R. Duane Sofia

The effect of Δ1-tetrahydrocannabinol on serotonin metabolism in the rat brain

Abstract Δ1-Tetrahydrocannabinol significantly altered 5-HT metabolism in the rat brain. Whole brain levels of 5-HT were elevated 66% over control 30 minutes after administration of 20 mg/kg of Δ1-THC. The hypothalamus plus midbrain region and cerebellum were most affected and apparently accounted for the overall increase seen in the whole brain levels of 5-HT. Since Δ-THC.did not affect MAO activity, the increase in 5-HT was evidently not due to inhibition of its degradation. However, synthesis rate of 5-HT was significantly reduced (50%) by Δ1-THC. Furthermore, pretreatment with Δ1-THC retarded the rate of reserpine-induced depletion of brain 5-HT. Alteration of the vesicular membrane is suggested as a possible mechanism for the effects of Δ1-THC on 5-HT metabolism.

Comparison of four vehicles for intraperitoneal administration of Δ1-tetrahydrocannabinol*

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Depressant effect of Δ1-tetrahydrocannabinol enhanced by inhibition of its metabolism

Abstract Prolongation of barbital sleeping time in mice by Δ1-tetrahydrocannabinol (Δ1-THC), 10 and 20 mg/kg, i.p., was enhanced when its hydroxylation to the 7-hydroxymetabolite was blocked by SKF 525-A (β-diethylaminoethyldiphenylpropylacetate hydrochloride), 12.5 and 25 mg/kg, i.p., which inhibits the drug-metabolizing microsomal enzymes. The SKF-525 alone had slight effect. Sleeping time was reliably longer after the lower dose of both compounds than afer the higher dose of either one alone. This central depressant effect of Δ1-THC is thus due to the parent compound rather than its metabolite.

Acute and chronic effects of δ9-tetrahydrocannabinol on food intake by rats

The effects of intraperitoneally injected δ9-tetrahydrocannabinol (THC) were compared with d-amphetamine sulfate (d-AMP) on food intake in rats which were given access to food for 6 hrs each day. Food intake was markedly reduced in a dose-related fashion by THC (2.5 and 5.0 mg/kg) in the first 2 hrs after drug administration. This anorexic effect persisted for the next 4 hrs and even on the next day. The anorexic potency of d-AMP (1.25 and 2.5 mg/kg) was approximately twice that of THC in the initial 2-hrs interval after a single dose, but during the next 4 hrs and on the next day there was a compensatory increase in food consumption. Daily administration of THC (2.5 mg/kg) for 9 days greatly decreased food intake and body weight gain of animals which were injected immediately before feeding, but had little effect on animals injected 16 hrs before feeding.

Anticonvulsant activity of Δ9-tetrahydrocannabinol compared with three other drugs

Delta9-tetrahydrocannabinol (THC) was compared with diphenylhydantoin (DPH), phenobarbital (PB) and chlordiazepoxide (CDP) using several standard laboratory procedures to determine anticonvulsant activity in mice, i.e., the maximal electroshock test (MES), and seizures induced by pentylenetetrazol, strychnine and nicotine. In the MES test, THC was the least potent and DPH the most potent blocker of hind limb tonic extensor convulsions whereas THC was the most potent and DPH the least potent in increasing the latency to this response and in preventing mortality. Seizures and mortality induced by pentylenetetrazol or by strychnine were enhanced by THC and DPH and were blocked by PB and CDP. In the test with nicotine, none of the four anticonvulsant agents prevented seizures; DPH was the only one which failed to increase latency; THC and DPH were less potent than PB and CDP in preventing mortality. THC most closely resembled DPH in the tests with chemical convulsant agents, but a sedative action of THC, resembling that of PB and CDP, was indicated by low ED5 0 for increased latency and for prevention of mortality in the MES test.

The effect of Δ1-tetrahydrocannabinol on the uptake of serotonin by rat brain homogenates

Abstract The uptake of 14C-serotonin by rat brain homogenates (synaptosomes) was inhibited by Δ1-tetrahydrocannabinol in concentrations of 1 × 10−7 M and greater. The antidepresdant agent desipramine had the same effect but showed greater potency, with a concentration as low as 1 × 10−8 M being needed to inhibit 14C-serotonin uptake.

The interaction of 9 -tetrahydrocannabinol pretreatment with various sedative-hypnotic drugs.

Pretreatment with a fixed dose of δ9-THC (20.0 mg/kg) produced a significant increase in the duration of action and number of mice exhibiting loss of the righting reflex (decrease in hypnotic dose50) after administration of several doses of nine different sedative-hypnotic drugs. Moreover, pretreatment with various doses of THC (0.625 to 40.0 mg/kg) caused a significant reduction in the onset to and duration of sleeping time of most of the sedative-hypnotic drugs tested. Careful statistical examination of all parameters measured revealed a rank order of sensitivity to the depressant actions of THC as follows: ethchlorvynol > meprobamate > hexobarbital > ethinamate > glutethimide > chloral hydrate > ethanol > methaqualone > paraldehyde.

Antitussive activity of some naturally occurring cannabinoids ins anesthetized cats

Experimental cough was elicited in pentobarbital-anesthetized cats by either electrical stimulation of the superior laryngeal nerve or by mechanical stimulation of the tracheal mucosa. Intravenous administration of delta9-tetrahydrocannabinol (THC) effectively reduced the amplitude of the cough response in both these models of experimentally induced cough with ED50 values (AtD50) of 1.84 and 0.78 mg/kg, respectively. This cough suppressant activity of THC was more similar to codeine-PO4 than dextromethorphan-HBr. On the other hand, both cannabinol (CBN) and cannabidiol (CBD) were devoid of antitussive activity at doses as high as 10.0 mg/kg.

Inactivity of ?9-tetrahydrocannabinol in antidepressant screening tests

With several standard procedures commonly used to detect antidepressant activity in experimental animals, Δ9-tetrahydrocannabinol (THC) was virtually inactive over a wide range of dose. The tests were (a) reversal of tetrabenazine-induced depression in mice, (b) reversal of reserpine-induced hypothermia in rats, (c) enhancement of yohimbine toxicity in mice, (d) inhibition of tremors and salivation induced by tremorine in mice. These findings are discussed with respect to previous studies indicating THC may possess antidepressant activity in animals and humans.

The effect of overcrowding stress on the development of adjuvantinduced polyarthritis in the rat

three drugs, particularly so with sulphasalazine, and R E F E R E N C E S appear to reflect fairly closely the relative prophylactic value of the drugs as used clinically. supported by a research grant from the Mersey Regional Health Authority. Watt, J . , McLean, C., Marcus, R. (1979) J . Pharm, Pharmacol. 3 I : 645-646 Watt, J., Marcus, R. (1980) Proceedings. 7th Symposium of the International Committee on Laborator” This work was