Learning impairment in the radial-arm maze following prolonged cannabis treatment in rats

Chronic oral administration of cannabis extract to rats (daily ⁹tetrahydrocannabinol dose 20 mg/kg) was examined in three experiments for its residual effect on radialarm maze learning following a 1-month drug-free period. Learning a simple eight-arm maze was significantly impaired in rats treated for either 6 months (Experiment I) or 3 months (Experiment II) with the drug. In Experiment III, animals that received the extract for 3 months exhibited significant learning deficits on a much more difficult 12-arm radial maze. The results demonstrate that the deleterious effects of cannabis on radial-arm maze learning are probably due to a tendency toward increased vigilance and perseveration, possibly combined with an impaired utilization of spatial cues.     

Effects of acute and chronic administration of cannabis sativa and (−)Δ9-trans-tetrahydrocannabinol on the behavior of rats in an open-field arena

The effects of acute and chronic administration of ⁹-THC, cannabis extract and control solution on the behavior of rats repeatedly exposed to an open-field arena have been studied. After the first dose both ⁹-THC and cannabis extract significantly decreased defecation, grooming and rearing; ambulation was not affected. After 20 injections of both marihuana compounds the rats showed values for defecation, grooming and rearing near to those obtained during the predrug phase; control rats, however, showed a significant decrease in these parameters indicating habituation to the open-field. The results are discussed in terms of effects of marihuana on emotional behavior of rats.This work was partially supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).With a fellowship iniciação científica from FAPESP.     

Lack of cross-tolerance in rats among (−) Δ9-trans-tetrahydrocannabinol (Δ9-THC), cannabis extract,mescaline and lysergic acid diethylamide (LSD-25)

Summary Using climbing rope and bar-pressing behavior methods, rats were rendered tolerant to ⁹-THC, cannabis extract, mescaline and LSD-25. Cross-tolerance experiments showed that rats refractory to ⁹-THC and cannabis extract were still sensitive to mescaline and LSD-25, and vice-versa.These results suggest that, in spite of the similarity of the clinical symptoms produced in man by the 3 drugs, ⁹-THC may have its psychotomimetic effects produced by different mechanisms from those of LSD-25 and mescaline.This work was partially supported by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).     

Δ 1-tetrahydrocannabinol-induced circling behavior in rats: A possible measure of psychotomimetic activity?

Relatively high dosages of ¹-tetrahydrocannabinol ( ¹-THC) markedly suppressed almost all normally occurring behavioral elements in rats as observed in both a small and a large open field. This effect persisted following repeated treatment and testing for 3 consecutive days. The psychotropically inert but related compound cannabidiol (CBD) did not suppress behavior, but in contrast had a mild activating effect. Both compounds decreased defecation during the test procedure. In addition, ¹-THC, but not CBD, induced a bizarre circling and turning response, that was evident over all 3 test days and occurred even when the rats were deeply sedated. It is suggested that an analysis of this phenomenon may be useful in measuring the psychotominetic action of ¹-THC and similar compounds in rats.     

Residual effects of chronic cannabis treatment on behavior in mature rats

Mature rats (starting weight at least 270 g) were treated daily with cannabis extract (daily THC dose 20 mg/kg) for 3 months. After a 1- to 4-month drug-free period, residual effects on a variety of behaviors were studied. No residual effects were found in learning of an eight-arm radial maze task, nor on a differential reinforcement of low-rate responding (DRL-20) task, nor on open field activity. On the other hand, two-way shuttle box avoidance learning was facilitated by previous cannabis treatment, since cannabis-treated rats exhibited shorter mean latencies to avoid footshock than vehicle controls. The findings indicate greater vulnerability of immature organisms (previous studies) than mature organisms (the present study) to long-term effects of chronic cannabis administration.     

