THC Self-administration Research Articles

Impact of early-life lead exposure on adult delta-9-tetrahydrocannabinol sensitivity in male and female C57BL6/J mice

Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (the main psychoactive component of which is delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3rd most widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. Here we establish a link between early life Pb exposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The study seeks to answer whether Pb exposure affects physiological/behavioral THC sensitivity (as measured by the cannabinoid-induced tetrad). It was hypothesized that Pb exposure would decrease THC sensitivity and that sex-dependent effects of Pb-exposure and THC would be observed. Interestingly, results showed that THC sensitivity was increased by Pb exposure, but only in female mice. Future research will fully explore the implications of these findings, namely how these effects impact THC self-administration and the mechanism(s) by which developmental Pb exposure produces these effects.

Pharmacokinetic and Pharmacodynamic Characterization of Tetrahydrocannabinol-Induced Cannabinoid Dependence After Chronic Passive Cannabis Smoke Exposure in Rats.

Introduction: Cannabis is the most widely used illicit drug in the US, and cannabis use among young adults continues to rise. Previous studies have shown that chronic administration of delta 9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, induces dependence in animal models. Because smoking is the most frequent route of THC self-administration, it is critical to investigate the effects of cannabis smoke inhalation. The goal of the current study was to develop a rat model to characterize the pharmacokinetics (PKs) of THC after cannabis smoke inhalation, and to determine if chronic cannabis smoke inhalation leads to the development of cannabis dependence. Materials and Methods: For the PK study, male Wistar rats were administered THC intravenously (1 mg/kg) or exposed to smoke from 5 or 10 sequentially smoked cannabis cigarettes (5.3% THC) in an automated smoking machine. Plasma samples were collected from 10 min to 10 hours post smoke exposure (or intravenous administration) and analyzed using liquid chromatography-mass spectrometry to characterize the PK of THC. A three-compartment PK model was used to characterize the PKs. In a separate study, three groups of male Wistar rats were trained in an intracranial self-stimulation (ICSS) procedure, and exposed to smoke from burning 5 or 10 cannabis cigarettes (or clean air control conditions), 5 days/week for 4 weeks. Discussion and Conclusions: Across exposure days, the change from baseline in ICSS thresholds for cannabis smoke-exposed groups was significantly lower and response latencies were significantly faster in the cannabis smoke-exposed groups compared to controls, suggesting that chronic cannabis smoke exposure has rewarding properties. Acute administration of the CB1 receptor antagonist rimonabant (0.3, 1.0, 3.0 mg/kg) induced a dose-dependent increase in ICSS thresholds in the smoke-exposed rats, suggestive of dependence and withdrawal. Finally, an effect compartment PK-pharmacodynamic model was used to describe the relationship between THC concentrations and changes in ICSS thresholds after cannabis smoke exposure.

Self-administration of edible Δ9-tetrahydrocannabinol and associated behavioral effects in mice

BackgroundWith increasing access to legal cannabis across the globe, it is imperative to more closely study its behavioral and physiological effects. Furthermore, with the proliferation of cannabis use, modes of consumption are changing, with edible formulations becoming increasingly popular. Nevertheless, there are relatively few animal models of self-administration of the primary psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), and almost all incorporate routes of administration other than those used by humans. The aim of the current study was to develop a model of edible THC self-administration and assess its impact on CB1 receptor-mediated behaviors in female and male mice. MethodsMice were given limited access to a palatable dough which occasionally contained THC in doses ranging from 1 to 10 mg/kg. Following dough consumption, mice were assessed for home cage locomotor activity, body temperature, or analgesia. Locomotor activity was also assessed in conjunction with the CB1 receptor antagonist SR141716A. ResultsDough was well-consumed, but consumption decreased at the highest THC concentrations. Edible THC produced dose-dependent decreases in locomotor activity and body temperature in both sexes, and these effects were more pronounced in male mice. Hypolocomotion induced by edible THC was attenuated by SR141716A, indicating mediation by CB1 receptor activation. ConclusionsIn contrast to other cannabinoid self-administration models, edible THC is relatively low in stress and uses a route of administration analogous to one used by humans. Potential applications include chronic THC self-administration, determining THC reward/reinforcement, and investigating consequences of oral THC use.

The effects of cannabidiol (CBD) on Δ⁹-tetrahydrocannabinol (THC) self-administration in male and female Long-Evans rats.

