Electrophysiological demonstration of both alpha 2-agonist and antagonist properties of RX 781094.

The effects of RX 781094, a new and potent alpha 2-adrenoceptor antagonist, on locus coeruleus (LC) unit activity were examined. Low doses of RX 781094 produced suppression of spontaneous LC unit activity which could be reversed with yohimbine. The increase in LC firing produced by WB 4101 could also be reversed with a low dose of RX 781094. Thus, at low doses, RX 781094 has clonidine-like alpha 2-agonist activity. At higher doses, RX 781094 reversed the effects of clonidine and markedly shifted the dose of clonidine required to suppress LC unit activity. These data suggest that at high doses RX 781094 has alpha 2-antagonist properties. It is concluded that RX 781094 may be a partial agonist at alpha 2-adrenoceptors in the CNS.

Gabamimetic properties of anxiolytic drugs.

Diazepam (5 mg/kg, ip) and tracazolate (40 mg/kg, ip), a nonbenzodiazepine anxiolytic, blocked electrically-induced head-turning without producing sedation. Bicuculline and picrotoxin, GABA antagonists, at doses not affecting head-turning (2 mg/kg, ip) antagonized the effects of diazepam and tracazolate on head-turning. However, at the same dose, bicuculline was more effective as an antagonist of diazepam whereas picrotoxin was more effective as an antagonist of tracazolate. These results suggest that benzodiazepine as well as nonbenzodiazepine anxiolytics possess GABAmimetic activity. The difference in potency between bicuculline and picrotoxin as antagonists of diazepam and tracazolate may be related to their reported differences as GABA antagonists (e.g., site of receptor interaction).

Effects of acute and subacute antidepressant treatment on kindled seizures in rats.

The effects of acute and subacute administration of the tricyclic antidepressants imipramine and amitriptyline, and the atypical antidepressants mianserin and iprindole, on seizures kindled from the amygdala and the cortex were examined. Whereas amitriptyline selectively antagonized seizures kindled from the amygdala after a single dose, neither amitriptyline nor imipramine was any more effective in antagonizing seizures kindled from the amygdala than from the cortex following subacute treatment. Both acute and subacute administration of iprindole failed to significantly alter seizures kindled from either site. Although only the highest acute dose of mianserin tested selectively attenuated amygdaloid seizures, a lower dose that was ineffective when given acutely, was selective when given subacutely. In contrast to an earlier report, the present findings suggest that kindling may not be a particularly useful model for the evaluation of potential antidepressant agents.

Comparative diuretic activity of delta9-tetrahydrocannabinol, cannabidiol, cannabinol and hydrochlorothiazide in the rat.

Orally administered delta9-tetrahydrocannabinol (THC) produced a dose-dependent increase in urine output in hydrated rats similar in mg/kg potency and magnitude of effect to hydrochlorothiazide (HCT). Whereas HCT promoted marked excretion of Na+, K+ and Cl- and an increase in the urinary Na+/K+ at all diuretic doses (1.25-20.0 mg/kg), THC had only a slight effect on Na+ and K+ excretion but not Cl- even after the highest dose tested (20.0 mg/kg). Hypophysectomy and adrenalectomy abolished the diuretic effect of THC, thus suggesting both central and peripheral sites of action for the diuretic effect of THC. Tolerance to the effect on urine output by THC developed after 15 days of repeated dosing, while urine output and electrolyte excretion remained significantly elevated after 25 days of HCT administration.

Effect of concurrent administration of aspirin, indomethacin or hydrocortisone with gold sodium thiomalate against adjuvant-induced arthritis in the rat.

