Ovarian hormones and chronic administration during adolescence modify the discriminative stimulus effects of delta-9-tetrahydrocannabinol (Δ⁹-THC) in adult female rats

Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6 mg/kg of Δ⁹-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Δ⁹-THC, OVX/saline, and OVX/Δ⁹-THC). These groups were then trained to discriminate Δ⁹-THC (0.32-3.2 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Δ⁹-THC were substituted for the training dose to obtain dose-effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Δ⁹-THC lower than the training dose, and 3) the OVX/Δ⁹-THC group was significantly less sensitive to the rate-decreasing effects of Δ⁹-THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Δ⁹-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Δ⁹-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal-regulated kinase (ERK) was not significantly affected by either hormone status or chronic Δ⁹-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development.     

Chronic ?-tetrahydrocannabinol during adolescence increases sensitivity to subsequent cannabinoid effects in delayed nonmatch-to-position in rats

Early-onset marijuana use has been associated with short- and long-term deficits in cognitive processing. In human users, self-selection bias prevents determination of the extent to which these effects result only from drug use. This study examined the long-term effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the major psychoactive constituent of marijuana, in a delayed nonmatch-to-position task (DNMP). Male Long-Evans rats were injected daily with 10 mg/kg Δ⁹-THC during or after adolescence [postnatal days (PN) 21-50 or PN50-79, respectively] or with vehicle. On PN91, training in DNMP was initiated. Successful acquisition and pharmacological challenge began on approximately PN300. Decreases in accuracy were observed at lower doses of Δ⁹-THC in Δ⁹-THC-treated rats (versus vehicle-treated rats). Administration of chronic Δ⁹-THC at a younger age tended to enhance this effect. While anandamide did not decrease accuracy in any group, rats treated with Δ⁹-THC during adolescence initiated fewer trials at the 30 mg/kg dose of anandamide than did rats in the other two groups. To the extent tested, these differences were pharmacologically selective for cannabinoids, as scopolamine (positive control) decreased accuracy at the same dose in all groups and amphetamine (negative control) did not affect accuracy in any of the groups at doses that did not impair overall responding. These results suggest that repeated administration of a modest dose of Δ⁹-THC during adolescence (PN21-50) or shortly thereafter (PN50-79) produces a long-term increase in latent sensitivity to cannabinoid-induced impairment of performance in a complex operant task.     

Exposure to a high-fat diet decreases sensitivity to Δ9-tetrahydrocannabinol-induced motor effects in female rats

Arachidonic acid, a fatty acid component of neuronal cell membranes, forms the backbone of endogenous ligands of the endocannabinoid system. The lipid nature of this system may make it particularly susceptible to changes in fat content of the diet, which may, in turn, affect endocannabinoid tone and subsequent changes in receptor expression or activity. The latter would also be expected to affect responses to exogenous cannabinoids. The purpose of the present study was to determine the effects of a high-fat diet on sensitivity to the pharmacological effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Male and female Long-Evans rats were fed either a diet of standard rodent chow or chow enhanced with corn oil. Subsequently, they were repeatedly assessed for Δ⁹-THC-induced hypomobility, catalepsy and hypothermia. Female rats that received the high-fat diet beginning in adolescence or in adulthood became significantly less sensitive to the effects of Δ⁹-THC on motor behavior, but not its hypothermic effects, with faster development of decreased sensitivity in female rats that began the high-fat diet as adults. In contrast, diet-induced differences either did not occur, or were less pronounced, in male rats of both ages. After acute injection, brain and blood levels of Δ⁹-THC and its two primary metabolites were similar regardless of diet. Combined with the fact that diet differentially affected only some of the measures, these results suggest that pharmacokinetic differences cannot fully account for the effects of the high-fat diet on response to Δ⁹-THC. Further, these results suggest that dietary fat content may represent an important consideration in predicting the effects of marijuana in females.     

