Metabolic mapping of the time-dependent effects of Δ9-tetrahydrocannabinol administration in the rat

RATIONALE: Delta(9)-Tetrahydrocannabinol (THC) has a long duration of action. Studies have shown that effects on some behavioral endpoints can persist for as long as 24 h after exposure, but the neural substrates underlying these long-lasting effects have not yet been determined. OBJECTIVES: The purpose of the present study was to identify the neuroanatomical substrates associated with the temporal course of the effects of the acute administration of moderate to high doses of THC using the quantitative autoradiographic 2-[(14)C]deoxyglucose (2DG) method. METHODS: Male Sprague-Dawley rats ( n=4-5 per group) were administered THC (0.0, 2.5 or 10 mg/kg, intraperitoneally), and the 2DG procedure was initiated 15 min, 6 h, or 24 h after treatment. To establish the behavioral profile of THC administration, locomotor activity and core body temperature were measured at corresponding time points. RESULTS: The administration of THC produced widespread dose-dependent reductions in rates of cerebral metabolism when the 2DG method was applied 15 min after treatment. A more limited set of structures was affected when the 2DG method was applied 6 h after THC administration, closely paralleling the effects of THC on locomotor activity and core body temperature. However, 24 h after administration, glucose utilization remained depressed within mesolimbic and amygdalar regions. CONCLUSIONS: These data demonstrate that the functional consequences of acute administration of THC follow a distinct temporal course that is regionally specific. That functional activity remains depressed in areas involved in the processing of motivational and emotional information suggests that behaviors subserved by these structures (e.g. anxiety, stress, and reward) may remain altered for as long as 24 h after a single exposure to THC.     

Influence of δ 9-tetrahydrocannabinol on partial reinforcement effects

Two experiments were performed with rats trained with either continuous reinforcement (food) or random 50% partial reinforcement for running in a straight alley. Half the rats were trained with daily injections of 0.5 mg/kg ⁹-tetrahydrocannabinol (THC) and half with vehicle injections, all animals being extinguished with vehicle injections in Expt. 1 and with THC injections in Expt. 2. The partial reinforcement acquisition effect was abolished by THC during training; the partial reinforcement extinction effect was abolished by THC either during training or during extinction. In these respects THC resembles amylobarbitone and alcohol.     

Naltrexone does not attenuate the effects of intravenous Δ9-tetrahydrocannabinol in healthy humans

Although a wealth of preclinical evidence indicates an interplay between the μ-opioid (MOR) and cannabinoid 1 receptor (CB1R) systems, the precise nature of the cross modulation in humans is unclear. The objective of this study was to evaluate the effects of pretreatment with the MOR antagonist, naltrexone, on the subjective, behavioural and cognitive effects of the CB1R agonist, Δ9-tetrahydrocannabinol (THC), in healthy human subjects. Healthy human subjects, screened carefully for any medical or psychiatric illness, were administered either placebo or active naltrexone (25 mg) orally on each test day, followed 45 min later by placebo and 165 min later by active i.v. THC (0.025 mg/kg) in a randomized, fixed-order, double-blind manner. Subjective, behavioural and cognitive effects were assessed before and at several points after each drug administration. THC produced expected effects, including euphoria, anxiety, transient perceptual alterations, transient psychotomimetic effects and cognitive impairments. However, naltrexone did not produce any effects alone, nor did it attenuate any of THC's effects. Thus, in healthy human subjects who use cannabis intermittently, MOR antagonism does not modulate the common acute subjective, behavioural and cognitive effects of THC.     