Despite widespread cannabis use in humans, few rodent models exist demonstrating significant Δ⁹-tetrahydrocannabinol (THC) self-administration, possibly due to THC's co-occurring aversive effects, which impact drug reinforcement. Cannabis contains a number of phytocannabinoids in addition to THC, one of which, cannabidiol (CBD), has been reported to antagonize some of the aversive effects of THC. Given such effects of CBD, it is possible that it might influence THC intravenous self-administration in rodents. Accordingly, male and female Long-Evans rats were trained to self-administer THC over a 3-week period and then were assessed for the effects of CBD on responding for THC at 1:1 and 1:10 dose ratios or for the establishment of cocaine self-administration (as a positive control for drug self-administration). Consistent with previous research, THC self-administration was modest and only evident in a subset of animals (and unaffected by sex). Cocaine self-administration was high and evident in the majority of animals tested, indicating that the design was sensitive to drug reinforcement. There was no effect of CBD pretreatment on THC intravenous self-administration at any CBD:THC dose ratio. Future developments of animal models of THC self-administration and the examination of factors that affect its display remain important to establish procedures designed to assess the basis for and treatment of cannabis use and abuse. (PsycINFO Database Record

Behavioral Determinants of Cannabinoid Self-Administration in Old World Monkeys.

Reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary active ingredient in marijuana, as assessed with self-administration (SA), has only been established in New World primates (squirrel monkeys). The objective of this study was to investigate some experimental factors that may enhance intravenous SA of THC and the cannabinoid receptor (CBR) agonist CP 55 940 in Old World monkeys (rhesus and cynomolgus), a species that has been used extensively in biomedical research. In one experiment, male rhesus monkeys (N=9) were trained to respond under a fixed-ratio 10 schedule of food presentation. The effects of CP 55 940 (1.0-10 μg/kg, i.v.) and THC (3.0-300 μg/kg, i.v.) on food-maintained responding and body temperature were determined in these subjects prior to giving them access to self-administer each drug. Both drugs dose-dependently decreased food-maintained responding. CP 55 940 (0.001-3.0 μg/kg) functioned as a reinforcer in three monkeys, whereas THC (0.01-10 μg/kg) did not have reinforcing effects in any subject. CP 55 940 was least potent to decrease food-maintained responding in the monkeys in which CP 55 940 functioned as a reinforcer. Next, THC was administered daily to monkeys until tolerance developed to rate-decreasing effects. When THC SA was reexamined, it functioned as a reinforcer in three monkeys. In a group of cocaine-experienced male cynomolgus monkeys (N=4), THC SA was examined under a second-order schedule of reinforcement; THC functioned as reinforcer in two monkeys. These data suggest that SA of CBR agonists may be relatively independent of their rate-decreasing effects in Old World monkeys. Understanding individual differences in vulnerability to THC SA may lead to novel treatment strategies for marijuana abuse.

Contraception continuation among female exotic dancers seeking mobile reproductive health services concurrent with syringe exchange

