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.     

Hemodynamic and myocardial effects of (-)-delta9-trans-tetrahydrocannabinol in anesthetized dogs

(?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC) (39 μg–2.5 mg/kg, i.v.) decreased blood pressure, heart rate, cardiac output and right ventricular contractile force in a dose-related manner in intact dogs under pentobarbital anesthesia. The Δ⁹-THC-induced hypotension appeared to result mainly from a consistent and reproducible attenuation of cardiac output since no marked alteration in total peripheral resistance occured. In these animals the decrease in cardiac output appeared to be related to the bradycardia since there was no change in stroke volume following Δ⁹-THC. However, when the change in heart rate was prevented by atrial pacing or cardiac denervation, a less but significant reduction in cardiac output was induced by Δ⁹-THC. Under these experimental conditions Δ⁹-THC also significantly attenuated stroke volume. In contrast, Δ⁹-THC did not induce any significant changes in cardiac output, blood pressure, and heart rate of dogs pretreated with a ganglionic blocker.Δ⁹-THC appeared to be devoid of any measurable direct effect on the myocardium since the compound neither significantly altered right ventricular contractile force of the denervated or ganglionic blocker-pretreated hearts nor interfered with the positive inotropic responses to i.v. calcium and isoproterenol.In the major vessel occlusion preparation administration of Δ⁹-THC was followed by a reduction in venous tone. Furthermore, measurements of blood and plasma volume excluded an effect of Δ⁹-THC in these parameters.From these findings it is suggested that the reduction in cardiac output induced by Δ⁹-THC is the result of the action of this compound on cardiac rate as well as venous return; no evidence could be documented for a direct effect of this compound on the myocardium.     

Tolerance to the hypothermic and aggression-attenuating effect of delta 8 - and delta 9 - tetrahydrocannabinol in mice

The effects of repeated administration of Δ⁸-andΔ⁹-tetrahydrocannabinol (Δ⁹-and Δ⁹-THC) on both temperature aggression of isolated aggressive mice were investigated. In the first experiment, Δ⁹-THC, mg/kg, caused significant hypothermia and diminished aggression. Acute tolerance to the hypothermic effect developed, which significant hypothermia and diminished aggression. Acute tolerance to the hypothermic effect developed, which could be overcome by doubling the dose. In the same mice no tolerance to the aggression inhibiting effect was seen. In the second experiment Δ⁸- and Δ⁸-THC were compared. Both compounds caused a dose-dependent decrease of body temperature. The effect of Δ⁹-THC on body temperature was about 1.5 times as strong as that Δ⁸-THC. Tolerance to the hypothermic effect appeared in one day for the 10 mg/kg dose, and in about 3 days in the 25 mg/kg group; no tolerance was seen to the aggression-attenuating effect.     

Suppression by delta 9-tetrahydrocannabinol of induction of hepatic tyrosine aminotransferase and tryptophan oxygenase.

The present study characterizes the action of Δ⁹-THC on enzyme induction by studying its effects on the induction of hepatic tyrosine aminotransferase (TAT) by steroids. In none of our studies did Δ⁹-THC inhibit TAT activity in the absence of steroid. Although treatment with hydrocortisone (HC, 150 mg/kg, 2 hr prior to sacrifice) caused a 2.1-fold induction of enzyme activity, pretreatment with Δ⁹-THC (200 mg/kg, 2 hr prior to sacrifice) decreased this induction to 1.3-fold. When mice were treated with Δ⁹-THC 1 hr prior to HC induction, TAT activity was induced only 1.1-fold over control while HC alone induced TAT activity 2.5-fold. Even when steroid treatment preceded Δ⁹-THC administration by 3 hr, there was significant inhibitory activity. Enzyme activity at 0, 3, and 6 hr after steroid was 18.7, 41.4, and 55.5 μmol of PPA/g of liver/hr, respectively. When Δ⁹-THC was administered at 3 hr after steroid and mice killed 3 hr later, enzyme activity was reduced to 36.2 μmol PPA/g liver/hr. Inhibition of steroid induction was dose-related over a range of 50–400 mg/kg of Δ⁹-THC. Δ⁹-THC had little effect on induction of TAT or tryptophan oxygenase in mouse liver by tryptophan and had no effect on tryptophan induction of tryptophan oxygenase in rat liver.     

