals. The purpose of this study was to 1) establish a range of parameters of THC vapor exposure in rats sufficient to produce a behavioral dose-effect curve in a battery of tasks sensitive to THC; 2) to investigate sex differences in the effects of THC vapor exposure and THC injection (intraperitoneal, IP) on these behaviors in two strains of outbred rats. Male and female Wistar and Sprague Dawley rats (N=22, 5-6/group) received THC via IP injection (1-20 mg/kg) and passive exposure to THC vapor (200 mg/ml; 5 conditions) in a within subject design. The effects of vaped and injected THC were determined using the tail-withdrawal assay for nociception, rectal measurements of body temperature, and progressive-ratio responding for food pellets. Plasma THC concentrations were assessed after 10 mg/kg IP THC or THC vapor. THC produced dose and exposure-dependent antinociception and hypothermia. THC vapor produced inverted U-shaped effects in motivation to obtain food, while IP THC reduced PR breakpoints. Plasma THC concentrations were higher after 10 mg/kg IP THC (152 ng/mL) compared to the highest vapor exposure condition tested (38 ng/mL). THC vapor exposure produces reliable, dose-orderly effects on nociception, body temperature, and food-maintained behavior that is comparable to effects observed after IP THC. There are considerable differences between the time course of behavioral outcomes produced by these two different routes of administration.

animal behavior and cognition↗

bioRxiv2020

A vapor inhalation 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. Effects in 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{degrees}C water bath, bi-phasically altered activity, and increased temperature in male and female rats. Inhalation of heroin 50 mg/mL for 15 minutes produced significant effects, as the lower bound on efficacy, whereas inhalation of heroin 100 mg/mL for 30 minutes 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 minutes. This technique may be useful to assess the health consequences of inhaled heroin and other opioid drugs.

pharmacology and toxicology↗

bioRxiv2020

Explication of CB1 receptor contributions to the hypothermic effects of Δ9-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats

The use of Δ9-tetrahydrocannabinol (THC) by inhalation using e-cigarette technology grows increasingly popular for medical and recreational purposes. This has led to development of e-cigarette based techniques to study the delivery of THC by inhalation in laboratory rodents. Inhaled THC reliably produces hypothermic and antinociceptive effects in rats, similar to effects of parenteral injection of THC. This study was conducted to determine the extent to which the hypothermic response depends on interactions with the CB1 receptor, using pharmacological antagonist (SR141716, AM-251) approaches. Groups of rats were implanted with radiotelemetry devices capable of reporting activity and body temperature, which were assessed after THC inhalation or injection. SR141716 (4 mg/kg, i.p.) blocked or attenuated antinociceptive effects of acute THC inhalation in male and female rats. SR141716 was unable to block the initial hypothermia caused by THC inhalation, but temperature was restored to normal more quickly. Alterations in antagonist pre-treatment time, dose and the use of a rat strain with less sensitivity to THC-induced hypothermia did not change this pattern. Pre-treatment with SR141716 (4 mg/kg, i.p.) blocked hypothermia induced by i.v. THC and reversed hypothermia when administered 45 or 90 minutes after THC (i.p.). SR141716 and AM-251 (4 mg/kg, i.p.) sped recovery from, but did not block, hypothermia caused by vapor THC in female rats made tolerant by prior repeated THC vapor inhalation. The CB2 antagonist AM-630, had no effect. These results suggest that hypothermia consequent to THC inhalation is induced by other mechanisms in addition to CB1 receptor activation.Competing Interest StatementAuthor SAV has consulted for La Jolla Alcohol Research, Inc., the vendor that supplies our vapor inhalation equipment.AbbreviationsPGpropylene glycol;SR141716 (SR)5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide;AM-251N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide;AM-6306-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone;THCΔ9-tetrahydrocannabinol;View Full Text

pharmacology and toxicology↗

bioRxiv2020

Self-administration of heroin by vapor inhalation in female Wistar rats

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 hours 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.

pharmacology and toxicology↗

bioRxiv2019

Vapor inhalation of cannabidiol (CBD) in rats

Cannabidiol (CBD) is increasingly available in e-cigarette liquids and other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. The objective of this study was 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. Blood samples were collected from rats exposed for 30 minutes 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. 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 this was partially attenuated by 5-HT1a receptor blockade. Nicotine (30 mg/mL) inhalation enhanced the effect of CBD. CBD inhalation had no effect on anti-nociception alone or in combination with {Delta}9-tetrahydrocannabinol inhalation. 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.