Acute and chronic effects on rats of (−)δ1-trans-tetrahydrocannabinol on unlearned motor tasks

Eighty-eight rats were either injected with. 5 mg/kg ¹-THC, 4 mg/kg ¹-THC, corresponding volumes of propylene glycol or were handled and/or pierced prior to being tested on five tasks; an open field, rotating rod, balance beam, black-white choice, and swimming. Each task was characterized by being self motivating and requiring only one trial, thus minimizing state-dependent effects. The number of drug administrations preceeding testing was either less than five (acute condition) or more than 25 (chronic condition). Under the acute conditions, doses of 4 mg/kg ¹-THC significantly impaired all the measured motor skills, whereas doses of .5 mg/kg had little effect except on the open field. However, those rats receiving 25 administrations of 4 mg/kg were equal or superior to control groups in the motor tasks and both the high and low chronic ¹-THC groups demonstrated a shift of preference from black to white. General reactivity, as measured by defecation, speed of swimming, open field behaviour and aggressiveness was increased following multiple injections.This work, portions of which were presented at the Canadian Psychological Association in June, 1971, was partially supported by an Ontario Mental Health grant to the second author.This article is based upon a Master's thesis submitted by the first author in partial fulfillment of the requirements for the Master's degree at Carleton University.     

Cannabis interferes with nest-building behavior in mice

Nest-building, a behavioral model shown to be disrupted by hallucinogens, has never been used to answer questions concerning the psychotomimetic effects of ⁹-THC. Several fractions of cannabis and tobacco pyrolysis products were tested consecutively in the same procedure. The following drugs were injected i.p. under a saline-drug-saline schedule: d-amphetamine (6 mg/kg), pentobarbital (25 mg/kg), ⁹-THC (10 mg/kg, 5 mg/kg, 2.5 mg/kg), the cannabis fractions designated I_s (water soluble products), II_s (nonsoluble, nonvolatile products), III_s (it comprises what is inhaled by a common hashish smoker), and analogous fractions of tobacco pyrolysis products designated III_B (what is inhaled by a common tobacco smoker), II_B and I_B.The effects of ⁹-THC (10 mg/kg), II_s, and III_s were quite similar as far as the disruption of the normal behavioral pattern is concerned. d-Amphetamine, ⁹-THC (5 mg/kg), and II_B disrupted the normal behavioral pattern as well. The similarity of the effects of II_s and III_s was unexpected in view of the different contents of cannabinoids in these fractions. Also unexpected was the similarity of the effects of ⁹-THC (10 mg/kg) and III_s (40 mg/kg containing 7% ⁹-THC) as well as the activity of fraction III_B.     

Pharmacological interaction between cannabidiol and δ9-tetrahydrocannabinol

The pharmacological interaction between cannabidiol (CBD) and (–) ⁹-trans-tetrahydrocannabinol ( ⁹-THC) has been studied in rabbits, mice and rats by administering mixtures containing varying amounts of both substances. CBD blocked the following effects of ⁹-THC: catatonia in mice, corneal areflexia in rabbits, the increased defecation and decreased ambulation after chronic treatment and exposures of rats in an open field arena, and the aggressiveness of rats previously stressed by REM sleep deprivation. On the other hand, CBD potentiated the ⁹-THC-induced analgesia in mice and the ⁹-THC-impairing effect on climbing rope performance of rats.These interactions are tentatively explained by postulating that CBD directly antagonizes the excitatory effects and/or indirectly potentiates the depressant effects of ⁹-THC.Work partially aided by Conselho Nacional de Pesquisas (CNPq)With a fellowship from FundaÇÃo de Amparo à Pesquisa do Estado de SÃo Paulo (FAPESP)Pesquisador conferencista-bolsista do CNPq.     

Genetic control of responsiveness of rat liver supernatant aldehyde dehydrogenase to phenobarbital and 3-methylcholanthrene

The responsiveness of the hepatic supernatant NAD⁺-dependent aldehyde dehydrogenase with a high Km value (high Km-AldDH) to phenobarbital (PB) and 3-methylcholanthrene (3-MC) treatment was studied in male rats of three strains; Wistar, Long-Evans, and Sprague-Dawley.A remarkable strain difference in the response of the enzyme to PB or 3-MC was observed. In rats of the Wistar strain the enzyme activity remained unchanged (non-responsive) in all rats after treatment with PB while it increased (responsive) 5- to 19-fold in all rats after treatment with 3-MC. The enzyme activity increased 8- to 20-fold and 2- to 8-fold respectively after treatment with PB and 3-MC in all rats of the Long-Evans strain. In rats of the Sprague-Dawley strain the enzyme activity remained unchanged in half of all the rats treated with PB or 3-MC and increased 2- to 7-fold over the basal level in half of the treated rats. The non-responsive rats to PB were all responsive to 3-MC treatment while the responsive rats to PB were responsive in 65% and non-responsive in 35% to 3-MC treatment.     