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.     

Metabolism and distribution of cannabinoids in rats after different methods of administration

Lungs of rats given ¹⁴C-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) by smoke inhalation showed a retention and metabolism of the cannabinoid, with further retention and metabolism by the liver. Only the liver showed retention and metabolism when ¹⁴C-Δ⁹-THC was given by i.v. injection. The brain showed a greater penetration or retention of unmetabolized cannabinoid after smoke inhalation than after i.v. injection. 11-Hydroxy-Δ⁹-THC was observed soon after smoke inhalation of ¹⁴C-Δ⁹-THC in all of the organs and tissues except brain, and concentrations of a dihydroxy metabolite increased with time. A still unidentified metabolite was retained in the liver and spleen 15 days after an i.v. or chronic i.p. injection of ¹⁴C-Δ⁸-THC or ¹⁴C-Δ⁹-THC.     

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.     

Involvement of hydroxylated metabolites in amphetamine-induced hypothermia in mice

• 1.1. The hydroxylated metabolites of amphetamine, p-hydroxyamphetamine (p-OHA) and p-hydroxynorephedrine (p-OHN), were administered intracerebroventricularly in mice in order to evaluate their ability to elicit hypothermia.
• 2.2. Intracerebroventricular (i.c.v.) administration of p-OHA and p-OHN (1, 3 and 9 μg/mouse) induced maximal hypothermia 30 min after injection. p-OHA and p-OHN (9 μg, i.c.v.) produced maximal decreases in rectal temperature of −6.48 ± 0.44°C and −3.82 ± 0.42°C, respectively. Both metabolites are more effective than amphetamine (at 9 μg, i.c.v., −3.32 ± 0.75°C).
• 3.3. Pretreatment with haloperidol (5 μg, i.c.v.) suppressed the fall in temperature produced by p-OHA (3 μg, i.c.v.) and reduced that produced by p-OHN (3 μg, i.c.v.), respectively. The selective dopaminergic D1 receptor antagonist, SCH 23390, and the D2 receptor antagonists, sultopride and metoclopramide, were without effect on the hypothermia induced by either metabolite. Similarly, amphetamine-induced hypothermia was only inhibited by haloperidol. Apomorphine (0.1 mg kg⁻¹, i.p.) did not potentiate the hypothermia induced by either metabolite, whereas the selective dopaminergic D2 agonist, quinpirole (0.2 mg kg⁻¹, i.p.) did. Amphetamine-induced hypothermia was potentiated by apomorphine and quinpirole.
• 4.4. Neither the 5-hydroxytryptamine (5-HT) receptor blocker, cyproheptadine, nor the 5-HT receptor agonist, quipazine, modified metabolite-induced hypothermia. In contrast, amphetamine-induced hypothermia was affected by these 5-HT drugs.
• 5.5. The neuropeptide CCK-8 (0.04 mg kg⁻¹, i.p.) and γ-butyrolactone (40 mg kg⁻¹, i.p.) potentiated the hypothermia produced by amphetamine and its metabolites. Conversely, desipramine (20 mg kg⁻¹, i.p.) antagonized it.
• 6.6. These results show that both hydroxylated metabolites of amphetamine can elicit a strong dose-dependent hypothermia. p-OHA is more potent than p-OHN, which is itself more potent than amphetamine. This potent activity of the metabolites indicates that they play an important role in amphetamine-induced hypothermia. While amphetamine-induced hypothermia involves dopaminergic and 5-hydroxytryptaminergic neurotransmission, metabolite-induced hypothermia is mainly mediated by direct and/or indirect dopaminergic mechanisms, probably by D2 receptor activation.

     

The effect of cannabinoids (Δ9-THC and Δ8-THC) on hepatic microsomal metabolism of testosterone in vitro

The effects of Δ⁹-THC and Δ⁸-THC on testosterone metabolism by rat liver microsomal enzymes were studied in vitro. Δ⁹-THC (25 μM) inhibit the 5α-reduction of testosterone while Δ⁸-THC has no effect at double the concentration. Both Δ⁹-THC and Δ⁸-THC inhibit the hydroxylation of testosterone. This inhibition is dose dependent over the dose range (25–100 μM) tested. At the same molar concentration, Δ⁸-THC inhibits testosterone hydroxylation to a greater extent than Δ⁹-THC. The kinetic data suggest that the observed inhibition on 5α-reduction and total hydroxylation by the tetrahydrocannabinoids is of the competitive type.     