Behavioral and biochemical effects of chronic Δ 9-tetrahydrocannabinol in rats

In an attempt to identify the possible role of brain biogenic amines and adrenocorticotrophic hormone (ACTH) release in the behavioral and physiological effects of ⁹-tetrahydrocannabinol (THC), the time course of drug action was studied. THC (20 mg/kg) was administered daily for 1, 4, 21, or 42 days to Sprague-Dawley rats that were examined for changes in body temperature, food and water intake, rearing and walking activity, compulsive motor routines, and mouse killing. Four hours after the last THC administration the animals were killed and concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in telencephalon, striatum, diencephalon, mesencephalon, and cerebellum, corticosterone in blood plasma, and epinephrine in the adrenal glands were determined. After initial THC administrations a marked hypothermia, anorexia, adipsia, and depression in locomotion were observed, all of which disappeared within 1 week of treatment. The reduced growth rate and decreased rearing activity persisted throughout the 42-day THC treatment. Compulsive motor routines and mouse killing were induced in a significant proportion of rats treated with THC for more than 3 weeks. Level of 5-HT was increased by 16–37% in all brain regions of rats given THC for 21–42 days. Plasma corticosterone was greatly increased after a single THC injection and remained elevated, to a lesser degree, for 42 days. Adrenal epinephrine was decreased after a single THC administration and increased after 42 days. None of the currently investigated biochemical changes correlated with the marked behavioral and physiological changes after initial THC administration to which tolerance develops. The syndrome of compulsive motor routines after prolonged THC treatment might be mediated by elevated brain 5-HT activity.     

Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Δ9-tetrahydrocannabinol

Rationale Cannabis use may precipitate schizophrenia especially if the individual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. Objectives The aim of this study was to investigate whether dysfunction in the Nrg1 gene modulates the behavioural effects of Δ⁹-tetrahydrocannabinol (THC), the major psychotropic component of cannabis. Materials and methods Heterozygous Nrg1 transmembrane-domain knockout mice (Nrg1 HET) were treated with acute THC (0, 5 or 10 mg/kg i.p.) 30 min before being tested using open field (OF), hole board (HB), light-dark (LD), elevated plus maze (EPM), social interaction (SI) and prepulse inhibition (PPI) tests. Results Nrg1 HET mice showed differences in baseline behaviour with regard to locomotor activity, exploration and anxiety. More importantly, they were more sensitive to the locomotor suppressant actions of THC compared to wild type-like (WT) mice. In addition, Nrg1 HET mice expressed a greater THC-induced enhancement in % PPI than WT mice. The effects of THC on anxiety-related behaviour were task-dependent, with Nrg1 HET mice being more susceptible than WT mice to the anxiogenic effects of THC in LD, but not in the EPM, SI and OF tests. Conclusions Nrg1 HET mice were more sensitive to the acute effects of THC in an array of different behaviours including those that model symptoms of schizophrenia. It appears that variation in the schizophrenia-related neuregulin 1 gene alters the sensitivity to the behavioural effects of cannabinoids.     

Effect of The effects of Δ 9-tetrahydrocannabinol on the metabolism of norepinephrine in rat brain on the morphine-induced hyperactivity of mice

The effect of ⁹-tetrahydrocannabinol (THC) on the locomotor activity-stimulating action of morphine has been investigated in mice. THC (10 mg/kg) has been found to potentiate morphineinduced hyperactivity. On the other hand, the stimulating action of morphine on motor activity strongly diminished in mice rendered tolerant by the implantation of a morphine pellet. The pretreatment of morphine-tolerant mice with the same dose of THC did not change the effect of morphine on the motor activity. These results suggest that tolerance also developed to the potentiating action of THC on morphine-induced hyperactivity during the development of tolerance to this action of morphine.     

Does the brain noradrenaline network mediate the effects of the CO2 challenge?