pharmacology and toxicology↗

bioRxiv2019

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

A novel inhalation system based on e-cigarette technology has been recently shown to produce hypothermic and anti-nociceptive effects of {Delta}9-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. 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, 100, 200 mg/mL of PG) for 30 or 40 minutes. Additional studies evaluated plasma THC levels and anti-nociceptive effects after THC inhalation as well as the thermoregulatory effect of intraperitoneal injection of THC (5-30 mg/kg). Hypothermic effects of inhaled THC was more pronounced in SD rats however 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 even more pronounced 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 anti-nociceptive 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 the hypothermia induced by THC following inhalation conditions that produced identical plasma THC and anti-nociception. Thus strain differences were not due to differential THC delivery via vapor inhalation.

pharmacology and toxicology↗

bioRxiv2018

Repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence: Sex differences inacute thermoregulatory tolerance and in feeding during adulthood

Adolescents are regularly exposed to {Delta}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 behavior and lasting tolerance in response to THC. Male and female rats inhaled THC vapor, or that from the propylene glycol (PG) vehicle, twice daily for 30 minutes from postnatal day (PND) 35-39 and PND 42-45 using an e-cigarette system. Thermoregulatory responses to vapor 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 four 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. Female, 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 with THC greater potency exhibited in females. Repeated-THC male rats consumed more food than their PG treated control group, in the absence of a significant bodyweight difference. Adolescent THC did not alter oxycodone self-administration in either sex, but increased fentanyl self-administration in females. Repeated THC vapor inhalation in adolescent rats results in lasting consequences observable in adulthood.\n\nAbbreviationsPG, propylene glycol; THC, {Delta}9tetrahydrocannabinol;

pharmacology and toxicology↗

bioRxiv2018

Effects of Nicotine and THC Vapor Inhalation Administered by An Electronic Nicotine Delivery System (ENDS) in Male Rats

BackgroundElectronic nicotine delivery systems (ENDS, e-cigarettes) are increasingly used for the self-administration of nicotine by various human populations, including previously nonsmoking adolescents. Studies in preclinical models are necessary to evaluate health impacts of ENDS including the development of nicotine addiction, effects of ENDS vehicles, flavorants and co-administered psychoactive substances such as {triangleup}9-tetrahydrocannabinol (THC). This study was conducted to validate a rat model useful for the study of nicotine effects delivered by inhalation of vapor created by ENDS. MethodsMale Sprague-Dawley rats (N=8) were prepared with radiotelemetry devices for the reporting of temperature and activity. Experiments subjected rats to inhalation of vapor generated by an electronic nicotine delivery system (ENDS) adapted for rodents. Inhalation conditions included vapor generated by the propylene glycol (PG) vehicle, Nicotine (1, 10, 30 mg/mL in the PG) and THC (12.5, 25 mg/mL). ResultsNicotine inhalation increased spontaneous locomotion and decreased body temperature of rats. Pretreatment with the nicotinic cholinergic receptor antagonist mecamylamine (2 mg/kg, i.p.) prevented stimulant effects of nicotine vapor inhalation and attenuated the hypothermic response. Combined inhalation of nicotine and THC resulted in apparently independent effects which were either additive (hypothermia) or opposed (activity). ConclusionsThese studies provide evidence that ENDS delivery of nicotine via inhalation results in nicotine-typical effects on spontaneous locomotion and thermoregulation in male rats. Effects were blocked by a nicotinic antagonist, demonstrating mechanistic specificity. This system will therefore support additional studies of the contribution of atomizer/wick design, vehicle constituents and/or flavorants to the effects of nicotine administered by ENDS.

pharmacology and toxicology↗

bioRxiv2017

Δ9-tetrahydrocannabinol Attenuates Oxycodone Self-Administration Under Extended Access Conditions

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis (\"medical marijuana\") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if {Delta}9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone.\n\nMale rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.

neuroscience↗

bioRxiv2017

Prophylactic vaccination protects against the development of oxycodone addiction

Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 minutes after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1-2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.

neuroscience↗

bioRxiv2017

Binge-like Acquisition of α-pyrrolidinopentiophenone (α-PVP) Self-Administration in Female Rats

