Effects of chronic Δ9-tetrahyrocannabinol administration on schedule-controlled behavior of pigeons: Cross-tolerance to pentobarbital and barbital

Pigeons responding under a variable-interval (VI) 75-s schedule of food presentation were used to study cross-tolerance from ⁹-tetrahyrocannabinol (⁹-THC) to pentobarbital and barbital. After initial dose-effect functions for pentobarbital and barbital were determined, the birds received ⁹-THC injections for 6 weeks. This chronic administration regimen resulted in a greater than 100-fold tolerance to ⁹-THC. Redetermination of the pentobarbital and barbital dose-effect functions during the chronic ⁹-THC regimen revealed statistically significant shifts to the right for the pentobarbital (0.191 log unit) and barbital (0.078 log unit) dose-effect curves. All six birds showed tolerance to pentobarbital, while four of the six showed tolerance to barbital. Blood barbital levels before and after chronic ⁹-THC administration did not differ significantly. Tolerance to ⁹-THC was more prolonged and of much greater magnitude than the cross-tolerance to pentobarbital or barbital. The results demonstrate that cross-tolerance can develop from ⁹-THC to a barbiturate that normally undergoes little metabolism.     

Clinical effects and plasma levels of Δ9-Tetrahydrocannabinol (Δ9-THC) in heavy and light users of cannabis

⁹-Tetrahydrocannabinol (⁹-THC) was administered in a crossover design by smoking and IV injection to groups of heavy and light users of marihuana. Plasma concentrations of ⁹-THC were similar for the groups after IV injection of 5.0 mg ⁹-THC, but the AUC_{0–240 min} showed a trend towards lower values for the heavy user group. To achieve a maximum desired high, both groups smoked similar amounts (about 13 mg) of ⁹-THC. Heavy users tended to have higher plasma levels than light users. The systemic availability of smoked ⁹-THC was significantly higher for the heavy users (heavy users 23±16% vs 10±7% for light users). These results also indicate that heavy cannabis users smoke more efficiently than casual smokers.Both light and heavy users showed more clinical effect following IV administration than after smoking. The response of the heavy users, both with respect to effect on heart and high, was quite comparable to that of light users.The present study does not suggest that tolerance readily develops in heavy users.     

Stimulus effects of Δ9-THC and its interaction with naltrexone and catecholamine blockers in rats

Rats trained in a T-shaped maze to discriminate the effects of i.p. injections of ⁹-tetrahydrocannabinol (⁹-THC, 4mg/kg) and the effects of the vehicle were tested for antagonism and generalization to the ⁹-THC stimulus by naltrexone (4 mg/kg), haloperidol (0.32 mg/kg), propranolol (20 mg/kg), and phenoxybenzamine (10 mg/kg). None of these drugs blocked the ⁹-THC stimulus, nor were they found to generalize to ⁹-THC.     

Influence of polymorphism on the surface energetics of salmeterol xinafoate crystallized from supercritical fluids

Purpose. To characterize the surface thermodynamic properties of two polymorphic forms (I and II) of salmeterol xinafoate (SX) prepared from supercritical fluids and a commercial micronized SX (form I) sample (MSX). Methods. Inverse gas chromatographic analysis was conducted on the SX samples at 30, 40, 50, and 60°C using the following probes at infinite dilution: nonpolar probes (NPs; alkane C5-C9 series); and polar probes (PPs; i.e., dichloromethane, chloroform, acetone, ethyl acetate, diethyl ether, and tetrahydrofuran). Surface thermodynamic parameters of adsorption and Hansen solubility parameters were calculated from the retention times of the probes. Results. The free energies of adsorption (-G_A) of the three samples obtained at various temperatures follow this order: SX-II > MSX SX-I for the NPs; and SX-II > MSX > SX-I for the PPs. For both NPs and PPs, SX-II exhibits a less negative enthalpy of adsorption (H_A) and a much less negative entropy of adsorption (S_A) than MSX and SX-I, suggesting that the high -G_A of SX-II is contributed by a considerably reduced entropy loss. The dispersive component of surface free energy (_s ^D) is the highest for MSX but the lowest for SX-II at all temperatures studied, whereas the specific component of surface free energy of adsorption (-G_A ^SP) is higher for SX-II than for SX-I. That SX-II displays the highest -G_A for the NP but the lowest _s ^D of all the SX samples may be explained by the additional -G_A change associated with an increased mobility of the probe molecules on the less stable and more disordered SX-II surface. The acid and base parameters, K_A and K_D, that were derived from H_A ^SP reveal significant differences in the relative acid and base properties among the samples. The calculated Hansen solubility parameters (_D, _P, and _H) indicate that the surface of SX-II is the most polar and most energetic of all the three samples in terms of specific interactions (mostly hydrogen bonding). Conclusions. The metastable SX-II polymorph possesses a higher surface free energy, higher surface entropy, and a more polar surface than the stable SX-I polymorph.     