The inhalation of carbon dioxide (CO2) is commonly used in patients and volunteers as a means of producing anxiety or panic. It is generally believed that patients with panic disorder are more vulnerable to the effects of CO2 than patients with other anxiety disorders or healthy volunteers and there is speculation and debate as to the mechanism for this apparent sensitivity. Recent work from our group has shown that a single inhalation of 35% CO2 activates the hypothalamic-pituitary-adrenocortical (HPA) axis, increases blood pressure (BP) and increases subjective fear responses in healthy volunteers. Correlation analyses reveal a relationship between the changes in BP and the cortisol increase. These findings led us to postulate that a common mechanism may mediate these and the subjective responses to inhalation of CO2. We propose that the noradrenergic system, particularly the locus coeruleus (LC), but including the A1 and A2 cell groups, may be a key mediator of these responses. This article examines the evidence and discusses the results of studies from our laboratory in relation to a neuroanatomical model centring on the LC.     

Effects of 20?mg oral Δ9-tetrahydrocannabinol on the olfactory function of healthy volunteers

AimsOlfactory loss impairs the patient''s quality of life. In individualized therapies, olfactory drug effects gain clinical importance. Molecular evidence suggests that among drugs with potential olfactory effects is Δ⁹-tetrahydrocannabinol (THC), which is approved for several indications, including neuropathic pain or analgesia in cancer patients. The present study aimed at assessing the olfactory effects of THC to be expected during analgesic treatment.MethodsThe effects of 20 mg oral THC on olfaction were assessed in a placebo-controlled, randomized cross-over study in healthy volunteers. Using an established olfactory test (Sniffin'' Sticks), olfactory thresholds, odour discrimination and odour identification were assessed in 15 subjects at baseline and 2 h after THC administration.ResultsΔ⁹-Tetrahydrocannabinol impaired the performance of subjects (n = 15) in the olfactory test. Specifically, olfactory thresholds were increased and odour discrimination performance was reduced. This resulted in a significant drop in composite threshold, discrimination, identification (TDI) olfactory score by 5.5 points (from 37.7 ± 4.2 to 32.2 ± 5.6, 95% confidence interval for differences THC vs. placebo, −7.8 to −2.0, P = 0.003), which is known to be a subjectively perceptible impairment of olfactory function.ConclusionsConsidering the resurgence of THC in medical use for several pathological conditions, the present results indicate that THC-based analgesics may be accompanied by subjectively noticeable reductions in olfactory acuity. In particular, for patients relying on their sense of smell, this might be relevant information for personalized therapy strategies.     

EEG spectral analysis for the evaluation of the central effects of δ6-tetrahydrocannabinol in rabbits

The effects of ⁶-THC on the frequency spectrum of the hippocampal EEG were examined with the assistance of an electronic integrator. Six rabbits bearing chronically implanted cortical and hippocampal electrodes were dosed intravenously with ⁶-THC (2.5% solution in polyethylene glycol 300; doses of 10, 50, 100, 250 and 1000 g/kg) once a week. A comparison of epochs of arousal in the pre-drug control and post-drug periods demonstrated that a dose as low as 50 g/kg produced a consistent, statistically significant diminution in power of the 7, 8, 9 Hz frequencies of the hippocampal EEG, with 8 Hz the most sensitive. Doses above 250 g/kg produced an overall decrease in the power spectrum from 7 to 27 Hz.Spectral analysis of the EEG offers a method which is sufficiently sensitive to reveal a central effect of ⁶-THC in rabbits at doses equivalent to the human threshold for psychic effects.Presented, in part, at the VIIIth International Congress of Electroencephalography and Clinical Neurophysiology, Marseilles, France, September 1–7, 1973.M. D. W. was supported by the Medical Research Council of Canada during the tenure of this work.The technical assistance of Mr. E. Deodati is gratefully acknowledged.     

