THE LACK OF β-ADRENOCEPTOR INVOLVEMENT IN THE CARDIAC ACTION OF Δ1-TETRAHYDROCANNABINOL IN RATS

1. Rat isolated hearts perfused with Δ¹-THC (0·5 μ/ml) showed a reduction in the rate of beating which was not altered by pretreatment with propranolol (2 μg/ml), atropine (4 μg/ml) or hexamethonium (4 μ/ml). 2. Propranolol (2 μg/ml) also caused a decrease in the rate of beating, which was not affected by pretreatment with Δ¹-THC (0·5 μg/ml). 3. In pithed rats, propranolol (2 mg/kg, i.v.) caused a decrease in the pulse rate, which was not altered by prior administration of Δ¹-THC (1 mg/kg, i.v.). 4. In both preparations, the responses to isoprenaline were markedly reduced or abolished by propranolol, but they were unaffected by Δ¹-THC. 5. It is concluded that the hypotensive and cardiac slowing actions of Δ¹-THC are not mediated by activation of parasympathetic nerves or by β-adrenoceptor blockade.     

TOLERANCE TO THE EFFECTS OF Δ1-TETRAHYDROCANNABINOL ON THE PRESSOR RESPONSES TO NORADRENALINE IN RATS

1. The depressor response, but not the cardiac slowing response, to the acute intravenous administration of delta 1-THC (1 mg/kg) was significantly reduced in urethane anaesthetized rats, which had been treated with daily injections of delta 1-THC (2 mg/kg, i.p.) for 10 days (P less than 0.01). 2. No significant differences in either the depressor or the negative chronotropic effects of an acute intravenous injection of delta 1-THC (1 mg/kg) were observed in anaesthetized rats which had been treated with PVP (8 mg/kg per day, i.p.) for 10 days. 3. The depressor and cardiac slowing responses to an acute intravenous dose of delta 1-THC (1 mg/kg) were not significantly different between delta 1-THC- and PVP-treated animals which had been pithed. 4. The potentiating effects of delta 1-THC on the pressor responses to intravenously administered noradrenaline were significantly reduced (P less than 0.001) in urethane anaesthetized rats which had been treated with delta 1-THC, but not in anaesthetized PVP-treated animals. 5. Tolerance to the potentiating effect of delta 1-THC on the responses to noradrenaline has also been demonstrated in anaesthetized delta 1-THC-treated rats, but not in pithed delta 1-THC treated ones. 6. It is concluded that the development of tolerance to the depressor action of delta 1-THC, and its potentiating effect on the noradrenaline pressor responses requires the presence of an intact central nervous system.     

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.     

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.     

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.     

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.     

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.     

THE EFFECT OF δ9-TETRAHYDROCANNABINOL (δ9-THC) ON THE TURNOVER RATE OF BRAIN SEROTONIN OF THE RAT

1. One isotopic and three non-isotopic methods were used to determine the effect of an acute intravenous dose of Δ⁹-tetrahydrocannabinol (Δ⁹-THC, 2 mg/kg) on the rat brain turnover rate of serotonin. 2. In control animals the turnover rate of serotonin was about 2 nmol/g per h. This rate was not altered by Δ⁹-THC when it was calculated from the rise of 5-hydroxyindoleacetic acid following probenecid or from the rise of serotonin following pargyline. 3. Δ⁹-THC did not alter the serotonin turnover rate when it was calculated from the conversion of ³H-tryptophan to ³H-serotonin. 4. The serotonin turnover rate was significantly increased by Δ⁹-THC when the rate was calculated from the decline of 5-hydroxyindoleacetic acid following pargyline. 5. These results suggest that Δ⁹-THC does not alter the turnover of rat brain serotonin. The previously reported Δ⁹-THC-induced changes in body temperature and increased brain levels of 5-hydroxyindoleacetic acid may be mediated by some other mechanism such as interference by Δ⁹-THC of the vesicular binding of serotonin.     

Role of opioidergic component in the antihypertensive effect of clonidine

The role of opioidergic system in the antihypertensive effect of clonidine was investigated in albino normotensive and renal-DOCA-salt hypertensive models of rats. Clonidine (2.5, 5 and 10.0 micrograms/kg, iv) produced a dose-related depressor response. Yohimbine (2 mg/kg, ip) blocked the clonidine-induced responses in both normotensive and hypertensive rats. Naloxone (2 mg/kg, iv) blocked the clonidine-induced depressor responses in hypertensive rats, but not in normotensive animals. Morphine (0.11 mg/kg, iv) produced a depressor response in both normotensive and hypertensive rats. Yohimbine (1 mg/kg, iv) did not affect the hypotensive effect of morphine in normotensive or hypertensive rats, whereas pretreatment with naloxone significantly blocked the hypotensive effect of morphine in both groups of animals. It is concluded that the hypotensive effect of clonidine in hypotensive rats could be due to an opioidergic mechanism since it is blocked by both naloxone and yohimbine.     