Antagonism of amphetamine locomotor stimulation in rats by single doses of marijuana extract administered orally

The influence of marijuana extract distillate on (+)-amphetamine stimulation of locomotor activity was examined in rats. Marijuana was administered orally and amphetamine was injected intraperitoneally. In rats acclimated to the activity cages, doses of the extract of 5, 10, and 20 mg/kg Δ⁹-THC administered one hour before amphetamine resulted in a significant antagonism of the locomotor stimulation induced by 1 mg/kg (+)-amphetamine; doses of 0·625, 1·25 and 2·5 mg/kg Δ⁹-THC had no effect on the amphetamine response. A dose of 10 mg/kg Δ⁹-THC (as the extract) antagonized the stimulation produced by 0·5,1 and 2 mg/kg (+)-amphetamine in acclimated animals without depressing baseline activity; however, the same dose of marijuana failed to alter significantly the stimulant effect of 1 mg/kg (+)-amphetamine in nonacclimated rats. Although pretreatment with marijuana extract 1 hr before injection of amphetamine resulted in a marked depression of the amphetamine response, when both drugs were administered at the same time only a small and non-significant decrement in the amphetamine response was observed. In conclusion, this study clearly demonstrates that orally administered marijuana antagonizes amphetamine-induced locomotor stimulation in the rat. Mo evidence of enhancement of the amphetamine effect was observed.     

Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception

We have previously demonstrated synergy between morphine and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in the expression of antinociception in acute pain models and in arthritic models of chronic pain. Our data has been extended to include acute pain in both diabetic mice and rats. In diabetic mice, Δ⁹-THC p.o. was more active in the tail-flick test in the diabetic mouse than in the non-diabetic mouse. Morphine (s.c.) was less potent in diabetic than in non-diabetic mice [6.1 (5.1-7.2) versus 3.2 (2.4-4.1) mg/kg, respectively], an effect previously extensively documented in pre-clinical and clinical testing. In addition, the combination of Δ⁹-THC with morphine produced a greater-than-additive relief of acute pain in mice. In the rat, the induction of the diabetic state decreased the antinociceptive effect of morphine, an effect temporally related to a decreased release of specific endogenous opioids. Conversely, Δ⁹-THC retained the ability to release endogenous opioids in diabetic rats and maintained significant antinociception. Extrapolation of such studies to the clinical setting may indicate the potential for use of Δ⁹-THC-like drugs in the treatment of diabetic neuropathic pain, alone or in combination with very low doses of opioids.     

Role of the central autonomic nervous system in the hypotension and bradycardia induced by (-)-delta 9-trans-tetrahydrocannabinol

(-)-Δ⁹-trans-Tetrahydrocannabinol (Δ⁹-THC), when given intravenously (2 mg kg^?1) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (C₁-C₂) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of Δ⁹-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after Δ⁹-THC administration. These observations support the hypothesis that Δ⁹-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that Δ⁹-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that Δ⁹-THC did not interact with α- or β- adrenoceptors. The possible action of Δ⁹-THC on central sympathetic structures was investigated by perfusion of Δ⁹-THC into the lateral cerebral ventricle. Δ⁹-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or ¹⁴C-Δ⁹-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that Δ⁹-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone.     

Pharmacological potency of R- and S-3′-hydroxy-Δ9-tetrahydrocannabinol: additional structural requirement for cannabinoid activity

The pharmacological potency of R- and S-3′-hydroxy-Δ⁹-tetrahydrocannabinol (THC) was compared to that of Δ⁹-THC as well as R/S-3′-OH-Δ⁹-THC. The S-isomer was found to be considerably more potent than the R-isomer in producing hypoactivity in mice, static-ataxia in dogs, and in generalization testing in rats trained to discriminate Δ⁹-THC from vehicle. S-3′-OH-Δ⁹-THC was more active than Δ⁹-THC in these tests which means that Δ⁹-THC may be either activated or inactivated in vivo depending upon which metabolite is formed. The difference in potency of these isomers suggests that the conformation of the side chain is critical for behavioral activity. The R and S isomers were found to be equally active in producing hypothermia in mice which is in contrast to the behavioral effects.     