Excitatory and depressant effects of Δ 9-tetrahydrocannabinol and cannabidiol on cortical evoked responses in the conscious rat

The influences of ⁹-tetrahydrocannabinol (THC) and cannabidiol on electrically evoked cortical potentials of conscious rats with chronically implanted electrodes were investigated. Specifically, the cannabinoids' effects on a transcallosal evoked response were compared with those of ethosuximide, phenytoin, and pentylenetetrazol. THC produced dose-related opposite effects: Low doses increased the amplitude of the response, whereas higher doses reduced the response. Other drugs that can cause or exacerbate seizures, i. e., phenytoin and pentylenetetrazol, also increased the amplitude of the cortical response. In contrast, cannabidiol, over a wide dosage range, caused only depression. Ethosuximide, like cannabidiol, elicited a depressant effect. The data indicate that under the conditions of the present investigation, cannabidiol shares electrophysiological properties with ethosuximide but not with phenytoin, and that cannabidiol is a relatively selective, centrally acting drug. In addition, our findings support the suggestion that augmentation of neurotransmission in central pathways may contribute to the convulsant actions of THC, and the cannabinoids' depressant effects may, at least partially, account for their anticonvulsant actions.     

Does olanzapine warrant clinical pharmacokinetic monitoring in schizophrenia?

Olanzapine, a second-generation antipsychotic, is a first-line agent in the treatment of schizophrenia. The objective of this review was to determine whether olanzapine warrants clinical pharmacokinetic monitoring in patients with schizophrenia, using a previously published decision-making algorithm. Although olanzapine is an appropriate therapy for patients with schizophrenia and is readily measurable in biological fluids, significant interindividual variation exists in its pharmacokinetics. While the duration of therapy is expected to be long term, the correlation of olanzapine concentrations with efficacy and toxicity has not been well defined in the literature. There are multiple tools readily available for the assessment of efficacy in schizophrenia, and clinical signs and symptoms can be used to monitor both for efficacy and for adverse effects. Therefore, routine monitoring of olanzapine concentrations does not appear warranted in the general schizophrenic population. However, patients in whom a change in olanzapine pharmacokinetics is expected--such as during addition or removal of an enzyme-inducing or -inhibiting drug, or during initiation or cessation of smoking--may benefit from clinical pharmacokinetic monitoring, as would patients in whom non-compliance is suspected. Patients who fail to respond to maximum recommended doses and those who experience adverse effects from therapeutic doses may also benefit from therapeutic drug monitoring, as they may have inherent variations in hepatic enzyme activity. However, in the population at large who suffer from schizophrenia, monitoring of olanzapine concentrations is not expected to offer additional benefit beyond appropriate clinical monitoring alone.     

The opioid antagonist naltrexone reduces the reinforcing effects of Δ9-tetrahydrocannabinol (THC) in squirrel monkeys

Rationale Experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. There is recent evidence for a role of the opioid system in the modulation of the reinforcing effects of synthetic cannabinoid CB1 receptor agonists in rodents. Since ⁹–tetrahydrocannabinol (THC), the natural psychoactive ingredient in marijuana, is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of THC in non-human primates.Objectives To study the effects of naltrexone, an opioid antagonist, on THC self-administration behavior in squirrel monkeys.Methods Monkeys pressed a lever for intravenous injections of THC under a ten-response, fixed-ratio (FR) schedule with a 60-s time-out after each injection. Effects of pre-session treatment with naltrexone (0.03–0.3 mg/kg intramuscularly, 15 min before session) for 5 consecutive days on self-administration of different doses of THC (2–8 µg/kg per injection) were studied.Results Self-administration responding for THC was significantly reduced by pretreatment with 0.1 mg/kg naltrexone for five consecutive daily sessions. Naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions.Conclusions Self-administration behavior under a fixed-ratio schedule of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone, but remained above saline self-administration levels. These findings demonstrate for the first time the modulation of the reinforcing effects of THC by an opioid antagonist in a non-human primate model of marijuana abuse.     