The effect of withdrawal from cannabis on pentylenetetrazol convulsive threshold in mice

Groups of mice were dosed with ethanol (2.5 and 5% w/v in drinking water) or cannabis extract (equivalent to 10, 20, 40 and 80 mg ⁹-THC/kg) orally, for 11, 13 and 28 days. The threshold to convulsions produced by the constant intravenous infusion of pentylenetetrazol was determined at various intervals after drug administration had ceased. The convulsive thresholds of mice tested 6 hrs after withdrawal from both doses of ethanol were significantly lower than controls. There was no significant difference from controls in the convulsive threshold of mice which had received cannabis extract at any of the doses employed when tested 6 hrs, 16 hrs, 1, 3 or 6 days after medication had been withdrawn.These findings support the contention that there is no abstinence syndrome evident following the withdrawal of cannabinoids after prolonged administration to mice and serve again to draw a distinction between cannabis and ethanol.     

Fasting and exercise increase plasma cannabinoid levels in THC pre-treated rats: an examination of behavioural consequences

Rationale

Δ⁹-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences.

Objectives

Here, we examined whether rats pre-treated with multiple or single doses of THC followed by a washout would show elevated plasma cannabinoids and altered behaviour following fasting or exercise manipulations designed to increase fat utilisation.

Methods

Behavioural impairment was measured as an inhibition of spontaneous locomotor activity or a failure to successfully complete a treadmill exercise session. Fat utilisation was indexed by plasma free fatty acid (FFA) levels with plasma concentrations of THC and its terminal metabolite (-)-11-nor-9-carboxy-?⁹-tetrahydrocannabinol (THC-COOH) also measured.

Results

Rats given daily THC (10 mg/kg) for 5 days followed by a 4-day washout showed elevated plasma THC-COOH when fasted for 24 h relative to non-fasted controls. Fasted rats showed lower locomotor activity than controls suggesting a behavioural effect of fat-released THC. However, rats fasted for 20 h after a single 5-mg/kg THC injection did not show locomotor suppression, despite modestly elevated plasma THC-COOH. Rats pre-treated with THC (5 mg/kg) and exercised 20 h later also showed elevated plasma THC-COOH but did not differ from controls in their likelihood of completing 30 min of treadmill exercise.

Conclusions

These results confirm that fasting and exercise can increase plasma cannabinoid levels. Behavioural consequences are more clearly observed with pre-treatment regimes involving repeated rather than single THC dosing.     

Differences in fear motivated behaviors among inbred mouse strains

The behavioral performance of inbred mouse strains was examined in animal models of anxiety to evaluate the potential contribution of genetic factors to fear-motivated behaviors. The preference that randomly bred mice and rats exhibit for the enclosed as opposed to the open arms of an elevated maze has been considered a fear-motivated behavior. Pronounced differences were observed in this measure among 16 inbred mouse strains. An estimate of the proportion of the variance attributable to between-strain differences, ², revealed that 78% and 69% of the variance in time and number of entries in the open arms of an elevated maze, respectively, can be attributed to genetic factors. In contrast, only 27% and 42% of the variance could be attributed to between-strain differences in ambulatory activity in the open field and elevated maze, respectively. Furthermore, performance in the elevated maze was predictive of behavior in other animal models of anxiety. Thus, significant negative correlations were observed among inbred mouse strains between the percent time spent in the open arms of the elevated maze and amplitude of an acoustic startle response (r _s=–0.88mP<0.01) or latency to initiate chow consumption in a hyponeophagia paradigm (r _s=–0.71,P<0.05). These results indicate that genetic factors substantially contribute to fear motivated behaviors in these animal models of anxiety. The use of such inbred mouse strains may provide a novel approach to investigate the biochemical and genetic bases of fear.     