Influence of several anesthetic agents on the effects of Δ9-tetrahydrocannabinol on the heart rate and blood pressure of the mongrel dog

Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) 1 mg/kg, i.v. produced a slight but significant reduction in the heart rate of conscious mongrel dogs, and these effects were greatly potentiated by pentobarbital and/or urethane anesthesia. However, significant increase in the heart rate was noted following Δ⁹-THC administration in the dogs anesthetized with a combination of morphine plus chloralose; further, neither morphine nor chloralose alone could reverse the bradycardic effects of Δ⁹-THC. Tachycardia induced by Δ⁹-THC in these dogs could be reversed by bilateral vagotomy or by pretreatment of the animals with methylatropine, or propranolol and/or practolol. The data indicated a complex interaction between Δ⁹-THC and morphine-chloralose combination and the tachycardia induced by Δ⁹-THC under this anesthesia may be due to release of epinephrine by a reflexogenic mechanism involving afferent vagi. Further, while the bradycardic effects of Δ⁹-THC were essentially identical under pentobarbital or urethane anesthesia, the hypotensive effects were similar in urethane or chloralose anesthetized dogs. The study emphasizes that anesthetic interaction should be taken into consideration while investigating mechanisms of actions of pharmacological agents.     

Hypothermia induced by Δ9-Tetrahydrocannabinol in rats with electrolytic lesions of preoptic region

The preoptic region (POR) is a primary central site for thermoregulation. Bilateral lesions of POR disrupt thermoregulation, and in rats, produce a characteristic syndrome including hyperthermia. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), a potent hypothermic agent, appears to mediate this effect via some central mechanism. The studies reported here suggest that Δ⁹-THC induces hypothermia at a site other than POR. Male Sprague-Dawley rats were divided into 2 groups, one with subsequently confirmed bilateral POR lesions and a sham operated group. The lesioned animals developed hyperthermia (+2.1° ± 0.1°C, p<0.01) within 2 hr after surgery when compared to the sham operated controls. Δ⁹-THC was administered intraperitoneally (5 and 10 mg/kg). Rectal temperature was recorded at 30 min intervals for 2.5 hr. Both lesioned and nonlesioned rats exhibited hypothermia within 30 min of Δ⁹-THC administration. The hypothermic response to 5 and 10 mg/kg Δ⁹-THC in the lesioned animals was significantly greater (p<0.05) and showed a trend toward longer duration than the hypothermia induced in the sham operated controls. These data demonstrate that Δ⁹-THC is able to induce a hypothermic response in rats whose body temperatures were elevated by POR ablation. Although Δ⁹-THC does not appear to act primarily at POR to induce hypothermia, it is evident that an intact POR plays a role in modifying the duration and magnitude of Δ⁹-THC induced hypothermia.     

The antiemetic interaction of Delta9-tetrahydrocannabinol when combined with tropisetron or dexamethasone in the least shrew

5-HT₃ receptor antagonists (e.g. tropisetron) combined with dexamethasone are effective for the acute phase of cisplatin (CIS)-induced emesis. This study determined the possible additive or synergistic antiemetic efficacy of Δ⁹-THC when combined with tropisetron or dexamethasone (DEX). Δ⁹-THC (0-10 mg/kg i.p.) was injected in combination with tropisetron (0-5 mg/kg i.p.) or dexamethasone (0-20 mg/kg i.p.) prior to CIS (20 mg/kg i.p.) in the least shrew, and the induced emesis was recorded for 60 min. CIS-induced vomiting was dose-dependently and significantly attenuated by individual administration of Δ⁹-THC (59-97% reductions) and tropisetron (79-100% attenuation), but not dexamethasone (26-40%), although a trend (p < 0.1) towards reduced vomiting frequency following DEX was noted. Low doses of Δ⁹-THC (0.25 or 0.5 mg/kg) when combined with low doses of tropisetron (0.025, 0.1, or 0.25 mg/kg) were more efficacious in reducing emesis frequency than when given individually, but Δ⁹-THC had no antiemetic interactions with DEX. However, no tested combination provided a significantly greater effect on the number of animals vomiting than their individually-administered counterparts. The modest interaction of Δ⁹-THC with tropisetron suggests they activate overlapping antiemetic mechanisms, while the lack of interaction with dexamethasone needs further clarification.     

