Albert Weissman

Drugs and Retrograde Amnesia

Publisher Summary The retrograde amnesia (RA) phenomenon occurs in both animals and man and overwhelming evidence exists showing that a single electroconvulsive shock (ECS) treatment given after acquisition produces RA. Because ECS constitutes such a reliable RA treatment, drugs can be studied for their ability to duplicate the effects of this treatment or to antagonize or facilitate its effects. This chapter discusses three types of drugs effects on RA: (a) induction of RA by drugs, (b) drug-induced blockade of the known amnestic action of ECS, and (c) drug-induced facilitation of the amnestic action ECS or of other treatments under conditions in which RA does not ordinarily occur. The most prominent symptom produced by ECS is convulsion. The chapter also discusses various types of convulsant drugs, such as pentylenetetrazol and strychnine. Studies show that pentylenetetrazol produce a profound RA effect in rats and exerts a virtually “complete” RA effect when administered 8 hours after acquisition and substantial RA when administered as long as 4 days after acquisition. The concept of general anesthesia in humans is discussed in the chapter.

Discriminative Stimulus Properties of Δ9‐Tetrahydrocannabinol: Mechanistic Studies

Abstract: Δ9‐Tetrahydrocannabinol (THC) produces a multiplicity of pharmacologic effects including analgesic, antiinflammatory, anticonvulsant, antidiarrheal, antiglaucoma, antihypertensive, and sedative effects. Efforts to elucidate the neurochemical systems mediating the THC effects have used these and related endpoints. However, animal models useful for evaluating the mechanisms by which THC produces its unique subjective effects have only recently been established. The use of drugs as discriminative stimuli provides a means for studying such mechanisms, since generalization data from this test closely correlate with subjective properties observed in clinical studies. The present study examined the ability of various drugs to mimic or block the cue produced by THC In rats. In animals trained to discriminate 3.2 mg/kg THC from vehicle, generalization occurred consistently with cannabinoids such as 11‐OH‐THC, HHC, and nabilone. Stereoselective generalization was also obtained with isomers of a potent analgesic, nantradol; potencies were consistent with results from other endpoints. In contrast, THC cueing was not produced by agents acting on adrenergic, cholinergic, serotonergic, GABAergic, or opiate systems. Similarly, a number of drugs previously reported to antagonize various nonunique effects of THC uniformly failed to block its subjective properties. These results indicate that the subjective properties of THC are mediated through as yet unidentified neurochemical systems.

Selective and potent analgetics derived from cannabinoids.

Abstract: Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (—)‐9‐nor‐9β‐hydroxyhexahydrocannabinol (HHC). A new grouping, the 1‐methyl‐4‐phenylbutyloxy C‐3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C‐5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.

Enhancement of brain [3H]flunitrazepam binding and analgesic activity of synthetic cannabimimetics

Novel, synthetic cannabimimetics and delta 9-tetrahydrocannabinol were found to enhance the binding of [3H]flunitrazepam to mouse brain in vivo. This property, suggestive of facilitation of binding to benzodiazepine receptors, is consistent with the potentiation of the anticonvulsant activity of diazepam against pentylenetetrazol by these compounds. The relative potencies of delta 9-tetrahydrocannabinol and the new cannabimimetics for enhancing [3H]flunitrazepam binding in vivo could also be correlated with their relative analgesic efficacies. Similar pharmacological stereospecificity was displayed for both binding enhancement and analgesic effects. The following order of decreasing potency was observed: N-methyllevonantradol and (-)-CP-55,244 greater than levonantradol, canbisol, CP-42,096 and (-)-CP-55,940 greater than 9-beta-normethyl-9-beta-hydroxyhexahydrocannabinol, nabilone and CP-47,497 greater than delta 9-tetrahydrocannabinol. Dextronantradol, (+)-CP-55,940 and (+)-CP-55,244 were considerably less active than the respective (-)-enantiomers; cannabidiol was inactive. Extensive investigation of structure versus activity led to N-methyllevonantradol and the 3-(2-hydroxyphenyl)cyclohexanols derivative, (-)-CP-55,244, which are approximately 1000-fold more potent than delta 9-tetrahydrocannabinol.