The activity of gold sodium thiomalate (GST) given i.m. to adjuvant-induced polyarthritic rats was studied alone or in combination with active doses of aspirin, indomethacin and hydrocortisone. In addition to paw volume and body weight changes, erythrocyte sedimentation rate, serum albumin/globulin and gold levels as well as plasma activities of beta-glucuronidase, acid phosphatase, lysozyme and lactic acid dehydrogenase were measured. In prophylactic studies the beneficial activity of GST was unaffected by aspirin, suggesting a positive drug interaction, but additive with indomethacin or hydrocortisone for the 1st but not 2nd lesion of the disease. These results were closely correlated with increased serum gold levels. Similar clinical findings were observed in therapeutic studies except that a positive drug interaction occurred between GST and hydrocortisone. Unlike in the prophylactic experiments, serum gold levels were unaffected by any of the agents tested in the therapeutic studies.

Comparative effects of various naturally occurring cannabinoids on food, sucrose and water consumption by rats.

The effects of intraperitoneally injected detla9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) were compared to d-amphetamine sulfate (d-AMP) on food and water consumption and intake of two different concentrations of sucrose solutions. Three groups of rats were given the following dietary regimens within a 6-hr feed period day: 1 - water and dry food; 2 - water, dry food and five percent sucrose solution; 3 - water, dry food and 20% sucrose solution. Food and water consumption were dramatically reduced by each test drug at feeding periods immediately following and in some instances up to 4 days after dosing in all 3 groups. However, sucrose consumption was much less affected by each cannabinoid, inidcating a preference for sweet calories, whereas d-AMP had an equal anorexic action on both food and sucrose consumption. These data suggest for the first time in rats that a preference for sweet calories occurs during an overall anorexic effect of THC, CBN and CBD.

Inhibition of the primary lesion of adjuvant. induced polyarthritis in rats (18-hour arthritis test) for specific detection of clinically effective anti-arthritic drugs.

Adjuvant-induced polyarthritis can be induced in rats 14 to 21 days after subplantar injection of 0.1 ml of a 0.5% suspension of Mycobacterium tuberculosis in heavy mineral oil into a hind paw. However, edema volume of the injected pay (primary lesion) developed rapidly and reached a peak in 18 hours after injection and persisted at this level for up to 90 hours. A single oral dose of 25 clinically effective or experimental antiarthritic agents given 1 hour prior to M. tuberculosis injection and tested 18 hours later significantly inhibited edema formation in a dose-related fashion. Only D-penicillamine and azathioprine which are clinically effected, gave false-negative responses in this test. However, cyclophosphamide, another immunosuppressive like azathioprine, was effective. The ED50 values for most drugs in this test were at least 2-fold greater than in the carrageenan edema test. On the other hand, of the 17 drugs considered as false-positives in the carrageenan test only the antihistaminic agent, chlorpheniramine maleate, was effective in the 18-hour arthritis test, whereas several other agents with this activity but different chemical structure proved ineffective. In addition, 18 other agents from various classes of therapeutic agents were also tested and found ineffective in each test. These data suggest that the 18-hour arthritis test in rats is highly specific and a more reliable screening procedure than carrageenan-induced edema for detecting potentially useful antiarthritic agents. The practical advantages of this method are also discussed.

Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats.

The analgesic effectiveness of delta-9-tetrahydrocannabinol (THC), a crude marihuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO-4 and aspirin following oral administration was directly compared in mice using the acetic-induced writhing and hot plate tests and the Randall-Selitto paw pressure test in rats. THC and morphine were equipotent in all tests except that morphine was significantly more potent in elevating pain threshold in the uninflamed rat hind paw. In terms of THC content, CME was nearly equipotent in the hot plate and Randall-Selitto tests, but was 3 times more potent in the acetic acid writhing test. On the other hand, CBN, like aspirin, was only effective in reducing writhing frequency in mice (3 times more potent than aspirin) and raising pain threshold of the inflamed hind paw of the rat (equipotent with aspirin). CBD did not display a significantly analgesic effect in any of the test systems used. The results of this investigation seem to suggest that both THC and CME possess narcotic-like analgesic activity similar to morphine, while CBN appears to be a non-narcotic type analgesic like aspirin.