Helmut Coper

Modification of Δ9-THC-actions by cannabinol and cannabidiol in the rat

Cannabinol (CBN) and Cannabidiol (CBD) were tested in several test procedures known to be altered by δ9-tetrahydrocannabinol (THC) or crude cannabis preparations. They were inactive in doses up to 80 mg/kg in tests on animal motility, food and water intake, body temperature and catalepsy. In contrast, CBD enhanced the hexobarbitone “sleeping time” more pronounced than δ9-THC whereas CBN increased the “sleeping time” only slightly. When administered in combination CBD prolonged all actions of THC, whereas CBN selectively blocked the effect of THC on hexobarbitone “sleeping time”. The enhancement by CBD is best explained by an inhibition of THC-metabolism.

The development of tolerance to morphine in the rat

Tolerance to various effects of morphine in the rat can be quantified by means of a shift of semilogarithmic dose-response curves. Tolerance to analgesia (hot plate, acetic acid writhing), catalepsy, and the tilted plane develops in a closely similar manner. Also, the stimulating effects of about 1 mg/kg morphine-HCl tested in an open-field procedure are somewhat less pronounced in chronically treated rats than in naive ones. There is no correlation between tolerance development and the acute ED50 of different tests.

Quantitative assessment of tolerance to and dependence on morphine in mice

Summary1.Tolerance to morphine-induced analgesia (hot plate and acetic acid whrithing test), hypothermia and lethality can be quantified in mice by measuring the degree of parallel shifts of semilog. dose-response relationships induced by repeated opioid administration.2.A similar procedure can be used for the quantification of naloxone-induced withdrawal as an indicator of dependence.3.The intensity of tolerance development with respect to time of administration and dosage of morphine varies with the test procedure. It is closely parallel, however, in both analgesic tests during acquisition of tolerance.4.Log-log-linear relationships exist between tolerance in analgesic tests and physical dependence as determined by naloxone-induced withdrawal.5.The minimum tolerance-inducing dose of morphine in different tests could not be correlated to the ED50s in these tests.6.Chronic opiate treatment leads to a decrease or an increase in motility response to morphine, depending on the time that has elapsed after the last morphine administration.

The effects of chronic treatment with d-amphetamine on food intake, body weight, locomotor activity and subcellular distribution of the drug in rat brain

Female Wistar rats were treated chronically with d-amphetamine sulphate in drinking water. The concentrations of amphetamine were 0.01%, 0.02%, 0.03%, 0.04% and 0.05% in the 1st, 2nd, 3rd, 4th, and 5th week of treatment. The consumed doses of amphetamine increased from 16 mg/kg on the first day up to 90 mg/kg on the 36th day of treatment. The effects of chronic treatment with amphetamine on food intake, body weight and locomotor activity of rats were determined. The rats developed tolerance to the overall toxicity and to the anorexigenic effect of maphetamine. No tolerance to the effects of the drug on body weight and locomotor activity was observed. The concentration of H3-d-amphetamine in brains of chronically treated rats is significantly higher than in controls. No difference in the pattern of distribution of radioactivity among the subcellular fractions of rat brain was observed between control and chronically treated groups. The relationship between developmen tof tolerance and the concentration of amphetamine in the brain is discussed.

Motor performance achievements in rats of different ages.

Motor performance of rats of different ages was determined in a cross sectional study. The design includes a test battery of seven motor tasks of graduated complexity. The results show a hierarchical order of impairments of motor functions in aging rats; that is, the more complex the task requirement, the earlier and more pronounced is the susceptibility to deterioration of motor coordination. In spontaneous activity and swimming no difference could be observed between young and old rats. With increasing requirements for the tilting-plane, horizontal wire, climbing and chimney tests as well as the rotarod test, the older rats show a differentiated decrease in performance. The findings are discussed in respect to the theory that aging is a reverse process of early development.

Pharmacological properties of tetrahydronorharmane (tryptoline).