Event-Specific Cannabis Use and Cannabis Use Motives

Background: Specific events such as Mardi Gras (MG) and St. Patrick's Day (SPD) have been identified as high-risk events for cannabis use. Further, some campuses may have traditions that are associated with more event-specific cannabis use. Objectives: Campus A has specific traditions regarding MG whereas Campus B has specific traditions regarding SPD and these campuses are differentially related to event-specific cannabis use (Buckner, Henslee, &; Jeffries, 2015 Buckner, J. D., Henslee, A. M., &; Jeffries, E. R. (2015). Event-specific cannabis use and use-related impairment: the relationship to campus traditions. Journal of Studies on Alcohol And Drugs, 76, 190–194. dx.doi.org/10.15288/jsad.2015.76.190[Crossref] , [Google Scholar]). Yet, little work has identified individual difference variables related to high-risk cannabis use events. Methods: Current cannabis using undergraduates (N = 154) at two campuses completed an online survey of event-specific cannabis use motives, cannabis use, and cannabis-related problems. Results: Campus A endorsed more MG-specific social and enhancement motives than Campus B. Campus A reported more socially, enhancement, coping, conformity, and expansion motivated cannabis use on MG than on SPD, whereas Campus B reported more socially and enhancement motivated cannabis use on SPD than on MG. Campus A was indirectly related to more MG-specific cannabis use through MG-specific social and enhancement motives. Conclusions/Importance: Event-specific cannabis motives are differentially related to specific high-risk cannabis use events and may be important therapeutic targets.     

Effect of Δ9-THC on the open-field activity of the rat

Using the open-field activity of the hooded rat as a model of overall activity, the dose-response and time-action effects of doses of ⁹-THC which did not adversely affect spontaneous activity or behavior on appetitively motivated tasks were studied. Subjects received two exposures to an open field one week apart. Prior to the first exposure subjects were treated with small doses of Tween 80-water. At 30 min or 3 h prior to the second exposure subjects were treated with Tween or ⁹-THC in doses which ranged from 0.5–5 mg/kg. Results indicated that ⁹-THC affected various indices of open-field activity such as grooming, sniffing and ambulation differently depending on the time after injection. Rearing and defecation were affected similarly by THC independent of post-injection intervals.This research was supported by USPHS Grant No. R01-MH18392-01. The ⁹-THC was supplied by Dr. John A. Scigliano, NIMH, Chevy Chase, Maryland. The authors wish to thank Dr. Patrick Deluca for assistance in the solvent studies.     

The effect of repeated-intermittent exposure to 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) during adolescence on learning and memory in adult rats

Background

According to the European Drug Report, the use of novel psychoactive substances (NPS) is constantly growing. NPS are widely abused by human adolescent subjects. 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is one of the most frequently used hallucinogenic NPS. 5-MeO-DIPT intoxication results in hallucinations, vomiting, and tachycardia. Long-term exposure to 5-MeO-DIPT was reported to lead to development of post-hallucinogenic perception disorder.The aim of the present study was to determine whether repeated-intermittent administration of 5-MeO-DIPT during adolescence affects learning and memory in adult rats.

Avoidance conditioning in different strains of rats: Neurochemical correlates

Two-way avoidance conditioning was compared in three strains of rats: Roman high avoiders (RHA), Roman low avoiders (RLA) and control Sprague-Dawleys (SD). RHAs performed more and RLAs fewer avoidance responses than SDs. RLAs injected with d-amphetamine improved their performance to levels comparable to SDs; however, d-amphetamine caused a time-dependent increase in intertrial crossings for the RLAs. Of the three strains, the RLAs had the lowest activities of tyrosine hydroxylase, dopamine--hydroxylase and phenylethanolamine-N-methyltransferase in their adrenal glands. Although there were no significant differences among the strains in respect to tyrosine hydroxylase activity in whole brain or regions, RLAs had higher dopamine--hydroxylase activity in the whole brain and cerebral cortex as compared to the SDs. RLAs and RHAs together had a significantly different turnover of intracisternally administered ³H-norepinephrine than SDs. After the intracisternal injection of ³H-L-tyrosine, twice as much ³H-dopamine accumulated in the brains of RLAs as compared to RHAs and SDs.     

Substance Use and Social Anxiety in Transsexual Individuals

Objective: This study examined social anxiety and use of cannabis and cocaine among transsexuals.