TENIDAP, A STRUCTURALLY NOVEL DRUG FOR THE TREATMENT OF ARTHRITIS : ANTIINFLAMMATORY AND ANALGESIC PROPERTIES

Tenidap is a new anti-rheumatic agent which has clinical properties characteristic of a disease modifying drug combined with acute antiinflammatory and analgesic activity. This paper details tenidaps cyclooxygenase (COX) inhibitory activity and the resulting pharmacological properties in experimental animals. Tenidap inhibited calcium ionophore-stimulated prostaglandin D2 synthesis by rat basophilic leukemia cells (COX-1) with an IC50 of 20 nM. In two different in vitro human test systems, tenidap inhibited COX-1 activity more potently than COX-2, although the relative potency ratio (COX-1/COX-2) differed markedly between the two systems. Tenidap inhibited the COX pathway when added to human blood in vitro (IC50, 7.8 μM) and when administered orally to monkeys, rats and dogs (at 5, 2.5 and 10 mg/kg p.o., respectively) and COX activity measured ex vivo in blood collected 2 to 4 hours post dose. After oral administration to rats, tenidap inhibited carrageenan-induced paw edema with an ED50 of 14 mg/kg and inhibited the glucocorticoid-resistant UV erythema in guinea pigs with an ED50 of 1.4 mg/kg. It retained antiinflammatory activity in adrenalectomized rats indicating that this property is independent of adrenal stimulation. Oral administration of tenidap inhibited the development of adjuvant-induced polyarthritis in the rat and exhibited antinociceptive activity in the murine phenylbenzoquinone and rat acetic acid abdominal constriction tests. These data indicate that tenidap is an effective antiinflammatory and analgesic agent in animal models. These cyclooxygenase-dependent pharmacologic activities do not explain tenidaps disease modifying anti-arthritic properties but add a useful symptom modifying component to its clinical profile.

Ampiroxicam, an anti-inflammatory agent which is a prodrug of piroxicam

Ampiroxicam is a nonacidic ether carbonate prodrug of piroxicam. Our results demonstrate that, in contrast to piroxicam, ampiroxicam does not possess detectable prostaglandin synthesis inhibitory activityin vitro. Ampiroxicam, however, has similarin vivo potency to piroxicam in suppressing paw swelling in rat adjuvant arthritis. In an acute model of paw inflammation in rats, ampiroxicam is less potent than piroxicam itself: the ED50s of ampiroxicam are 9- and 3.5-fold higher than those of piroxicam following a single or multiple (5) daily oral doses, respectively. Using the phenylbenzoquinone stretching test as a method of evaluating acute analgetic activity, the ED50 for ampiroxicam is about 3-fold higher than that of piroxicam. These tests of activity share the property of being partially prostaglandin-dependent. Ampiroxicam itself is not observed in plasma after oral dosing to man [24], nor in the rat, dog, and monkey as reported here. Bioavailability studies show that conversion to piroxicam is about 100%, 90%, 70%, and 50% in these four species, respectively. These results indicate that ampiroxicams anti-inflammatory activity is producedin vivo by conversion to piroxicam and support its credentials as an efficacious prodrug of piroxicam.

The discriminability of aspirin in arthritic and nonarthritic rats

Aspirin, 56 mg/kg IP, was shown to be mildly, but significantly discriminable from saline in a group of 12 nonarthritic rats exposed to a 2-lever fixed ratio 10 drug discrimination protocol for 56 trials. In a concurrently-tested group of 12 rats made arthritic by injection of Mycobacterium butyricum into a hind paw, the discrimination of aspirin from saline was enhanced. The results exemplify how drug discriminability may vary depending on the pathological state of the subjects exposed to drug-discrimination training.

Effects of benzquinamide on avoidance behavior and brain amine levels

Abstract Benzquinamide, the acetate of 2-hydroxy-3-diethylcarbamyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzoquinolizine, interferes with conditioned avoidance behavior in rats and monkeys. After doses of benzquinamide that reliably disrupt avoidance behavior, concentrations of noradrenaline (NA) and serotonin (5-HT) in the brain are within normal limits, and overt sedative or parasympathetic symptoms do not occur. Moreover, benzquinamide is only mildly susceptible to antagonism by monoamine oxidase (MAO) inhibition. The high specificity of behavioral activity demonstrated by benzquinamide contrasts with the nonspecific effects of its parent alcohol : the alcohol is a potent depletor of brain NA and 5-HT, highly susceptible to reversal by an MAO inhibitor, and active in producing reserpine-like symptoms. The rapid and potent effect of benzquinamide on avoidance behavior leads to the conclusion that its avoidance-disrupting activity is mediated by a mechanism other than depletion of NA and 5-HT from the brain.

Drugs as Discriminative Stimuli

Drug studies have long been a magnet for behavioral biologists. The biochemical changes drugs produce in brain, the neurophysiological effects they bring about, their alterations of unconditioned and conditioned behavior, their interactions with stimuli-including drug stimuli-that produce all manner of central effects: all these subjects have been of utmost importance. Drugs may be considered as a class of stimuli with effects so varied that the usual stimuli that psychologists use as independent variables -lights, sounds, feeds, electric shocks -- seem barren by comparison.

Correlation between baseline nondiscriminated avoidance behavior in rats and amphetamine-induced stimulation

SummaryThirty-two rats were first trained to emit a stable baseline of nondiscriminated avoidance behavior. They were then treated with d-amphetamine. Relative and absolute increments in response rates induced by the drug were significantly correlated with baseline shock rates, but not with baseline response rates.