Interactions of several cannabinoids with the hepatic drug metabolizing system

Spectral interactions of various cannabinoids with rat liver musomes and their effects on several musomal enzymes were studied. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), Δ⁸-tetrahydrocannabinol (Δ⁸-THC), cannabinol (CBN), and cannabidiol (CBD) produced type I spectral changes; the spectral dissociation constants K_s were 42, 37, 46 and 11·2 μM, respectively,. Aminopyrine demethylation was competitively inhibited by Δ⁸-THC, Δ⁸-THC, CBN and CBD, by the latter only in concentrations below 10 μM. The inhibitor constants were found to be 58, 60, 68 and 49 μM, respectively. In a similar way morphine demethylation was inhibited. Δ⁸-THC, however, did not inhibit this reaction, and inhibition by CBD was of mixed type at all concentrations. There was no effect of cannabinoids on aniline hydroxylation. The inhibitory potencies of cannabis constituents on drug metabolism in vitro parallel the in vivo results obtained by interaction studies with hexobarbitone. It must be concluded that CBD, which is by far more potent in inhibiting drug metabolism than other cannabinoids, contributes significantly to the effects of crude cannabis preparations at least in rodents.     

Comparison in mice of pharmacological effects of delta 8-tetrahydrocannabinol and its metabolites oxidized at 11-position

Pharmacological effects of Δ⁸-tetrahydrocannabinol (Δ⁸-THC) and its metabolites, 11-hydroxy-Δ⁸-THC, 11-oxo-Δ⁸-THC and Δ⁸-THC-11-oic acid were compared using mice. The cataleptogenic effect of the 11-hydroxy and 11-oxo metabolites was 5 and 1.5 times greater respectively, than that of the parent compound. The hypothermic effect of Δ⁸-THC, 11-hydroxy-Δ⁸-THC and 11-oxo-Δ⁸-THC was almost equivalent in both potency and duration at a dose of 10 mg/kg i.v., but the metabolites exhibited a somewhat higher potency and longer duration that the parent compound at a dose of 5 mg/kg i.v. In addition, 11-hydroxy- and 11-oxo-Δ⁸-THC were more active to prolong pentobarbital-induced sleeping time than Δ⁸-THC. In spite of the loss of cataleptogenic and hypothermic effects, Δ⁸THC-11-oic acid slightly prolonged pentobarbital-induced sleeping time at a dose of 10 mg/kg i.v. The LD₅₀s (i.v.) with their 95% confidence limits of Δ⁸-THC, 11-hydroxy-Δ⁸-THC and 11-oxo-Δ⁸-THC were estimated to be 27.5 (23.1–32.7), 110.0 (79.1–152.9) and 63.0 (54.5–72.8) mg/kg (P < 0.05), respectively. No animals were killed with the 150 mg/kg dose of Δ⁸-THC-11-oic acid.These results indicate that both 11-hydroxy- and 11-oxo-Δ⁸-THC can be categorized as active metabolites of Δ⁸-THC. Further studies are necessary, however, to clarify whether or not these metabolites contribute, at least in part, to the effect of Δ⁸-THC on biological systems in vivo.     

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.     

Interactions of Δ9-tetrahydrocannabinol with phenobarbital,ethanol and chlordiazepoxide

The acute, reciprocal dose-response interactions between Δ⁹-tetrahydrocannabinol (Δ⁹-THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three depressants — phenobarbital (PB; 10, 20 and 40 mg/kg; IP), ethanol (ETOH; 0.5, 1.0 and 2.0 g/kg; IP), and chlordiazepoxide (CDP; 2.5, 5.0 and 10.0 mg/kg; IP) — were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. Δ⁹-THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three depressants significantly influenced CAR performance but they all decreased photocell activity and impaired rotarod performance at one or more doses. PB and ETOH also decreased heart rate and body temperature at the highest doses. When combined with Δ⁹-THC each of the three drugs at some dose combinations caused greater depressant effects on most measures than caused by either drug alone. Only CDP did not augment the impairment of CAR performance caused by Δ⁹-THC. The highest dose combinations of Δ⁹-THC and each of the three drugs almost completely eliminated photocell activity and rotarod performance. The interactions were also studied after subacute treatment for six days with Δ⁹-THC and/or each of the three depressants. There was clear evidence for tolerance to the effects of Δ⁹-THC and each of the depressants. There was also evidence for tolerance to the effects of PB and ETOH on some measuresbut not CDP. The reduction of effects alone or combined with Δ⁹-THC could be accounted for by assuming a partial loss of potency after subacute treatment that decreased the pharmacologically effective doses of either or both interacting drugs.     