THE EFFECTS OF ADRENALECTOMY ON THE CARDIOVASCULAR RESPONSES TO A'-TETRAHYDROCANNABINOL IN RATS

1. In urethane anaesthetized sham-operated rats, intravenous administration of Δ¹-THC (1 mg/kg) caused an immediate and prolonged fall in blood pressure, with a concomitant reduction in pulse rate. 2. In rats which had been adrenalectomized 24 h previously, Δ¹-THC (1 mg/kg, i.v.) also caused a depressor response, but it was significantly shorter in duration than that observed in sham-operated animals. The durations of the cardiac slowing effect were similar in both groups of rats. 3. Hydrocortisone pretreatment (25 μg/kg> i-v), given 45 min before Δ¹-THC, restored the duration of the depressor response to Δ¹-THC in adrenalectomized rats, but it did not have any effect on the bradycardia induced by Δ-THC. 4. Hydrocortisone did not produce any significant effect on the hypotensive action of Δ¹-THC in sham-operated rats, but the cardiac slowing effect was markedly potentiated. 5. These results suggest a lack of correlation between the hypotensive and cardiac slowing actions of the drug and that a certein level of adrenal steroids is necessary for the maintenance of the depressor response to Δ¹-THC.     

The effect of (minus)-delta 9-trans-tetrahydrocannibinol on myocardial contractility and venous return in anesthetized dogs

Administration of (?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC, 2.5 mg/kg i.v.) to pentobarbital-anesthetized dogs in which heart rate was maintained constant by electrical pacing, decreased aortic blood pressure, cardiac output, left ventricular peak pressure and left ventricular end diastolic pressure and dP/dt. However, the contractility index (max. dP/dt)/I.P. was not altered by the compound. Furthermore, it was shown that the decrease in cardiac output due to Δ⁹-THC could be restored to original levels by an infusion of saline-dextran in quantities sufficient to elevate the left ventricular end diastolic pressure to pre-Δ⁹-THC level.In dogs in which cardiac output was maintained constant by a right heart bypass procedure Δ⁹-THC decreased blood pressure and total peripheral resistance and augmented intravascular blood volume. This increase in intravascular blood volume was significantly less (74%) in animals in which the splanchnic (superior, inferior and celiac) arteries were ligated prior to the administration of Δ⁹-THC. On the other hand, in spinal dogs Δ⁹-THC was devoid of any measurable cardiovascular effects.These observations clearly support the hypothesis that the diminution of cardiac output induced by Δ⁹-THC in animals with constant cardiac rate is primarily due to diminished venous return to the heart and not to an impaired ability of the myocardium.     

Inhibition of naloxone-induced withdrawal in morphine dependent mice by l-trans-Δ9-tetrahydrocannabinol

The effects of various doses of l-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) on naloxone-induced withdrawal were studied in mice rendered dependent on morphine by the pellet implantation procedure. When administered i.p., 30 min prior to naloxone, Δ⁹-THC, inhibited the naloxone-induced withdrawal jumping response. Two other signs of morphine withdrawal (defecation and rearing behavior) were also suppressed by Δ⁹-THC. It is suggested that Δ⁹-THC or some of its derivatives may have potential use in narcotic detoxification.     

Studies on the bradycardia induced by (-)- -trans-tetrahydrocannabinol in anesthetized dogs

