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R Karler

Publications and source records attributed to R Karler.

At least 55 records · Page 3Linked to original sources
PubMed1983

Effects of delta 9-tetrahydrocannabinol on cat spinal motoneurons.

The influence of delta 9-tetrahydrocannabinol (delta 9-THC) on cat spinal motoneurons was investigated with intracellular recording techniques in order to identify possible mechanisms of action of the drug's central excitatory and depressant properties. delta 9-THC increased the amplitude of the excitatory postsynaptic potentials (EPSPs) and decreased the amplitude of the inhibitory postsynaptic potentials (IPSPs); these excitatory effects do not appear to be the result of changes in the afferent input. However, an observed increase in membrane resistance may account for, or contribute to, the enhanced EPSPs. The cannabinoid also concomitantly caused depression, as evidenced by a rise in the firing threshold for the motoneuron action potential. The responses of the motoneuron to the drug suggest synaptic sites and mechanisms of action.

Action Potentials↗
PubMed1983

Influence of different barbiturate anesthetics on delta-9-tetrahydrocannabinol effects on spinal monosynaptic reflexes.

Two barbiturates, pentobarbital and methohexital, were used as general anesthetics to evaluate their interactions with the effects of delta-9-tetrahydrocannabinol (delta-9-THC) on spinal monosynaptic reflexes in cats with transected spinal cords and ischemically destroyed brains. In animals initially anesthetized with pentobarbital, delta-9-THC over a wide dosage range produced only an enhancement of the reflex, whereas in methohexital-treated animals only depression was elicited. Because delta-9-THC is known to produce both excitatory and depressant effects in conscious animals, the results of the present study demonstrate that the choice of anesthetic may determine which effects manifest themselves. Therefore, if anesthesia is used in the investigation of any cannabinoid, the possibility of such interactions must be considered when interpreting the results.

Anesthetics↗
PubMed1982

Influence of 22-day treatment on the anticonvulsant properties of cannabinoids.

Mice were given delta-9-tetrahydrocannabinol (delta-9-THC) cannabidiol (CBD) or phenytoin (PHT) daily for 22 days. Drug activity was measured weekly in three different anticonvulsant tests: the maximal electroshock threshold, the 60-Hz-electroshock threshold and the 6-Hz-electroshock threshold. In order to correlate potential pharmacodynamic and pharmacokinetic changes resulting from repeated treatment, brain-drug concentrations were determined at each test time. The results from the delta-9-THC study indicate that, although tolerance developed in all three tests, there were no changes in the brain-drug concentration. For CBD the pharmacodynamics were strikingly different: an increase in sensitivity to the drug developed in two of the tests, tolerance in only one test. Here again, there were no changes in brain-drug concentrations. The results of the PHT study differed from both the cannabinoids, for tolerance developed in one test, an increase in sensitivity in one test, and the activity was unchanged in the third test. Again, the brain concentrations remained constant throughout. The results demonstrate that both tolerance and increased sensitivity can develop concomitantly with anticonvulsant effects of the cannabinoids and PHT, and that these modifications in drug activity appear to result from cellular or functional rather than dispositional changes.

Animals↗
PubMed1982

Central excitatory properties of delta 9-tetrahydrocannabinol and its metabolites in iron-induced epileptic rats.

The effects of delta 9-tetrahydrocannabinol (delta 9-THC), two of its metabolites, 8 beta-hydroxy-delta 9-THC and 11-hydroxy-delta 9-THC, and cannabidiol were comparatively studied by means of an iron-induced cortical focal epilepsy in conscious rats with chronically implanted electrodes. delta 9-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-delta 9-THC did not precipitate convulsions, but it did elicit all the other effects of delta 9-THC; the 8 beta-hydroxy derivative, on the other hand, exerted only two delta 9-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 delta 9-THC. Furthermore, pretreatment with cannabidiol markedly altered the responses to delta 9-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 delta 9-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 delta 9-THC are not a universal characteristic of this class of drugs.

Animals↗
PubMed1982

Kindling-like effect induced by repeated corneal electroshock in mice.

The present study demonstrates that with the use of corneal electrodes mice can be kindled to minimal convulsions by repeated 60-Hz electroshocks. The efficacy of kindling was found to be dependent upon several stimulus parameters, including duration and intensity as well as the intertrial interval. Because the complexity and generalization of the minimal convulsions increased with the number of electroshock treatments, it was apparent that such kindling had quantitative as well as qualitative characteristics. Moreover, the fact that 50% of the mice remained completely kindled to minimal convulsions 8 weeks after cessation of repeated stimulation indicated that the phenomenon is relatively long-lived. Finally, the increase in CNS excitability associated with kindling extended to some, but not all, chemo- and electroshock tests of excitability. Altogether, the results show that mice kindled by corneal electrode stimulation have many features in common with animals kindled by stimulation of discrete brain areas. Because the procedure can readily and rapidly yield large numbers of kindled animals, an important application for the method will be in the evaluation of drug effects on kindled animals.