The mechanism of action of Δ 9 -tetrahydrocannabinol on body temperature in mice

The effect of ⁹-tetrahydrocannabinol ( ⁹-THC) on body temperature of the mouse was studied. A dose-response relationship (5–100 mg/kg) for the hypothermic effect of ⁹-THC was seen. The investigation as to the mechanism underlying the hypothermic action of ⁹-THC was also investigated. The relatively specific dopamine antagonist haloperidol potentiated ⁹-THC-induced hypothermia as did the -adrenoceptor antagonist phenoxybenzamine. However, depletion of serotonin with P-chlorophenylalanine reduced the hypothermic response to ⁹-THC as did pretreatment with the serotonin antagonist methysergide. Inhibition of re-uptake of serotonin with clomipramine potentiated the hypothermia following ⁹-THC. It is suggested that the hypothermic effect of ⁹-THC in the mouse is mediated to a large extent via serotonergic mechanisms.     

Δ9-THC as a discriminative stimulus in rats and pigeons: Generalization to THC metabolites and SP-111

In a drug discrimination paradigm pigeons and rats were trained with an operant procedure to discriminate between the presence and absence of the effects of ⁹-THC (1.0 and 3.0 mg/kg, injected IM 90 min and I.P. 30 min before the start of the session). Once trained, various THC metabolites as well as a water-soluble derivative of THC (SP-111), were substituted for ⁹-THC to test for generalization to the training drug. Generalization to ⁹-THC occurred with the 11-hydroxy metabolites and the potency order was 11-OH-⁹-THC >11-OH-⁸-THC ⁹-THC. Among the other metabolites tested (8-OH-⁹-THC, 8, 11-di-OH-⁹-THC, 8-OH-⁹-THC, 8, 11-di-OH-⁹-THC), it was only 11-di-OH-⁹-THC that completely substituted for ⁹-THC in pigeons, albeit at very high dose levels (rats were not tested with these metabolites). SP-111 generalized to ⁹-THC in both species. However, the onset of action of SP-111 was slower than that for ⁹-THC, especially in pigeons. These studies show the importance of obtaining complete dose-effect determinations over time when assessing structure-activity relationships with drug-discrimination procedures.A brief account of the results, which are summarized in Neuropharmacology 18:1023–1024, 1979), was presented at the British Association for Psychopharmacology Summer Conference, July 15–17, Birmingham, England, 1979     

Δ9-Tetrahydrocannabinol and the extrapyramidal system

The behavioural effects of stereotypy and catalepsy by ⁹-Tetrahydrocannabinol (⁹-THC) in the rat were estimated and the possible involvement of the basal ganglia in these behaviours was studied using brain lesion techniques. In addition, the interactions of ⁹-THC with a dopaminergic (amphetamine) and a cholinergic stimulant (RS-86) were evaluated using the above methods.The excitatory effects of ⁹-THC alone, i.e., circling, sniffing, and head movements, were of low intensity and short duration and they were not significantly affected by lesions in the basal ganglia. On the other hand, ⁹-THC was found to depress behaviour, including catalepsy and atonic muscular prostration, the former being markedly potentiated, while prostration was unaffected by such lesions.⁹-THC was also found to potentiate cholinergic-induced catalepsy, extrapyramidal lesions causing further potentiation.Amphetamine-induced circling, sniffing, and gnawing emerged as a triad of related behaviour fragments. This was altermated by pallidal lesions and ⁹-THC treatment, the combination of the two being additive. The potentiation by ⁹-THC of amphetamine-induced rhythmic head and body movements was unaffected by pallidal lesions and so could be mediated by another brain area.The hypothesis is proposed that ⁹-THC exerts its cataleptogenic and some of its amphetamine interaction effects by reducing dopaminergic transmission in the basal ganglia.     