Methods: A total of 379 transsexuals seeking treatment or consultation participated in this study, providing data on sociodemographics, substance use, and anxiety. Analyses were based on (a) lifetime but not current use versus never used and (b) current use only versus no current use (lifetime only or never used).

Results: Lifetime only cannabis users (n = 72, 19%) and lifetime only cocaine users (n = 36, 9.8%) were older, had more victimization, and received more mental health treatment that those who never used. Current cannabis users (n = 47, 12.4%) had higher scores on fear of negative evaluation and social avoidance than those not currently using (p <.01). Multivariate analysis showed that social avoidance and fear of negative evaluation were associated with current cannabis use (p <.05), but not cocaine. Further, being single was associated with current cannabis use, after controlling for social avoidance and fear of negative evaluation (p <.05).

Conclusions: Transsexuals’ levels of anxiety and cannabis/cocaine use are comparable to those in the general population. Cannabis may be used to control anxiety and can have detrimental clinical implications for transsexuals.     

Single doses of THC and cocaine decrease proficiency of impulse control in heavy cannabis users

BACKGROUND AND PURPOSE

Cannabis is the most popular drug used in the European Union, closely followed by cocaine. Whereas cannabis impairs neurocognitive function in occasional cannabis users, such impairments appear less prominent in heavy users, possibly as a result of tolerance. The present study was designed to assess whether the impairing effects of Δ⁹-tetrahydrocannabinol (THC) in heavy cannabis users would present in a wide range of neuropsychological functions or selectively affect specific performance domains. We also assessed the acute effects of cocaine on neurocognitive functions of heavy cannabis users.

EXPERIMENTAL APPROACH

Heavy cannabis users, who had a history of cocaine use (n = 61), participated in a double-blind, placebo-controlled, three-way crossover study. Subjects received single doses of cocaine HCl (300 mg), cannabis (THC μg·kg⁻¹) and placebo, and completed a number of tests measuring impulse control and psychomotor function.

KEY RESULTS

Single doses of cannabis impaired psychomotor function and increased response errors during impulsivity tasks. Single doses of cocaine improved psychomotor function and decreased response time in impulsivity tasks, but increased errors.

CONCLUSIONS AND IMPLICATIONS

Heavy cannabis users display impairments in a broad range of neuropsychological domains during THC intoxication. Impairments observed in psychomotor tasks, but not in impulsivity tasks, appeared smaller in magnitude as compared with those previously reported in occasional cannabis users. Heavy cannabis users were sensitive to the stimulating and inhibitory effects of cocaine on psychomotor function and impulsivity respectively. The reduction in proficiency in impulse control may put drug users at increased risk of repeated drug use and addiction.     

Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents

Introduction: To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents.

Areas covered: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper.

Expert opinion: Δ⁹-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.     

Clozapine decreases [<Superscript>3</Superscript>H] CP 55940 binding to the cannabinoid<Subscript>1</Subscript> receptor in the rat nucleus accumbens

Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB₁ receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-³H) ([³H]CP 55940) to measure the density of the CB₁ receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs. Clozapine significantly decreased [³H]CP 55940 binding in the nucleus accumbens compared with vehicle after 1 (35.0±14.0 vs. 71.2±8.5 fmol/mg estimated tissue equivalent (ete); P=0.03) and 3 months (42.3±4.0 vs. 71.1±16.3 fmol/mg ete; P<0.04) of treatment, an effect not observed with haloperidol, chlorpromazine or olanzapine. In rats treated with clozapine for 3 months and then left for 1 month without treatment, [³H]CP 55940 binding was not different in the nucleus accumbens (100.5±22.2 vs. 100.9±25.4 fmol/mg ete; P>0.10). By contrast, there were significant increases in accumbal [³H]CP 55940 binding in rats treated with haloperidol (136.5±14.2 fmol/mg ete; P<0.05), chlorpromazine (137.4±12.7 fmol/mg ete; P<0.05) and olanzapine (144.7±10.1 fmol/mg ete; P<0.01). These data indicate that in the nucleus accumbens clozapine differs from other antipsychotic drugs in its effects on [³H]CP 55940 binding. If these results can be extrapolated into humans, then this effect of clozapine on the CB₁ receptor may be a mechanism that makes it uniquely effective in schizophrenia and comorbid cannabis use.