Tolerance to the effects of Δ 9-tetrahydrocannabinol in mice on intestinal motility,temperature and locomotor activity

The onset and duration of tolerance to three effects of ⁹-tetrahydrocannabinol ( ⁹-THC) given orally to mice were compared. The effects of ⁹-THC studied were: hypothermia, the depression of intestinal motility and the effect on spontaneous locomotor activity. When mice were dosed and tested at 24 hrs intervals it was apparent that tolerance was complete to its hypothermic and locomotor depressant effects after the first doses and to depression of intestinal motility after the fourth dose. Duration of tolerance also differed so that the normal hypothermic response had returned after 12 dose-free days, but not after 5 drug-free days; the effect on locomotor activity had returned within 4 days; and, apparent partial tolerance to the depressant effect of an acute challenging dose of ⁹-THC on intestinal motility still existed after 19 dose-free days.It is apparent that the time of onset and the duration of tolerance to ⁹-THC in mice showed a different pattern in the three parameters studied. It seems unlikely therefore that any one mechanism, such as metabolic tolerance, explains all the results observed and that several mechanisms should be explored to explain the phenomenon of tolerance to ⁹-THC.     

The effects of morphine and Δ-9-tetrahydrocannabinol on motor activity in rats

Acute treatment of rats either by high doses of morphine or ⁹-tetrahydrocannabinol (THC) decreased locomotor activity. Naloxone reversed morphine-induced depression completely and reversed THC-induced depression only partially. On day 3 of treatment, tolerance developed to the locomotor inhibitory action of THC or morphine and partial cross-tolerance was observed to the depressant action of THC. Naloxone slightly depressed locomotor activity in THC-tolerant rats, but increased motor activity in morphine-tolerant rats.     

Enhancement by α-fluoromethylhistidine of the thiopental sleep-prolonging action of Δ9-tetrahydrocannabinol

The effect of -fluoromethylhistidine (-FMH), a specific inhibitor of histidine decarboxylase, on the potentiation of thiopental-induced sleep by ⁹-tetrahydrocannabinol (THC), which inhibits the histamine turnover in the brain, was examined in mice and rats. The sleeping time after injection of thiopental sodium (40 mg/kg, IV) was prolonged by THC (10 mg/kg, IP, 1 h before) to approximately twice the control value. -FMH (50 mg/kg, IP) administered alone had no significant influence on the thiopental sleeping time. However, -FMH given 1 or 3 h before THC treatment markedly enhanced the THC potentiation of thiopental-induced sleep. Such an enhancement by -FMH was not observed when -FMH was administered 15 h before THC treatment. The brain histamine level decreased by 60% during the first 4 h after -FMH injection and remained low until 15 h after the treatment. The thiopental sleep-potentiating action of morphine, chlorpromazine and diazepam was not affected by pretreatment with -FMH. The transient enhancing effect of -FMH on the THC potentiation of thiopental-induced sleep suggests that the histaminergic system is one of the activating transmitter systems in the brain.     

Comparison of the subjective effects of Δ<Superscript>9</Superscript>-tetrahydrocannabinol and marijuana in humans

RATIONALE: There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marijuana differ from the effects of its primary active ingredient, Delta(9)-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marijuana and THC using matched doses administered either by the smoked or the oral form.OBJECTIVE: Two studies were conducted to compare the subjective effects of pure THC to whole-plant marijuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking.METHODS: In each study, marijuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marijuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-carboxy-THC.RESULTS: In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marijuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marijuana). In both the oral study and the smoking study, THC-only and whole plant marijuana produced similar subjective effects, with only minor differences.CONCLUSION: These results support the idea that the psychoactive effects of marijuana in healthy volunteers are due primarily to THC.     

Relationships between several pharmacokinetic parameters and psychometric indices of subjective effects of Δ9-tetrahydrocannabinol in man

This study explored the relationships in man between various pharmacological effect of delta 9-tetrahydrocannabinol (THC), plasma THC concentration, and pharmacokinetic parameters of THC. Three male and three female experienced marihuana users smoked two standard marihuana cigarettes. The relationships between heart rate, subjective "high" rating, Linear Mood Scale factors, and plasma THC concentration were assessed. Significant correlations were observed between various Linear Mood Scale factors and pharmacokinetic parameters reflecting the magnitude of drug intake and the degree of temporal dissociation between the time courses of plasma THC concentration and pharmacological effects (tachycardiac effect, "high"). In particular, the disturbed/weird and sensitive/aware mood factors correlated positively with pharmacokinetic measures of drug intake and time lag to effect. A more reliable index of intoxication with THC may be provided by the global subjective "high" rating, rather than other ratings more specific for particular moods.     