Generalization of the discriminative stimulus properties of x0394; 9 in rats

Rats were trained in a water maze to discriminate between IP injections of 3 mg/kg ⁹- (⁹⁽¹¹⁾-THC) and its vehicle. Both ⁸- and ⁹⁽¹¹⁾ were generalized to the training drug. In contrast to our observations in rhesus monkeys, where ⁹-THC is at least 100 times less potent than ⁹-THC, ⁹⁽¹¹⁾ was found to be only seven times less potent in the rat. Relative potencies, expressed as the dosage at which 50% of the animals gave drug responses (ED₅₀) were 1.8 mg/kg and 12.2 mg/kg for ⁹-THC and ⁹⁽¹¹⁾ respectively. Twenty-four hours after receiving 7×ED₅₀=12 mg/kg ⁹ the tests showed intermediate results when conducted with the training dosage; 4×ED₅₀=50 mg/kg ⁹-THC 48 h prior to the training dosage of 3 mg/kg ⁹-THC completely blocked drug-appropriate responses. Coinjection of ED₅₀ dosages of ⁹- and ⁹⁽¹¹⁾-THC led to 90% drug responses, demonstrating the additivity of the cannabis-like effect of both cannabinoids. Differences in the individual sensitivity of the rats to the tested cannabinoids were observed. Findings are interpreted in terms of the receptor mechanism for cannabis-like activity.This paper is dedicated to the memory of Dr. M. Binder who died on February 15, 1984     

Δ 1-tetrahydrocannabinol but not cannabidiol reduces contact and aggressive behavior of rats tested in dyadic encounters

A low and a high dose of ¹-Tetrahydrocannabinol ( ¹-THC) and of cannabidiol (CBD) were IP injected in rats that had been isolated for 7 days. Forty-five minutes after injection, the rats were tested for social interactions with non-isolated, untreated test partners in dyadic encounters under standardized conditions. Different aspects of social behavior were analyzed. The high dose of ¹-THC (10 mg/kg) prevented nearly all social interactions. The low dose of ¹-THC (1 mg/kg) exerted selective and specific effects on social interactions. Social contact behavior, including crawl over/mounting, and social grooming, and aggressive behavior, including fighting, kicking, and biting, were markedly decreased, whereas social exploratory behavior (exploration of the partner and anogeniaal investigation) and the behavioral item, approach/follow, were hardly affected by ¹-THC treatment. Both doses of CBD (2 and 20 mg/kg) failed to change the various aspects of social interaction. It is postulated that the effects of ¹-THC on close and intimate contact behavior of rats may contribute to the understanding of marihuana taking in humans.     

EEG and behavioral effects of natural,synthetic and biosynthetic cannabinoids

The pharmacological effects of marihuana in man and animals have been attributed to ¹ and ⁶ tetrahydrocannabinol (THC).Recently, one of the metabolites of THC, 7-OH-THC, has been reported to have intoxicating properties. A comparative study was carried out on the EEG and behavioral effects of cannabinol, cannabidiol, ⁶-THC, 7-OH- ⁶-THC and 7-Acetoxy ⁶-THC acetate in six chronically implanted rabbits bearing cortical and subcortical leads. Drugs were dissolved in polyethyleneglycol and administered i.v. once every 7 days in a crossover experimental design. 7-OH- ⁶-THC and 7-Acetoxy- ⁶THC acetate proved to be at least twice as active as ⁶-THC in inducing EEG changes (disruption of theta waves, appearance of spikes and waves, blockade of the arousal reaction) and behavioral alterations (excitation, exophthalmus, mydriasis, corneal arreflexia, ataxia and swaying). Pretreatment with 1 or 2 mg/kg of reserpine, s.c., did not substantially alter the subjects response to THC.Amphetamine 2 mg/kg, i.v., in animals pretreated with 2 or 4 mg/kg ⁶-THC, reverses in part the depression induced by THC.     