SummaryEarlier in vitro experiments led to the hypothesis that tetrahydronorharmane (THN) modulates the effect of serotonin. This assumption has now been tested in vivo on rats. In addition dopaminergic mechanisms were investigated. Findings in favour of a serotonergic action of THN were: 1.The analgesic effect of THN which was antagonized by 9,10-dihydro, 10-(1-methyl-4-piperidyliden)-9-anthrol, a serotonin-receptor antagonist2.the hypothermic effect of THN3.the appetite-reducing effect of long-term treatment with THN. An antidopaminergic effect of THN was suggested by: 1.The motility-reducing effect of THN2.the antagonistic effect against apomorphine-induced licking movements of acute and chronic treatment with THN and the development of supersensitivity to apomorphine one week after withdrawal of THN.3.the antagonistic effect of THN against the contralateral turning response to apomorphine in animals with unilateral medial forebrain bundle lesions. The antidopaminergic effects were elicited by lower doses of THN than the stimulation of serotonergic mechanisms.The observed prolongation of hexobarbital sleeping time might be an unspecific effect. A reduction of the elimination rate of the barbiturate was not detected.

On the mode of formation of tetrahydro-β-carbolines

Abstract The condensation of tetrahydro-β-carboline (TBC) takes place if serotonin is incubated with 5-MTHF and the cytosol fraction from rat brain as an enzymatic source. Such a formation occurs to a lesser extent if the enzyme(s) is omitted from the incubation mixture. The conditions of the enzymatic as well as the non-enzymatic mode of formation of TBC are investigated. It could be shown by addition of semicarbazide to the incubation medium that formaldehyde is an intermediate in the production of TBC. The biological significance of TBC will be discussed.

Decline in motor functions in aging is related to the loss of NMDA receptors.

The aim of the study was to assess the contribution of central dopaminergic and glutamatergic systems to the age-dependent loss of motor functions in rats. Rats of three age groups were compared: young (3-5-month-old), middle-aged (20-21-month-old) and old (29-31-month-old). The obtained results showed an age-dependent decline in the electromyographic (EMG) resting and reflex activities in the gastrocnemius and tibialis anterior muscles, as well as in the T-maze performance. Although these disturbances were accompanied with significant age-dependent decreases in the binding to NMDA, AMPA and dopamine D2 receptors, and a decline in the number of nigral dopamine neurons, they were significantly correlated with the loss of the binding to NMDA receptors only. The reduction in T-maze performance with aging was additionally correlated with a decrease in motor functions (EMG activity). The study suggests a crucial role of the loss of NMDA receptors in age-dependent motor disabilities, as well as in disturbances measured in the T-maze.

Development and loss of tolerance to morphine in the rat

The development of a differential tolerance to morphine was investigated with respect to the mean effective dose, the threshold dose of tolerance, the degree of tolerance after a fixed dose, and the speed of tolerance loss. The mean effective doses, the threshold doses of tolerance, and the degree of tolerance differed considerably from effect to effect, whereas in all tests tolerance loss remained the same. The mean effective doses were not correlated to threshold doses of tolerance, degree of tolerance, or to the loss of tolerance, but a strong correlation exists between threshold doses of tolerance and degree of tolerance to all effects measured. Consequences of these results upon current theories of tolerance are discussed.

Effect of subchronic treatment with (-) 8 -trans-tetrahydrocannabinol ( 8 -THC) on food intake, body temperature, hexobarbital sleeping time and hexobarbital elimination in rats.

In a series of experiments in rats it was possible to prove that δ8-THC has the same type of effectiveness as the stereo-isomeric δ9-THC.Body temperature was reduced to 35.5‡ C 90 min after injection of 10 mg/kg δ8-THC; 5 mg/kg δ8-THC extended the duration of hexobarbital sleeping time from 119 min in control animals to 205 min. Following treatment with δ8-THC for 9 and 10 days the effects on hypothermia and prolongation of sleeping time were less pronounced than in acute experiments. Body temperature dropped to 36.4‡ C 90 min p.i. and the duration of hexobarbital sleeping time was only extended to 156 min. This attenuation of effects after subchronic THC treatment was regarded as due to the development of tolerance.In order to exclude the possibility that the extension of sleeping time might be due to an effect of THC on hexobarbital metabolism, the hexobarbital concentration in cerebral tissue and blood was determined 30, 60, 90 and 120 min after the administration of 100 mg/kg hexobarbital-Na. There was no difference in hexobarbital elimination between rats treated with THC in a single dose or over a 10-day period and control animals.