Animals↗
PubMed1981

Post-column derivatization procedure for the colorimetric analysis of tissue cannabinoids separated by high-performance liquid chromatography.

A new method for quantitating cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) in mouse plasma and brain involves (1) the separation of CBD and THC from their major metabolites by the use of isocratic, reversed-phase high-performance liquid chromatography (HPLC), and (2) the on-line reaction of the cannabinoids with Fast Blue Salt B (FBB) as a the former elute from the column; the colored cannabinoid-FBB derivatives are then detected at 490 nm in a spectrophotometer with a sensitivity of less than 50 ng. In addition to this HPLC--FBB analytical procedure, a method for extracting CBD and THC from brain and plasma is described, and selected examples illustrate the procedure's application to the analysis of CBD and THC in mouse plasma and brain samples taken from animals injected with these two cannabinoids.

Animals↗
PubMed1981

Excitatory and depressant effects of delta 9-tetrahydrocannabinol and cannabidiol on cortical evoked responses in the conscious rat.

The influences of delta 9-tetrahydrocannabinol (THC) and cannabidiol on electrically evoked cortical potentials of conscious rats with chronically implanted electrodes were investigated. Specifically, the cannabinoids' effects on a transcallosal evoked response were compared with those of ethosuximide, phenytoin, and pentylenetetrazol. THC produced dose-related opposite effects: Low doses increased the amplitude of the response, whereas higher doses reduced the response. Other drugs that can cause or exacerbate seizures, i. e., phenytoin and pentylenetetrazol, also increased the amplitude of the cortical response. In contrast, cannabidiol, over a wide dosage range, caused only depression. Ethosuximide, like cannabidiol, elicited a depressant effect. The data indicate that under the conditions of the present investigation, cannabidiol shares electrophysiological properties with ethosuximide but not with phenytoin, and that cannabidiol is a relatively selective, centrally acting drug. In addition, our findings support the suggestion that augmentation of neurotransmission in central pathways may contribute to the convulsant actions of THC, and the cannabinoids' depressant effects may, at least partially, account for their anticonvulsant actions.

Animals↗
PubMed1980

Subacute cannabinoid treatment: anticonvulsant activity and withdrawal excitability in mice.

1 The effects of subacute treatment with cannabidiol, delta 9-tetrahydrocannabinol (delta 9-THC), phenytoin and phenobarbitone on anticonvulsant activity and on withdrawal excitability in mice were compared in three electrically induced seizure-threshold tests. 2 In the maximal electroshock-threshold test, subacute treatment did not alter the anticonvulsant activity of cannabidiol, phenytoin or phenobarbitone, but tolerance developed to delta 9-THC. 3 In the 60 Hz electroshock-threshold test, the activity of delta 9-THC and cannabidiol did not change, but tolerance developed to phenobarbitone, and there was an increase in sensitivity to phenytoin. 4 In the 6 Hz electroshock-threshold test, there was an increase in sensitivity to both delta 9-THC and cannabidiol, there was tolerance to phenobarbitone, while the activity of phenytoin did not change. 5 Although tolerance developed in some of the seizure-threshold tests to delta 9-THC and phenobarbitone, tolerance to cannabidiol and phenytoin did not develop in any of the tests. 6 Hyperexcitability followed withdrawal from only delta 9-THC (6 Hz and 60 Hz electroshock-threshold tests) and phenobarbitone (maximal electroshock-threshold and 60 Hz electroshock-threshold tests). 7 The delta 9-THC withdrawal hyperexcitability suggests that the use of marihuana may jeopardize the control of seizures in epileptics.

Animals↗
PubMed1979

An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats.

The effects of cannabidiol (CBD) on electrically evoked kindled seizures were studied in conscious, unrestrained rats with chronically implanted cortical and limbic electrodes, and the results were compared with those of delta 9-tetrahydrocannabinol (delta 9-THC), phenytoin (PHT), and ethosuximide (ESM). All drugs were anticonvulsant, but there were marked differences in their effects on afterdischarge (AD) threshold, duration, and amplitude. CBD, like PHT and delta 9-THC, elevated the AD threshold; in contrast, ESM decreased the threshold but suppressed AD spread. CBD, however, also resembled ESM inasmuch as both drugs decreased AD duration and amplitude. Electrophysiologically, the antiseizure effects of CBD were a combination of those of PHT and ESM. The combination of effects may account for the observation that CBD was the most efficacious of the drugs tested against limbic ADs and convulsions. Other properties of CBD were also noted: For example, compared with delta 9-THC, it is a much more selective anticonvulsant vis-à-vis motor toxicity. CBD also lacks the CNS excitatory effects produced by delta 9-THC, PHT, and ESM. These characteristics, combined with its apparently unique set of electrophysiological properties, support the suggestion that CBD has therapeutic potential as an antiepileptic.