α-Bungarotoxin, κ-bungarotoxin, α-cobratoxin and erabutoxin-b do not affect [3H]acetylcholine release from the rat isolated left hemidiaphragm

Endplate preparations of the rat left hemidiaphragm were incubated with [³H]choline to label neuronal transmitter stores. Nerve evoked release of newly-synthesized [³H]acetylcholine was measured in the absence of cholinesterase inhibitors to investigate whether snake venom neurotoxins by blocking presynaptic nicotinic autoreceptors affect evoked transmitter release. Contractions of the indirectly stimulated hemidiaphragm were recorded to characterize the blocking effect of -neurotoxins at the postsynaptic nicotinic receptors.Neither the long chain neurotoxins -cobratoxin (1 g ml^–1) and -bungarotoxin (5 g ml^–1) nor the short chain neurotoxin erabutoxin-b (0.1, 1 and 10 gml^–1) affected the nerve-evoked release of [³H]acetylcholine. -Bungarotoxin (1 and 5 g ml^–1), a toxin preferentially blocking neuronal nicotinic receptors, did also not affect evoked [³H]acetylcholine release, whereas (+)-tubocurarine (1 M) under identical conditions reduced the release by about 50%. -Bungarotoxin, -cobratoxin and erabutoxin-b concentration-dependently (0.01–0.6 g ml^–1)inhibited nerve-evoked contractions of the hemidiaphragm. All neurotoxins except erabutoxin-b enhanced the basal tritium efflux immediately when applied to the endplate preparation or to a non-innervated muscle strip labelled with [³H]choline. This effect was attributed to an enhanced efflux of [³H]phosphorylcholine, whereas the efflux of [³H]choline and [³H]acetylcholine was not affected.It is concluded that the -neurotoxins and -bungarotoxin do not block presynaptic nicotinic receptors of motor nerves. These nicotinic autoreceptors differ from nicotinic receptors localized at the muscle membrane and at autonomic ganglia.     

Hydroxysteroid-Dehydrogenasen, Δ5-3-Ketosteroid-Isomerase und Δ4-Steroid-Hydrogenase in roten Blutzellen

Zusammenfassung 18 ausgewählte Steroide werden auf ihre Umsetzung durch rote Blutzellen von Ratte, Rind und auch Mensch untersucht. Über die papierchromatographische und teilweise auch spektrophotometrische Identifikation der erhaltenen Metaboliten wird nachgewiesen, daß die Erythrocyten eine Vielzahl von Steroidfermenten enthalten. Gefunden werden vor allem 3-, 3-, 16-, 17- und 17-Hydroxysteroid-Dehydrogenasen. Dagegen lassen sich 11- und 16-Hydroxysteroid-Dehydrogenasen nicht nachweisen. Die relativen Aktivitäten der verschiedenen Fermente in der jeweiligen Blutart werden beschrieben. Die Erythrocyten zeigen artgebundene Unterschiede in Stereospezifität und Aktivität der Hydroxysteroid-Dehydrogenasen. Neben den genannten Enzymen sind in den roten Blutzellen der Ratte noch eine Isomerase (^{5 4}) und eine ⁴-Hydrogenase enthalten. Außer den Reaktionen, die durch die aufgezählten Fermentnamen bezeichnet sind, werden von den Zellen noch Umsetzungen bewirkt, die ihrer Art nach nicht aufgeklärt wurden. Die Ergebnisse werden im Hinblick auf den Stoffwechsel der 16,17-substituierten Oestrogene und auf die Natur der Hydroxysteroid-Dehydrogenasen diskutiert.Mit 3 TextabbildungenEin Teil der Ergebnisse wurde am 24. 9. 1959 auf der Tagung der Gesellschaft für physiologische Chemie e. V. in Berlin vorgetragen.Meinem verehrten Lehrer, Herrn Professor P. Wels, in Dankbarkeit zum 70. Geburtstag gewidmet.     

The effect of two tetrahydrocannabinols, (Δ9-THC and Δ8-THC) on conditioned avoidance learning in rats and its transfer to normal state conditions

Rats trained in conditioned avoidance responding (CAR) after injections of either 7.5 mg/kg ⁹-THC (tetrahydrocannabinol) or 15 mg/kg ⁸-THC, showed no transfer when tested in the non-drugged state. Furthermore, these doses of the isomeric tetrahydrocannabinols exerted a disruptive effect on previously established CAR in rats, trained under normal conditions.Only the ⁹-THC-group showed an impairment of acquisition which was statistically significant compared to the control group.     