Antidepressant-like effects of Δ⁹-tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depression

The endocannabinoid signalling system is widely accepted to play a role in controlling the affective state. Plant cannabinoids are well known to have behavioural effects in animals and humans and the cannabinoid CB₁ receptor antagonist rimonabant has recently been shown to precipitate depression-like symptoms in clinical trial subjects. The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ⁹-tetrahydrocannabinol (THC) and rimonabant on intact and olfactory bulbectomised (OB) rats used as a model of depression.As expected, OB rats were hyperactive in the open field. Repeated THC (2 mg/kg, i.p. once every 48 h for 21 days) and rimonabant (5 mg/kg, i.p. once every 48 h for 21 days) reduced this hyperactivity, which is typical of clinically effective antidepressant drugs. In intact animals, chronic THC increased brain derived neurotrophic factor (BDNF) expression levels in the hippocampus and frontal cortex but rimonabant had no effect. Rimonabant increased the levels of phosphorylated extracellular signal regulated kinases (p-ERKs_1/2) in the hippocampus and prefrontal cortex and THC also increased expression in frontal cortex. OB did not affect BDNF or p-ERK_1/2 expression in the hippocampus or frontal cortex and in, contrast to the intact animals, neither THC nor rimonabant altered expression in the OB rats.These findings indicate antidepressant-like behavioural properties of both THC and rimonabant in OB rats although additional studies are required to clarify the relationship between the chronic effects of cannabinoids in other pre-clinical models and in human depression.     

Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9-tetrahydrocannabinol

Rationale Drug discrimination can be used to examine tolerance and dependence in agonist-treated animals by establishing an appropriate antagonist as a discriminative stimulus.Objective Establish intravenous SR 141716A as a discriminative stimulus in four rhesus monkeys pretreated with a relatively small dose of Δ⁹-tetrahydrocannabinol (Δ⁹-THC).Methods Rhesus monkeys received i.v. Δ⁹-THC (0.32 mg/kg) and discriminated i.v. SR 141716A (1 mg/kg) from vehicle while responding under a fixed ratio (FR) 5 schedule of stimulus-shock termination.Results The discriminative stimulus effects of SR 141716A were dose-dependent (ED₅₀=0.33 mg/kg) and were mimicked by the CB₁ antagonist AM 251 (ED₅₀=0.98 mg/kg), but not by a benzodiazepine (midazolam) or an N-methyl-D-aspartate antagonist (ketamine). An additional dose (0.32 mg/kg in addition to 0.32 mg/kg administered before the session) of Δ⁹-THC shifted the SR 141716A dose–effect curve 3-fold rightward. Omitting Δ⁹-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Δ⁹-THC (ED₅₀=0.13 mg/kg), CP 55940 (ED₅₀=0.013 mg/kg), and WIN 55212-2 (ED₅₀=0.35 mg/kg); midazolam and ketamine did not attenuate responding on the SR 141716A lever. SR 141716A (1 mg/kg) shifted the Δ⁹-THC and CP 55940 dose–effect curves 3.4-fold rightward; the WIN 55212-2 dose–effect curve was not significantly modified by a dose of 1 mg/kg of SR 141716A.Conclusions SR 141716A can be established as a discriminative stimulus in animals pretreated with Δ⁹-THC, and this assay is selective for cannabinoid activity. Differential antagonism of cannabinoids by SR 141716A might indicate that the mechanism of action of WIN 55212-2 is not identical to other cannabinoids. This study demonstrates that, under the appropriate conditions, drug discrimination has utility for examining cannabinoid dependence and withdrawal.