s / Drug and Alcohol Dependence 140 (2014) e86–e168 e135 Contraception continuation among female exotic dancers seeking mobile reproductive health services concurrent with syringe exchange Caitlin E. Martin1, Mishka Terplan2, J. Han3, P. Chaulk4, C. Serio-Chapman3 1 Johns Hopkins Schools of Medicine and Public Health, Baltimore, MD, United States 2 Departments of Obstetrics, Gynecology, and Reproductive Sciences & Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States 3 Community Risk Reduction Services, Baltimore City Health Department, Baltimore, MD, United States 4 Bureau of HIV/STD Services, Baltimore City Health Department, Baltimore, MD, United States Aims: Female exotic dancers are an understudied population with a high prevalence of drug and alcohol use, risk factors for transactional sex and inconsistent condom use. In 2009, the Baltimore City Health Department expanded their mobile syringe exchange program to include reproductive health services in the “Red Light” district. The objective of this study was to describe depot medroxyprogesterone acetate (Depo-Provera) continuation patterns among female exotic dancers seeking these mobile health services. Methods: We performed a retrospective analysis of 75 clients who initiated Depo-Provera at a mobile health clinic attached to a syringe exchange from November 2009 to August 2012. Demographics, Depo-Provera uptake and continuation over 12 months were assessedby chart review. Characteristics between clientswho continued Depo-Provera at 3 months and those who did not were compared using chi-square and t-tests. Results: Seventy-two percent (N=52) of clients were African American, and 62% (N=42) were 24 years or younger. At 3 months, 36% (N=25) continued Depo-Provera. Clients who were Caucasian (p=0.03) and received other reproductive health services (p<0.01) were more likely to continue. At 6 and 12 months, 29% and 7% of all clients who initiated Depo-Provera continued, while successive continuation rates for those receiving the previous injection were higher at 54% and 63%. Conclusions: Continuation of Depo-Provera among female exotic dancers is similar to that of the general population, with low overall but higher successive continuation after 3 months. Our study illustrates that integrating mobile reproductive health services into a needle exchange program can help fulfill the unique health needs of this high-risk population. Financial support: None. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.383 9-tetrahydrocannabinol does not substitute in rats trained to self-administer WIN55212-2 Julie A. Marusich, T. Lefever, J. Wiley Discovery & Analytical Sciences, RTI International, Research Triangle Park, NC, United States Aims: Although THC i.v. self-administration has been demonstrated in nonhuman primates, establishing THC selfadministration in rodents has proven difficult. In contrast, self-administration of a synthetic cannabinoid, WIN55212-2 (WIN), in rats has been reported. The purpose of this study was to examine if rats trained to self-administer WIN would also self-administer THC. Methods: Male Long-Evans rats were trained to self-administer cocaine (COC; 0.03mg/kg/infusion) or WIN (0.01mg/kg/infusion) through autoshaping. Rats were thenmaintained on a fixed ratio 3, with 3 priming infusions given at the beginning of each 3h session. Dose-effect curves of the training drugs were assessed followed by pretreatment with rimonabant. Dose–effect curves were then determined for WIN in the COC group, and THC in the WIN group. Results: Rats self-administered COC and WIN at levels significantly above vehicle. Rimonabant decreased responding for both drugs. When WIN was substituted for COC, rats did not acquire self-administration of WIN. Similarly when THC was substituted for WIN, rats did not acquire self-administration of THC. Conclusions: Themethodsusedhereproduced similar amounts of WIN intake compared to previous studies in rats; however, THC did not substitute for WIN. Between subject variability was high for both WIN and THC. Given the typical within class substitution observed in previous self-administration studies, these results suggest that the reinforcing effects of WIN and THC differ in rats. In previous research, establishing self-administration of other drug classes (e.g. stimulants) has also been largely unsuccessful in producing THC self-administration. Similarly, in the present study rats with a history of COC self-administration did not self-administer WIN, suggesting that exposure to a more reinforcing drug may decrease the likelihood of self-administration of cannabinoids, or that substitution across drug classes is not a reliable method for assessing abuse liability for cannabinoids. Financial support: RTI International internal research and development funds and NIDA Grants DA-03672 and DA-031988. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.384 Binge alcohol consumption in emerging adults: Altered anterior cingulate cortical thickness is associated with alcohol use consequences Yasmin Mashhoon1,3,4, C. Czerkawski2, D.J. Crowley1,2,4, J.E. Cohen-Gilbert1,2,4, J.T. Sneider1,2,4, M.M. Silveri1,2,4 1 McLean Imaging Center, McLean Hospital/HMS, Belmont, MA, United States 2 Neurodevelopmental Lab, McLean Hospital/HMS, Belmont, MA, United States 3 Behavioral Psychopharmacology Research Lab, McLean Hospital/HMS, Belmont, MA, United States 4 Psychiatry, Harvard Medical School, Boston, MA,

Cannabis reward: biased towards the fairer sex?

In contrast to drugs such as alcohol, amphetamine and cocaine, cannabis use in humans has proven difficult to model in laboratory animals. Recent breakthrough discoveries of intravenous THC self-administration in rhesus monkeys and self-administration of the synthetic cannabinoid agonist WIN 55,212-2 in rats have allowed new studies of the genetic, neural and environmental determinants of cannabis use. In the present issue of BJP, Fattore and colleagues further demonstrate genetic (strain) differences in WIN 55,212-2 self-administration in rats, with Long Evans (LE) and Lister Hooded (LH), but not Sprague-Dawley, rats self-administering this drug. They then show that female LE and LH rats self-administer more WIN 55,212-2 than male rats. Ovariectomy abolished this sex difference, suggesting a permissive role for oestrogen in cannabis reward. This accompanying Commentary reviews recent progress in animal models of cannabis use and highlights the role of genetic, developmental and endocrine factors in driving cannabis use and dependence.

Neurochemical and behavioural correlates of the interaction between amphetamine and Δ9-tetrahydrocannabinol in the rat

A single dose of Δ 9-tetrahydrocannabinol (THC) (10 or 100 mg/kg) was administered via stomach gavage following the single injection intraperitoneally of an acute dose of amphetamine (1 or 3 mg/kg) in the rat. The THC effects, which included a reduction in spontaneous locomotor activity, the development of prostration, and circling behaviour, were antagonized in a dose-dependent manner by pretreatment with amphetamine. Although no change in the endogenous levels of noradrenaline, dopamine and serotonin in hypothalamus, hippocampus, caudate-putamen or the rest of brain occurred with THC, it appears that THC may have increased dopamine turnover in the brain. The dose-dependent amphetamine antagonism to the behavioural effects of THC was paralleled by a dose-related increase in brain dopamine concentration. This elevation in dopamine levels may be instrumental in triggering the neuronal events responsible for the amphetamine antagonism of the actions of THC. The subtle interaction of THC with brain dopamine neural systems may be involved in the reinforcing properties of the self-administration of THC.