Effect of some cannabinoids on naloxone-precipitated abstinence in morphine-dependent mice

Mice were rendered morphine-dependent by the subcutaneous implantation of a pellet containing 75 mg of morphine base; 72 h after the implantation, the animals were injected intraperitoneally either with vehicle or with various doses of ₉-tetrahydrocannabinol, ₈-tetrahydrocannabinol, cannabidiol, cannabinol, or 11-hydroxy-₈-tetrahydrocannabinol. Thirty minutes after injection of the cannabinoids, the antagonist, naloxone HCl, was administered to induce the stereotyped withdrawal jumping syndrome. The dose of naloxone needed to induce withdrawal jumping in 50% of the animals (ED₅₀) was determined for each dose of the cannabinoids. All of the cannabinoids inhibited the naloxone-precipitated morphine abstinence as evidenced by an increase in the naloxone ED₅₀. Two additional signs of morphine abstinence, defecation and rearing behavior, were also suppressed by the cannabinoids. The relative effectiveness of the cannabinoids in inhibiting morphine abstinence appeared to be in the following order: ₉-tetrahydrocannabinol > ₈-tetrahydrocannabinol > 11-hydroxy-₈-tetrahydrocannabinol > cannabidiol > cannabinol.These data suggest that cannabinoids may be useful in facilitating narcotic detoxification.     

Effects of 2-propyl 2-pentenoic acid on the acquisition of conditioned behavior with negative reinforcement in mice

2-Propyl 2-pentenoic acid (PP), at a dose of 6 mg/kg (0.04 mM/kg), has a facilitating action on the acquisition of conditioned avoidance reactions. This effect of PP is correlated with increase of the level of brain gamma-aminobutyric acid, following administration of PP.     

Syntheses of di- and tetrahydropyrroles

Conclusions N-Alkyl-2,4,4-trimethyl-'-pyrrolinium salts were produced by alkylating 2,4,4-trimethyl-'-pyrroline with various alkylating agents.For communication IV, see [1].Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 8, pp. 30–34, August, 1968.     

Pre- and postganglionic stimulation-induced noradrenaline overflow is markedly facilitated by a prejunctional β2-adrenoceptor-mediated control mechanism in the pithed rat

The aim of the study was to further explore the prejunctional -adrenoceptor-mediated control mechanism of noradrenaline release from sympathetic nerves in response to preganglionic nerve stimulation (PNS) and local nerve stimulation of the portal vein, respectively, in the pithed rat.Baseline values as well as the increments of mean arterial blood pressure (-BP), heart rate (-HR) and plasma noradrenaline levels (-NA) in response to four PNS episodes (0.8 Hz, 3 ms, 75 V for 45 s at 20 min intervals), respectively, were evaluated. Fenoterol administration (0.25 mg/kg, i.v.) reduced significantly the basal blood pressure but did not alter d-BP in response to PNS. Basal heart rate markedly increased after fenoterol without any further change in heart rate induced by PNS.The ₁-selective antagonist CGP 20712A attenuated -BP in response to PNS and prevented the fenoterol-induced increase in basal heart rate. The ₂-selective antagonist ICI 118,551 per se did not change the blood pressure and heart rate values, but antagonized the fenoterol-induced decrease in basal blood pressure.Fenoterol enhanced plasma -NA in response to PNS by 105% in comparison to the corresponding control value. This effect of fenoterol could be blocked by pretreatment with ICI 118,551 but not with CGP 20712A (a selective ₁-adrenoceptor antagonist) which per se did not significantly change plasma -NA.Repeated local stimulation of the portal vein (S1–S 3, 2 Hz, 3 ms, 10 mA, for 120 s at 30 min intervals) increased portal plasma noradrenaline without changing mean blood pressure and heart rate in pithed rats. Fenoterol enhanced the increase in portal-vein plasma noradrenaline evoked by nerve stimulation by 110%. Pretreatment with ICI 118,551 antagonized this effect of fenoterol, but had per se no effect on the portal vein nerve stimulation-evoked increase in portal plasma noradrenaline.It is concluded that the increase in plasma noradrenaline evoked both by pre- and postganglionic nerve stimulation can be markedly enhanced by activation of a facilitatory prejunctional ₂-adrenoceptor control mechanism. Correspondence to: V.I. Tarizzo     