(?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC) (39 μg-5 mg/kg, i.v.) decreased heart rate in a dose related manner in dogs under pentobarbital anesthesia. This cardiac effect of Δ⁹-THC was neither due to an impairment of transmission across the sympathetic ganglia nor to a specific stimulation of parasympathetic ganglia. Selective blockade of either parasympathetic (atropine, bilateral vagotomy) or sympathetic (propranolol, spinal section at C₂C₄ neurogenic activity to the heart partially prevented the negative chronotropic effect of Δ⁹-THC. However the bradycardic effect of Δ⁹-THC was completely abolished in animals in which the autonomic pathways to the heart were pharmacologically or surgically inactivated.Administration of Δ⁹-THC into the vascularly isolated, neurally intact cross-perfused head of dogs significantly slowed the heart rate in intact as well as debuffered recipients. This bradycardia was reduced in recipients in which the trunk was atropinized prior to cerebral administration of Δ⁹-THC into the femoral vein of the recipient in the dog cross circulation preparation also caused a significant decrease in heart rate which was essentially abolished either by bilateral vagotomy or by atropinization of the recipients.These results are compatible with the hypothesis that the negative chronotropic effects of Δ⁹-THC in dogs under pentobarbital anesthesia is of central origin and involves both a direct and reflexogenic alteration of central autonomic outflow regulating the heart rate.     

Comparison of smoked marijuana and oral Δ<Superscript>9</Superscript>-tetrahydrocannabinol in humans

Abstract Rationale. Although smoked marijuana contains at least 60 cannabinoids, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is presumed to be the cannabinoid primarily responsible for many marijuana-related effects, including increased food intake and subjective effects. Yet, there has been no systematic comparison of repeated doses of oral Δ⁹-THC with repeated doses of smoked marijuana in the same individuals. Objective. To compare the effects of oral Δ⁹-THC and smoked marijuana in humans under controlled laboratory conditions. Methods. Eleven healthy research volunteers, who reported smoking an average of six marijuana cigarettes per day, completed an 18-day residential study. Marijuana cigarettes (3.1% Δ⁹-THC, q.i.d.) were smoked or Δ⁹-THC (20 mg, q.i.d.) was taken orally using a staggered, double-blind, double-dummy procedure for three consecutive days. Four days of placebo administration separated each active drug condition. Psychomotor task performance, subjective effects, and food intake were measured throughout the day. Results. Relative to placebo baseline, oral Δ⁹-THC and smoked marijuana produced similar subjective-effect ratings (e.g., "high" and "mellow"), although some effects of smoked marijuana were more pronounced and less prone to the development of tolerance. Additionally, participants reported "negative" subjective effects (e.g., "irritable" and "miserable") during the days after smoking marijuana but not after oral Δ⁹-THC. Both drugs increased food intake for 3 days of drug administration, but had little effect on psychomotor performance. Conclusion. These results indicate that the behavioral profile of effects of smoked marijuana (3.1% Δ⁹-THC) is similar to the effects of oral Δ⁹-THC (20 mg), with some subtle differences. Electronic Publication     

Catalepsy induced by intrastriatal injections of delta9-THC and 11-OH-delta9-THC in the rat

Intrastriatal injections of Δ⁹-THC and 1 l-hydroxy-Δ⁹-THC induced dose-dependent catalepsy in the rat, the parent compound being more potent than the metabolite. Catalepsy was not induced following intrapallidal injection of either drug. The results suggest that the caudate-putamen could be a “specific site” in the mediation of catalepsy induced by Δ⁹-THC.Intrastriatal amphetamine attenuated Δ⁹-THC-induced catalepsy whereas intrapallidal amphetamine potentiated the effect indicating a complex interaction with dopaminergic systems in the basal ganglia.Δ⁹-THC and the central cholinergic stimulant, RS-86 synergize on administration to either area indicating a possible cholinergic involvement in the phenomenon.     

Chronic Δ<Superscript>9</Superscript>-Tetrahydrocannabinol Administration Reduces IgE<Superscript>+</Superscript>B Cells but Unlikely Enhances Pathogenic SIV<Subscript>mac251</Subscript> Infection in Male Rhesus Macaques of Chinese Origin