The synthetic cathinone -pyrrolidinopentiophenone (-PVP) has been associated with violent and/or bizarre public behavior in users. Association of such behavior with extended binges of drug use motivates additional investigation, particularly since a prior study found that half of male rats experience a binge of exceptionally high intake, followed by sustained lower levels of self-administration during the acquisition of intravenous self-administration (IVSA) of a closely related drug, 3,4-methylenedioxypyrovalerone. The binge-like acquisition pattern appeared to be novel for rat IVSA, thus the present study was designed to determine if this effect generalizes to IVSA of -PVP in female rats. Female Wistar rats were trained in IVSA of -PVP (0.05 mg/kg/inf) in experimental chambers that contained an activity wheel. Groups of animals were trained with the wheels fixed (No-Wheel group), fixed for the initial 5 days of acquisition or free to move throughout acquisition (Wheel group). The groups were next subjected to a wheel-access switch and then all animals to dose-substitution (0.0125-0.3 mg/kg/inf) with the wheels alternately fixed and free to move. Approximately half of the rats initiated their IVSA pattern with a binge day of exceptionally high levels of drug intake, independent of wheel access condition. Wheel activity was much lower in the No-Wheel group in the wheel switch post-acquisition. Dose-effect curves were similar for wheel-access training groups, for binge/no binge phenotypic subgroups and were not altered with wheel access during the dose-substitution. This confirms the high reinforcer efficacy of -PVP in female rats and the accompanying devaluation of wheel activity as a naturalistic reward.

neuroscience↗

bioRxiv2017

Withdrawal-induced escalated oxycodone self-administration is mediated by kappa opioid receptor function

BackgroundPrescription opioid addiction is a significant health problem characterized by compulsive drug seeking, withdrawal and chronic relapse. We investigated the neurobiological consequences of escalation of prescription opioid use using extended access to intravenous oxycodone self-administration in rats.\n\nMethodsMale Wistar rats acquired oxycodone self-administration (0.15 mg/kg/infusion, i.v.) in 1h or 12h access sessions. Electrophysiological and immunohistochemical studies investigated the effects of oxycodone self-administration on kappa opioid receptor (KOR) regulation of GABAergic signaling and dynorphin expression in the central nucleus of the amygdala (CeA).\n\nResultsRats given 12h access to oxycodone for 5 sessions/week (LgA) escalated their responding more than rats given 1h oxycodone (ShA) or 12h saline access. Slowed escalation of responding was found in rats given 12h access for 7 sessions/week (LgA-7day) or rats pretreated with the KOR antagonist nor-binaltorphamine dihydrochloride (norBNI) before LgA (norBNI+LgA). The KOR agonist U-50488 decreased GABA release in CeA neurons of all groups except LgA. norBNI increased GABA release in control group neurons, suggesting tonic KOR activity. This activity was abolished in ShA, norBNI+LgA, and LgA-7day rat neurons, consistent with decreased CeA dynorphin immunoreactivity observed in LgA-7day rats. However, norBNI effects were reversed (decreased CeA GABA release) in LgA rat neurons.\n\nConclusionsThe experience of intermittent extended withdrawal periods accelerates the escalation of oxycodone self-administration and causes greater dysregulation of CeA KOR-mediated GABAergic signaling. A KOR agonist/antagonist switch effect seen with other drugs of abuse was absent, which suggests that oxycodone-induced neuroadaptations may be distinct from those resulting from other drugs of abuse.

neuroscience↗

bioRxiv2017

Repeated vapor inhalation of Δ9-tetrahydrocannabinol induces tolerance to hypothermia in female rats

RationaleA reduced effect of a given dose of {Delta}9-tetrahydrocannabinol (THC) emerges with repeated exposure to the drug. This tolerance can vary depending on THC dose, exposure chronicity and the behavioral or physiological measure of interest. A novel THC inhalation system based on e-cigarette technology has been recently shown to produce the hypothermic and antinociceptive effects of THC in rats.\n\nObjectiveTo determine if tolerance to these effects can be produced with repeated vapor inhalation.\n\nMethodsGroups of male and female Wistar rats were exposed to 30 minutes of inhalation of the propylene glycol (PG) vehicle or THC (200 mg/mL in PG) two or three times per day for four days. Rectal temperature changes and nociception were assessed after the first exposure on the first and fourth days of repeated inhalation.\n\nResultsFemale, but not male, rats developed tolerance to the hypothermic and antinociceptive effects of THC after four days of twice-daily THC vapor inhalation. Thrice daily inhalation for four days resulted in tolerance in both male and female rats. The plasma THC levels reached after a 30 minute inhalation session did not differ between the male and female rats.\n\nConclusionsRepeated daily THC inhalation induces tolerance in female and male rats, providing further validation of the vapor inhalation method for preclinical studies.\n\nAbbreviationsPG, propylene glycol; THC; {Delta}9tetrahydrocannabinol;

neuroscience↗

bioRxiv2017

Locomotor and Reinforcing Effects of Pentedrone, Pentylone and Methylone in Rats

The broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the -alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), -pyrrolidinopentiophenone (-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025-0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for -PVP and -pyrrolidinohexiophenone (-PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5-10.0 mg/kg), pentedrone (0.5-10.0 mg/kg) or mephedrone (0.5-10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 {degrees}C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4-0.8 {degrees}C) was observed for four hours after 10 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than -PVP or -PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone.