Trennung und Bestimmung der Nucleotide des Gehirns

Ohne ZusammenfassungFolgende Abkürzungen werden in der Arbeit verwendet AMP Adenosin-5-monophosphat - ADP Adenosin-5-diphosphat - ATP Adenosin-5-triphosphat - GMP Guanosin-5-monophosphat - GDP Guanosin-5-diphosphat - GTP Guanosin-5-triphosphat - IMP Inosin-5-monophosphat - UMP Uridin-5-monophosphat - UDP Uridin-5-diphosphat - UTP Uridin-5-triphosphat - UDPAG Uridin-5-diphosphat-N-acetylglucosamin - UDPG Uridin-5-diphosphat-glucose - DPN Diphosphopyridinnucleotid - TPN Triphosphopyridinnucleotid Mit 10 TextabbildungenMit Unterstütznng der Deutschen Forschungsgemeinschaft.     

Facilitory effect of Δ9-tetrahydrocannabinol on hypothalamically induced feeding

Six male Lewis rats were tested for the effect of ⁹-tetrahydrocannabinol (⁹-THC) on feeding evoked by electrical stimulation of the lateral hypothalamus. Treatment with ⁹-THC (0.4 mg/kg IP) decreased frequency threshold for feeding by 20.5% (±4.3), causing a leftward shift in the function relating stimulation frequency to the latency to begin eating 45-mg food pellets upon stimulation onset; there was no change in the asymptotic performance that was approached with sufficiently high stimulation frequencies. Naloxone (1 and 2 mg/kg) reduced the facilitory effect of ⁹-THC, but did so at doses that can inhibit feeding in the no-drug condition. These data are consistent with evidence implicating endogenous opioids in feeding, and suggest (but do not confirm) that the facilitation of feeding by ⁹-THC may be mediated by endogenous opioids. The facilitation of stimulation-induced feeding by doses of ⁹-THC that have been found to facilitate brain stimulation reward is consistent with evidence suggesting common elements in the brain mechanisms of these two behavioral effects of medial forebrain bundle stimulation.     

Discriminative effects of combinations of Δ9-Tetrahydrocannabinol and pentobarbital in pigeons

The purpose of the present study is to examine potentially additive effects of pentobarbital and ⁹-Tetrahydrocannabinol ⁹-THC using a drug discrimination paradigm. Three groups of pigeons were trained to discriminate between the effects induced by i.m. administrations of either (a) 0.25 mg/kg ⁹-THC and vehicle, (b) 4 mg/kg pentobarbital and saline, and (c) ⁹-THC and pentobarbital. Test probes under extinction conditions produced orderly dose generalization gradients among the drug-vs nondrug-trained animals. ED₅₀ for pentobarbital was 1.60 mg/kg and ED₅₀ for ⁹-THC was 0.10 mg/kg. Tests in birds discriminating between pentobarbital and ⁹-THC suggested a sharpening of the drug cue effects; tests with the vehicles resulted in approximately a random key selection (33%–66%) while tests with combinations of the two training drugs suggested that ⁹-THC was the more salient cue in this group. Tests with combinations of various doses of pentobarbital and ⁹-THC in the drug-vs nondrug-trained birds did not increase responding on the respective drug-training associated key. Thus the cue effects of pentobarbital and ⁹-THC were not summational under these experimental conditions. In conclusion, rather low doses of pentobarbital and ⁹-THC are effective as discriminative cues in pigeons and the cues thus induced are different. Combinations of the two drugs are not necessarily summational, and the pentobarbital vs the ⁹-THC discriminations augmented the discriminable effects of the two drugs. In addition, the analeptic drug, bemegride, antagonizes the pentobarbital (4 mg/kg) stimulus in the group trained to discriminate between this barbiturate and saline, which agrees with earlier drug antagonism data obtained among mammals (gerbils and rats), required to discriminate between barbiturates and the nondrug condition.