Delta9-tetrahydrocannabinol (Δ⁹-THC) is the major psychoactive component of the cannabis plant. Δ⁹-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ⁹-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Here, we determine the chronic effect of Δ⁹-THC administration using 0.32 mg/kg or placebo (PBO), i.m., twice daily for 428 days on SIV_mac251 infected male Chinese-derived rhesus macaques. Sixteen animals were divided into four study groups: Δ⁹-THC⁺SIV⁺, Δ⁹-THC⁺SIV^?, PBO/SIV⁺ and PBO/SIV^? (n = 4/group). One-month after daily Δ⁹-THC or PBO administrations, macaques in groups one and three were challenged intravenously with pathogenic SIV_mac251/CNS, which was isolated from the brain of a Chinese macaque with end-staged neuroAIDS. No significant differences in peak and steady state plasma viral loads were seen between Δ⁹-THC⁺SIV⁺ and PBO/SIV⁺ macaques. Regardless of Δ⁹-THC, all infected macaques displayed significant drop of CD4/CD8 T cell ratio, loss of CD4⁺ T cells and higher persistent levels of Ki67⁺CD8⁺ T cells compared with uninfected animals. Moreover, long-term Δ⁹-THC treatment reduced significantly the frequency of circulating IgE⁺B cells. Only one Δ⁹-THC⁺SIV⁺ macaque died of simian AIDS with paralyzed limbs compared with two deaths in the PBO/SIV⁺ group during the study period. These findings indicate that chronic Δ⁹-THC administration resulted in reduction of IgE⁺B cells, yet it unlikely enhanced pathogenic SIV_mac251/CNS infection in male Rhesus macaques of Chinese origin.     

Electroencephalographic study of the effects of tetrahydrocannabinols on sleep in the rat

This study examined the effects of tetrahydrocannabinols on sleep-wake states, and especially on paradoxical sleep (PS), in rats bearing chronically implanted EEG and EMG electrodes. Greatest attention was given to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), but Δ⁸-tetrahydrocannabinol and marihuana extract distillate were also studied. These agents in i.p. doses of 5 and 10 mg/kg reduced PS in rats non-deprived (ND) of PS, caused an apparent dissociation of phasic and tonic events of PS in PS-deprived (PSD) rats, and tended to decrease slow-wave sleep and increase wakefulness. No PS rebound was detected during 5 post-drug days in ND rats. In PSD rats the normal PS rebound was replaced by a form of “incomplete PS” characterized by tonic hippocampal theta rhythm, absence of muscle activity and continuous cortical spindling in the absence of normal phasic activity. The effect of 10 mg/kg of Δ⁹-THC administered daily for 20 days was initially to suppress PS; this was followed by rapid development of tolerance to effects on both sleep and behavior. Partial tolerance remained upon retesting at the 13th withdrawal day. When Δ⁹-THC was withdrawn no PS rebound occurred in rats. In preliminary experiments in cats, single doses of Δ⁹-THC (10 mg/kg i.p.) caused a clear-cut inhibition of PS in both ND and PSD cats which was followed by a significant PS rebound on the first post-drug day.     

The effect of cannabinoids on the number of nuclear membrane-attached ribosomes in infant rat brain

The pharmacologically active cannabinoids Δ⁹-THC, Δ⁹-THC and 11-OH-Δ⁹, -THC each caused a highly significant reduction in nuclear membrane-attached ribosomes of infant rat brain cells. The pharmacologically inactive agents cannabinol and cannabidiol had only a slight effect while cannabigerol had a moderate effect. The activity was measured 3 hr after a 10 mg/kg s.c. dose. The duration of effect was tested with Δ⁹-THC. It was significant after 1 hr, maximally developed after 3 hr, and almost completely diminished after 6 hr.     

Metabolomics of Δ9-tetrahydrocannabinol: implications in toxicity

Cannabis sativa is the most commonly used recreational drug, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) being the main addictive compound. Biotransformation of cannabinoids is an important field of xenobiochemistry and toxicology and the study of the metabolism can lead to the discovery of new compounds, unknown metabolites with unique structures and new therapeutic effects. The pharmacokinetics of Δ⁹-THC is dependent on multiple factors such as physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol. This review aims to discuss metabolomics of Δ⁹-THC, namely by presenting all known metabolites of Δ⁹-THC described both in vitro and in vivo, and their roles in the Δ⁹-THC-mediated toxic effects. Since medicinal use is increasing, metabolomics of Δ⁹-THC will also be discussed in order to uncover potential active metabolites that can be made available for this purpose.