Antipyretic, analgesic and anti-inflammatory effects of delta 9-tetrahydrocannabinol in the rat

The effects on body temperature produced by graded doses of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and phenylbutazone were compared in both normal and pyretic rats. Dose related hypothermic responses were produced by the oral administration of Δ⁹-THC in normal animals. Moreover, Δ⁹-THC significantly reduced elevated temperatures in yeast-induced pyretic rats to near normal levels at doses which exhibited little hypothermic activity in normal rats. The oral antipyretic potency of Δ⁹-THC was approximately 2 times that of phenylbutazone. The comparative oral antinociceptive activity of Δ⁹-THC and selected narcotic and non-narcotic analgesics was determined by the increase in response latency to pressure applied to normal and yeast-inflamed paws. Δ⁹-THC administered orally was essentially inactive at dose levels below those producing pronounced central nervous system depression. The oral anti-inflammatory efficacy of Δ⁹-THC was compared to phenylbutazone and acetylsalicylic acid. Δ⁹-THC was ineffective in inhibiting carrageenin-induced edema of the rat paw following acute or chronic administration.     

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.     

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.     

Contribution of the metabolite 7-hydroxy-Δ1-tetrahydrocannabinol towards the pharmacological activity of Δ1tetrahydrocannabinol in mice

Tritium-labelled 7-hydroxy-Δ¹-tetrahydrocannabinol (³H-7-hydroxy-Δ¹-THC, specific activity 571 Ci/mmole) was prepared from ³H-Δ¹-THC by oxidation with a rat liver microsome preparation. Brain levels of 7-hydroxy-Δ¹-THC and Δ¹-THC in mice were measured 20 min after intravenous injection of either Δ¹-THC (2.0, 1.0 and 0.5 mg/kg) or 7-hydroxy-Δ¹-THC (1.0, 0.5 and 0.25 mg/kg) and correlated with the inhibition of spontaneous motor activity. A theoretical dose-response relationship for Δ¹-THC in the absence of the metabolite was derived on the assumption of additivity of the behavioural effects due to Δ¹THC and 7-hydroxy-Δ¹-THC present together in the mouse brain. The theoretical dose-response line for Δ¹THC and that obtained experimentally for 7-hydroxy-Δ¹-THC were parallel; on the basis of brain concentrations, 7-hydroxy-Δ¹-THC was found to be more potent than Δ¹-THC in producing behavioural changes and the calculated equipotent molar ratio was 7.1. The ratio of the concentrations of Δ¹THC and 7-hydroxy-Δ¹-THC in the mouse brain 20 min after intravenous injection of Δ¹-THC was 5.3 and the contribution of the metabolite to the overall behavioural effect was calculated as 55–63 per cent. Although metabolites of 7-hydroxyΔ¹-THC accounted for only about 10 per cent of the radioactivity present in the mouse brain 20 min after intravenous injection of ³H-7-hydroxy-Δ¹-THC, about 50 per cent of the radioactivity in the blood was present as a chromatographically more mobile material which has not yet been identified.     

Blunted pressor responsiveness to intravenous quinpirole in conscious, chronic spinal cord-transected rats: peripheral vs. spinal mechanisms

Intravenous quinpirole (1 mg/kg) in conscious rats with chronic spinal cord transection (at T5-T7) induced an initial pressor effect, which was significantly reduced in both magnitude and duration compared with that in sham-operated rats, which was then followed by a long-lasting depressor effect. To distinguish the spinal and/or peripheral origin of this phenomenon, conscious, spinal cord-transected rats were also pretreated with either intravenous (0. 5 mg/kg), intrathecal (40 microg/kg) or combined intravenous and intrathecal domperidone, a dopamine D(2) receptor antagonist that does not cross the blood-brain barrier. Intravenous pretreatment with domperidone enhanced, but did not completely restore, the pressor effect of quinpirole, and had no effect upon the depressor component. However, both the depressor component and the reduction of the pressor effect induced by spinal section were fully abolished by intrathecal or combined intrathecal and intravenous domperidone. Quinpirole-induced changes in mean aortic pressure were also fully abolished by intravenous pretreatment with metoclopramide (5 mg/kg). Neither the pressor nor the bradycardiac response to intravenous phenylephrine differed between sham-operated and spinal rats. These results suggest that the blunted pressor response to quinpirole after spinal cord transection is related to an enhanced spinal dopamine D(2) receptor-mediated depressor effect rather than to hypersensitivity of peripheral dopamine D(2) receptors or vascular hyporesponsiveness to alpha(1)-adrenoceptor stimulation. Thus, in conscious intact rats, the prominent central pressor effect of quinpirole seems to oppose, not only a peripheral sympathoinhibitory depressor effect, as previously thought, but also a spinal depressor effect.     

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.     