Animals↗
PubMed1979

The influence of cannabidiol and delta 9-tetrahydrocannabinol on cobalt epilepsy in rats.

The mechanisms of the anticonvulsant activity of cannabidiol (CBD) and the central excitation of delta 9-tetrahydrocannabinol (delta 9-THC) were investigated electrophysiologically with conscious, unrestrained cobalt epileptic rats. The well-known antiepileptics, trimethadione (TMO), ethosuximide (ESM), and phenytoin (PHT), were included as reference drugs. Direct measurements were made of spontaneously firing, epileptic potentials from a primary focus on the parietal cortex and convulsions were monitored visually. ESM and TMO decreased the frequency of focal potentials, but PHT and CBD exerted no such effect. Although CBD did not suppress the focal abnormality, it did abolish jaw and limb clonus; in contrast, delta 9-THC markedly increased the frequency of focal potentials, evoked generalized bursts of polyspikes, and produced frank convlusions. 11-OH-delta 9-THC, the major metabolite of delta 9-THC, displayed only one of the excitatory properties of the parent compound: production of bursts of polyspikes. In contrast to delta 9-THC and its 11-OH metabolite, CBD, even in very high doses, did not induce any excitatory effects or convulsions. The present study provides the first evidence that CBD exerts anticonvulsant activity against the motor manifestations of a focal epilepsy, and that the mechanism of the effect may involve a depression of seizure generation or spread in the CNS.

Animals↗
PubMed1979

Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol.

1 The effects of acute and subacute cannabidiol (CBD) administration on hexobarbitone sleeping time and on some constituents of the hepatic microsomal drug-metabolizing system were assessed in the mouse.2 Acutely administered CBD prolonged sleeping time; but with subacute treatment, tolerance to the effect rapidly developed.3 Brain hexobarbitone concentration upon awakening was unchanged by either acute or subacute CBD treatment, which suggests that neither the prolongation of sleeping time nor the tolerance is the result of a change in sensitivity of the central nervous system to the barbiturate.4 Acute CBD treatment increased the half-time of hexobarbitone in the brain, which returned toward normal with the development of tolerance.5 Acutely, CBD caused a 30% decrease in hepatic cytochrome P-450 level; with tolerance, the cytochrome concentration returned to normal.6 The evidence suggests that the CBD-induced prolongation of barbiturate sleeping time and the tolerance to this effect are the result of changes in the rate of drug metabolism, which are related to changes in the amount of cytochrome P-450.7 The effects of CBD on the hepatic microsomal drug-metabolizing enzyme system are different from those attributed to SKF 525-A and piperonyl butoxide because the cannabinoid does not decrease cytochrome P-450 quantitatively by complex formation, it does not produce a recovery overshoot in the cytochrome concentration and, finally, it does not cause an induction of the hexobarbitone-metabolizing enzymes.

Animals↗
PubMed1977

Influence of delta9-tetrahydrocannabinol and cannabidiol on photically evoked after-discharge potentials.

Two cannabinoids, delta9-tetrahydrocannabinol and cannabidiol, and several reference drugs were compared relative to their effects in a recently developed anticonvulsant test system, the after-discharge potentials of the visually evoked response; the potentials were recorded electrophysiologically from electrodes permanently mounted over the visual cortices of conscious rats. In anticonvulsant doses, trimethadione and ethosuximide produced an extensive depression of after-discharge activity, whereas diphenylhydantoin and cannabidiol exerted no such effect. In contrast, anticonvulsant doses of delta9-tetrahydrocannabinol and subconvulsant doses of pentylenetetrazol markedly increased after-discharge activity, which may represent a manifestation of their central nervous system excitatory properties. The data from the present study support our previously published ovservations from several other anticonvulsant tests that indicate the anticonvulsant characteristics of cannabidiol resemble those of diphenylhydantoin rather than those of trimethadione and that the central excitatory properties of delta9-tetrahydrocannabinol distinguish it from cannabidiol. The results consistently suggest that the cannabinoids will be effective against grand mal but not absence seizures.

Animals↗