Effect of delta9-tetrahydrocannabinol on rat liver microsomal lipid peroxidation.

In vivo ip administration of saline-Tween 80 suspensions of pure Δ⁹-tetrahydrocannabino (Δ⁹-THC) under both acute (10 and 50 mg/kg) and chronic (10 mg/kg/day for 21 days) conditions, to adult male albino rats inhibited liver microsomal lipid peroxidation. In vitroΔ⁹-THC (0.5–8 μg/mg protein) also markedly lowered NADPH- and ascorbate-induced microsomal lipid peroxidation. Δ⁹-THC was also effective in lowering CCl₄-induced lipid peroxidation in vitro. These results suggest that Δ⁹-THC exerts a stabilizing effect on hepatic microsomal membrane.     

Central excitatory properties of Δ9-tetrahydrocannabinol and its metabolites in iron-induced epileptic rats

The effects of δ⁹-tetrahydrocannabinol (Δ⁹-THC), two of its metabolites, 8β-hydroxy-Δ⁹-THC and 11-hydroxy-Δ⁹-THC, and cannabidiol were comparatively studied by means of an iron-induced cortical focal epilepsy in conscious rats with chronically implanted electrodes. Δ⁹-Tetrahydrocannabinol produced depression of the spontaneously firing epileptic focus, excitatory behavior, generalized after-discharge-like bursts of epileptiform polyspikes and frank convulsions. The pharmacological profiles of the two metabolites differed from that of the parent compound: 11-Hydroxy-Δ⁹-THC did not precipitate convulsions, but it did elicit all the other effects of Δ⁹-THC; the 8β-hydroxy derivative, on the other hand, exerted only two Δ⁹-THC-like effects; that is, it evoked polyspike bursts and convulsions. In contrast, cannabidiol, even in large doses (100 mg/kg) was devoid of all the effects of Δ⁹-THC. Furthermore, pretreatment with cannabidiol markedly altered the responses to Δ⁹-THC in the following ways: focal depression was partially blocked, polyspike activity was enhanced and convulsions abolished. Phenytoin pretreatment elicited similar effects, but it failed to block the Δ⁹-THC-induced convulsions. In general, the cannabinoids exhibit a wide spectrum of CNS effects ranging from focal depression to convulsions; specifically, however, the pharmacological profile of each agent can differ markedly; for example, the convulsant properties of Δ⁹-THC are not a universal characteristic of this class of drugs.     

Involvement of brain histamine in Δ9-tetrahydrocannabinol tolerance and withdrawal

The involvement of brain histamine (HA) in Δ⁹-tetrahydrocannabinol (Δ⁹-THC) tolerance and dependence was studied in rats. Rats treated for 5 days with Δ⁹-THC (2–6 mg/kg, IV) developed tolerance to the hypothermic effects of the drug. Tolerance also developed over the 5 day period to the decrease in brain regional HA concentrations observed after an acute injection of Δ⁹-THC. Administration of the tricyclic antidepressant drug clomipramine hydrochloride to tolerant rats induced a withdrawal-like behavioural syndrome. Accompanying this behaviour was a fall in HA concentrations of the midbrain, cortex, medulla oblongata/pons and the cerebellum. Administration of Δ⁹-THC, but not of the Δ⁹-THC vehicle, prior to clomipramine challenge attenuated both the intensity of the withdrawal-like syndrome and the reductions in brain regional HA concentration.     

Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys

For preclinical toxicologic evaluation, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), Δ⁸-THC, and Cannabis extract were administered po to rats, dogs and monkeys as solutions in either absolute ethanol, sesame oil, or sesame oil with 2.5–9.0% ethanol. All three compounds were significantly more potent in female than in male Wistar-Lewis and Fischer rats. However, within the dosage range of 225–3600 mg/kg, Δ⁹-THC and Δ⁸-THC produced the same lethality, while both isomers were approximately twice as potent as the Cannabis extract. Death due to all three compounds consistently occurred between 36 and 72 hr after treatment regardless of the dose level or sex of the rats. Mortality in rats apparently resulted from severe hypothermia and other central effects. Toxicity was characterized by severe hypothermia, bradypnea, rapid weight loss, inactivity, wide stance, ataxia, muscle tremors, and prostration. Rats treated with equimolar amounts of tetrahydrocannabinol from the three compounds exhibited equivalent diversities and severities of clinical signs. In dogs and monkeys, single oral doses of Δ⁹-THC and Δ⁸-THC between 3000 and 9000/mg/kg were nonlethal. Predominant toxic signs in dogs included drowsiness, ataxia, prostration, anesthesia, tremors, mild hypothermia, salivation, emesis, and anorexia. Toxic signs in monkeys included hyperreactivity to stimuli, lethargy, drowsiness, characteristic huddled posture, slow movements, abnormal eating procedures and sedation. Histopathologic alterations did not occur in either dogs or monkeys.     

Physical withdrawal in rats tolerant to Δ-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist

Tolerance to Δ⁹-tetrahydrocannabinol (Δ⁹-THC) was produced in rats by twice daily injections (15 mg/kg i.p.) for 6.5 days. Administration of the cannabinoid antagonist SR141716A (i.p. or i.c.v.) induced a profound precipitated withdrawal syndrome in Δ⁹-THC-tolerant animals. The syndrome was characterized by a disorganized pattern of constantly changing brief sequences of motor behavior. Autonomic signs were not evident. THC-tolerant animals that were treated with vehicle remained quiet throughout the observation period.     

Tolerance to the effects of Δ9-THC on shuttle-box performance and body temperature

Two groups of rats were trained in a shuttle-box and received Δ⁹-tetrahydrocannabinol (Δ⁹-THC), either before of after being tested. The drug-before group showed tolerance — within 3–6 sessions — to the response-inhibiting effect of THC. The drug-after animals appeared also to be tolerant when they received Δ⁹-THC before being tested. It is concluded that the tolerance to this effect probably is not learned, but has a physiological base. This is corroborated by the finding that during the same study all the animals developed tolerance to the hypothermic effect of Δ⁹-THC.     

Modulation of Δ9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat

1. It has been suggested that the dose of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) that induces hypothermia in the rat increases the release of brain 5-hydroxytryptamine (5-HT). In light of this, we investigated the hypothermia produced by Δ⁹-THC, and the effect the selective serotonin reuptake inhibitor fluoxetine has on this response.
2. A significant dose-dependent decrease in body temperature occurred after i.v. administration of 0.5 to 5 mg kg⁻¹ Δ⁹-THC; maximum decreases being 0.8±0.2°C to 2.9±0.3°C. This hypothermic response was attenuated by the cannabinoid CB₁ receptor antagonist SR 141716.
3. Fluoxetine (10 mg kg⁻¹ i.p.) alone caused a decrease in body temperature of 0.6±0.1°C (n=32, P<0.05) after 40 min. However, pretreatment with fluoxetine (10 mg kg⁻¹ i.p.) 40 min before Δ⁹-THC significantly reduced the Δ⁹-THC-induced hypothermia (n=7–8, P<0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after Δ⁹-THC significantly potentiated the Δ⁹-THC-induced hypothermia, producing a maximum decrease of 3.2±0.3°C.
4. It is suggested that the effect of fluoxetine on the Δ⁹-THC-induced hypothermic response is dependent on the time of its administration relative to that of Δ⁹-THC. Pretreatment with fluoxetine increases extracellular 5-HT due to reuptake inhibition. Increased extracellular 5-HT can activate autoreceptors which may decrease serotonergic activity, thereby reducing the Δ⁹-THC-induced hypothermia. Conversely, when fluoxetine is adminstered after Δ⁹-THC, the reuptake block is thought to potentiate the already activated serotonegic system, hence potentiating the Δ⁹-THC-induced hypothermia.