The lack of beta-adrenoceptor involvement in the cardiac action of delta 1-tetrahydrocannabinol in rats

1. Rat isolated hearts perfused with delta 1-THC (0.5 micrograms/ml) showed a reduction in the rate of beating which was not altered by pretreatment with propranolol (2 micrograms/ml), atropine (4 micrograms/ml) or hexamethonium (4 micrograms/ml). 2. Propranolol (2 micrograms/ml) also caused a decrease in the rate of beating, which was not affected by pretreatment with delta 1-THC (0.5 micrograms/ml). 3. In pithed rats, propranolol (2 mg/kg, i.v.) caused a decrease in the pulse rate, which was not altered by prior administration of delta 1-THC (1mg/kg, i.v.). 4. In both preparations, the responses to isoprenaline were markedly reduced or abolished by propranolol, but they were unaffected by delta 1-THC. 5. It is concluded that the hypotensive and cardiac slowing actions of delta 1-THC are not mediated by activation of parasympathetic nerves or by beta-adrenoceptor blockade.     

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.     

Mechanism of the depressor response to dopamine in the rat treated with phenoxybenzamine.

Alterations of hypotensive responses to dopamine by antagonists were characterized in alpha-blocked, anaesthetized rats. Responses were not affected by d-propranolol (0.1 mg/kg) whereas d,1-propranolol (0.1 mg/kg) or haloperidol (1.0 mg/kg) attenuated them; higher doses of inhibitors (1.0 mg/kg; 5.0 mg/kg, respectively) failed to produce a higher inhibition, but combinations of low doses abolished the depressor responses. In adrenalectomized rats, hypotensive responses decreased; haloperidol always attenuated the responses while d,1-propranolol became ineffective. Dopamine produced an enhancement of plasma adrenaline and noradrenaline levels, which was decreased by d,1-propranolol and increased by haloperidol. The data suggest that in rats the depressor component of dopamine is due to activation of both dopaminergic and beta-adrenoceptors. The beta component appears to be due to the release of adrenaline. The results also support the concept of the existence in sympathetic nerve endings and adrenal glands of stimulatory beta-adrenergic and inhibitory dopaminergic prejunctional receptors.     

AN INVESTIGATION INTO THE MECHANISMS OF THE CARDIOVASCULAR EFFECTS OF 5-HYDROXYTRYPTAMINE IN CONSCIOUS NORMOTENSIVE AND DOCA-SALT HYPERTENSIVE RATS

• 1 The actions of intravenously administered 5-hydroxytryptamine (5-HT) have been analysed in conscious DOCA-salt hypertensive rats using selective 5-HT receptor agonists and antagonists to determine the receptor mechanisms involved and to compare them with those in conscious normotensive rats.
• 2 In both normotensive and hypertensive rats 5-HT, 3 and 10 μg i.v., produced a complex triphasic effect on blood pressure consisting of an initial short lasting depressor response, which was followed by a pressor response and then, finally, a hypotensive phase. Marked decreases in heart rate were observed immediately after dosing, which were followed by small increases in rate.
• 3 The selective 5-HT₃-receptor agonist, 2-methyl 5-HT, 3–30 μg i.v., produced immediate and marked dose-related decreases in blood pressure and heart rate in both normotensive and DOCA-salt hypertensive rats. The 5-HT₃-receptor antagonist, MDL 72222, 0.03 and 0.1 mg/kg i.v., antagonised these effects in both normotensive and DOCA-salt hypertensive rats. Treatment with MDL 72222, 0.3 mg/kg i.v., abolished the initial depressor response and bradycardia produced by 5-HT.
• 4 The 5-HT₂ receptor agonist, α-methyl 5-HT, 3–30 μg i.v., produced dose-related increases in blood pressure which were significantly greater in magnitude in DOCA-salt hypertensive than normotensive rats. Bradycardia was observed consistently at 30 μg only. The 5-HT₂ receptor antagonist, ketanserin, 0.03-0.3 mg/kg i.v., caused a dose-dependent antagonism of the pressor responses produced by α-methyl 5-HT, but had no effect on the increases in blood pressure produced by angiotensin. Ketanserin also antagonised the pressor responses produced by 5-HT in rats pretreated with MDL 72222.
• 5 5-Carboxamidotryptamine (5-CT), the selective ‘5-HT₁-like’ receptor agonist, at doses of 0.1–3 μg i.v. produced dose-related decreases in blood pressure which were more pronounced in the DOCA-salt hypertensive rats than in normotensive rats. These depressor responses were dose-dependently antagonised by methiothepin, 0.3 and 1 mg/kg, i.v. which did not antagonise the depressor responses produced by isoprenaline 0.1 μg/kg i.v. In rats pretreated with MDL 72222 and ketanserin, 5-HT produced dose-related depressor responses which were also antagonised by methiothepin 1 mg/kg i.v. and presumably mediated by 5-HT₁-like receptors.
• 6 In this study, selective 5-HT receptor agonists and antagonists have been used to mimic and block, respectively, the various phases of the 5-HT response. It is concluded that in the conscious rat, the complex cardiovascular effects of 5-HT involve stimulation of at least three different 5-HT receptors (for nomenclature see Bradley, Engel, Feniuk, Fozard, Humphrey, Middlemiss, Mylecharane, Richardson & Saxena, 1986). The initial depressor response and bradycardia involves activation of 5-HT₃-receptors, the secondary vasopressor effect, which is significandy greater in DOCA-salt than normotensive rats results from stimulation of 5-HT₂ receptors and the late vasodepressor response is due to vasodilatation via ‘5-HT₁-like’ receptors.

     

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.