neuroscience↗

bioRxiv2017

Effects Of Δ9-THC And Cannabidiol Vapor Inhalation In Male And Female Rats

Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection, however most human use is via smoke inhalation and, increasingly, vapor inhalation. The aim of this study was to compare thermoregulatory and locomotor responses to inhaled {Delta}9-tetrahydrocannabinol (THC), cannabidiol (CBD) and their combination using an e-cigarette based model in male and female rats.\n\nGroups of male and female Sprague-Dawley rats (N=8 per group) were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor (4 puffs/5 minutes) using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/ml) and CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 minutes). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation.\n\nTHC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity and anti-nociceptive responses to THC did not differ between the estrus and diestrus phases. CBD inhalation alone induced hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex.\n\nIn summary the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. Sex differences were subtle and mostly reflected in a more prolonged body temperature disruption in females.

pharmacology and toxicology↗

bioRxiv2017

Wheel running increases hyperthermia and mortality rate following 3,4-methylenedioxymethamphetamine (MDMA) in rats

Hyperthermic responses are commonly reported in cases of human medical emergency following recreational use of 3,4-methylenedioxymethamphetamine (MDMA, \"Ecstasy\"), but a precise determination of contributing environmental factors has been elusive given the relative scarcity of threatening and fatal reactions in humans. This study was conducted to determine if elevated physical activity contributes to hyperthermic responses to MDMA in a well controlled animal model. Unrestrained male Wistar rats were monitored with minimally-invasive radiotelemetry techniques following challenge with MDMA (1.0, 5.6 and 10.0 mg/kg, s.c.). Studies were conducted in low (23-25{degrees}C) and high (27{degrees}C) ambient temperature (TA), with and without access to an activity wheel. The study confirmed dose dependent effects on body temperature, chamber activity and wheel activity which were modified by different TA conditions. Increases in wheel and home chamber activity produced by 10 mg/kg MDMA increased the magnitude of hyperthermia under 27{degrees}C TA. Furthermore, greater subject mortality was observed in the wheel-access condition compared with the no-wheel condition. These data provide direct evidence that sustained physical activity increases the hyperthermic response to MDMA and that this is associated with increased lethality. This is the first direct experimental confirmation that increased physical activity may be a risk factor for adverse reactions to MDMA in human user populations.

pharmacology and toxicology↗

bioRxiv2017

High Ambient Temperature Facilitates The Acquisition Of 3,4-Methylenedioxymethamphetamine (MDMA) Self-Administration

RationaleMDMA alters body temperature in rats with a direction that depends on the ambient temperature (TA). The thermoregulatory effects of MDMA and TA may affect intravenous self-administration (IVSA) of MDMA but limited prior reports conflict.\n\nObjectiveTo determine how body temperature responses under high and low TA influence MDMA IVSA.\n\nMethodsMale Sprague-Dawley rats were trained to IVSA MDMA (1.0 mg/kg/infusion; 2-hr sessions; FR5 schedule of reinforcement) under TA 20{degrees}C or 30{degrees}C. Radiotelemetry transmitters recorded body temperature and activity during IVSA.\n\nResultsMDMA intake increased under both TA during acquisition, but to a greater extent in the 30{degrees}C group. The magnitude of hypothermia was initially equivalent between groups but diminished over training in the 30{degrees}C group. Within-session activity was initially lower in the 30{degrees} C group, but by the end of acquisition and maintenance, activity was similar for both groups. When TA conditions were swapped, the hot-trained group increased MDMA IVSA under 20 {degrees}C TA and a modest decrease in drug intake was observed in the cold-trained group under 30 {degrees}C TA. Subsequent non-contingent MDMA (1.0-5.0 mg/kg, i.v.) found that rats with higher MDMA IVSA rates showed blunted hypothermia compared with rats with lower IVSA levels; however, within-session activity did not differ by group. High TA increased intracranial self-stimulation thresholds in a different group of rats and MDMA reduced thresholds below baseline at low, but not high, TA.\n\nConclusionsHigh TA appears to enhance acquisition of MDMA IVSA through an aversive effect and not via thermoregulatory motivation.

pharmacology and toxicology↗