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     

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.     

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     

α1-adrenoceptor subtype affinities of drugs for the treatment of prostatic hypertrophy

Summary We have used radioligand binding and inositol phosphate accumulation studies to determine the affinity at mixed _1A- and _1B-adrenoceptors (rat cerebral cortex and kidney), _1A-adrenoceptors (rat cerebral cortex and kidney following inactivation of _1B-adrenoceptors by chloroethylclonidine treatment) and _1B-adrenoceptors (rat spleen) for drugs currently under investigation for the treatment of benign prostatic hypertrophy, alfuzosin, naftopidil and (–)- and (+)-tamsulosin. Alfuzosin and naftopidil had similar affinities in all model systems (approximately 10 nM and 130 nM, respectively) and lacked relevant selectivity for ₁-adrenoceptor subtypes. Their potency to inhibit noradrenaline-stimulated inositol phosphate formation in cerebral cortex matched their affinities as determined in the binding studies. Tamsulosin had higher affinity at _1A- than at _1B-adrenoceptors, and was slightly more potent than alfuzosin and naftopidil at _1B- and considerably more potent at _1A-adrenoceptors. However, the interaction of the tamsulosin isomers with chloroethylclonidine-insensitive (_1A-like) adrenoceptors was complex. A detailed analysis of the tamsulosin data and those obtained with other drugs, most notably noradrenaline and oxymetazoline, suggested that chloroethylclonidine-insensitive ₁-adrenoceptors may be heterogenous and that this heterogeneity may differ between cerebral cortex and kidney of the rat.     

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.     

Immobilized Artificial Membrane (lAM)-HPLC for Partition Studies of Neutral and Ionized Acids and Bases in Comparison with the Liposomal Partition System

Purpose. To study the partitioning of model acids ((RS)-warfarin and salicylic acid), and bases (lidocaine, (RS)-propranolol and diazepam), with immobilized artificial membrane (lAM)-HPLC, as compared to partitioning in the standardized phosphatidylcholine liposome/buffer system. Methods. The pH-dependent apparent partition coefficients D were calculated from capacity factors (k_IAM) obtained by IAM-HPLC, using a 11-carboxylundecylphosphocholine column. For lipophilic compounds k_IAM, values were determined with organic modifiers and extrapolation to 100% water phase (k_IAMw) was optimized. Temperature dependence was explored (23 to 45° C), and Gibbs free energy (G), partial molar enthalpy (H) and change in entropy (S) were calculated. Equilibrium dialysis was used for the partitioning studies with the liposome/buffer system. Results. For extrapolation of k_IAMw, linear plots were obtained both with the respective dielectric constants and the mole fractions of the organic modifier. All tested compounds showed a similar pH-D diagram in both systems; however, significant differences were reproducibly found in the pH range of 5 to 8. In all cases, G and H were negative, whereas S values were negative for acids and positive for bases. Conclusions. In both partitioning systems, D values decreased significantly with the change from the neutral to the charged ionization state of the solute. The differences found under physiological conditions, i.e. around pH 7.4, were attributed to nonspecific interactions of the drug with the silica surface of the IAM column.     

CB<Subscript>1</Subscript> receptor mediation of cannabinoid behavioral effects in male and female rats

Rationale Cannabinoids have been shown to produce greater behavioral effects in female than male rats. Although central nervous system CB₁ receptors are known to mediate cannabinoid-induced behavioral effects in male rats, it is not known whether the same is true for females.Objective To determine if cannabinoid-induced antinociception and catalepsy are similarly mediated by central CB₁ receptors in male and female rats.Methods The ability of SR141716A, a CB₁ receptor selective antagonist, administered ICV (1–1000 g) or IT (1–600 g) to block 10 mg/kg IP ⁹-THC-induced antinociception (paw pressure) and catalepsy (bar test), was compared in male and female rats.Results ⁹-THC alone produced slightly greater antinociception, and significantly greater catalepsy in females than males. When administered ICV, SR141716A partially antagonized ⁹-THC-induced antinociception in both females and males. IT SR141716A also antagonized ⁹-THC-induced antinociception in both sexes; it was slightly more potent in males but equally effective in males and females. SR141716A antagonized ⁹-THC-induced catalepsy in a similar manner in males and females when given ICV or IT.Conclusions These results confirm that ⁹-THC-induced behavioral effects are mediated by central CB₁ receptors in male and female rats.     

Dependence of the cardiovascular effects of pindolol on the individual sympathetic nervous activity

Summary To investigate the mechanism of the relative beta-antagonist and agonist properties of pindolol, the cardiovascular effects of i.v. pindolol 0.01 mg/kg were studied in 23 subjects with different baseline levels of cardiac beta-adrenergic function. Baseline cardiac beta-adrenergic activity was assessed by the decrease in heart rate following intravenous propranolol 0.2 mg/kg (HR) after parasympathetic blockade with intravenous atropine 0.04 mg/kg. Cardiac beta-adrenergic sensitivity was defined by the positive chronotropic effect of a three minute infusion of isoprenaline 0.005 µg/kg/min. The chronotropic effect of intravenous pindolol was negatively correlated with resting beta-adrenergic activity (R=–0.81, p<0.001). The traditional point of HR, at which pindolol shifted from beta-antagonist to beta-agonist action, was 17 beats/min, i.e. pindolol decreased heart rate in subjects with HR greater than 17 bpm, and increased heart rate in those with HR less than 17 bpm. The chronotropic effect of intravenous pindolol, however, was positively correlated with beta-sensitivity (R=+0.73, p<0.001). Thus subjects with the greatest increment in heart rate with isoprenaline had an increased heart rate with pindolol, while those with the lowest increment in heart rate with isoprenaline had a decreased heart rate with pindolol. Intravenous pindolol decreased cardiac index and increased total peripheral resistance in the group with HR more than 17 bpm, and it had the contrary actions in the group with HR less than 17 bpm. Blood pressure in both groups was not significantly changed by pindolol. Compared to endogenous catecholamines, pindolol was considered to possess higher beta-adrenocepter affinity and weaker beta-adrenoceptor stimulating action. Therefore, pindolol produced a net beta-blocking action in subjects with elevated cardiovascular sympathetic nervous activity and beta-stimulating action in subjects with reduced sympathetic nervous activity.     

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.     

Δ9-THC-induced cognitive deficits in mice are reversed by the GABAA antagonist bicuculline

Rationale The results of recent in vitro studies have underscored the important role that activation of CB₁ receptors has on GABAergic activity in brain areas associated with memory.Objectives The primary purpose of this study was to test the hypothesis that the memory disruptive effects of ⁹-tetrahydrocannabinol (⁹-THC) in vivo are mediated through GABAergic systems. Conversely, we also evaluated whether blocking CB₁ receptor signaling would alter memory deficits elicited by GABA agonists.Methods The GABA_A antagonist bicuculline and GABA_B antagonist CGP 36742 were evaluated for their ability to ameliorate ⁹-THC-induced deficits in a mouse working memory Morris water maze task. Mice were also assessed in a T-maze task, as well as non-cognitive behavioral assays. Additionally, the effects of GABA_A and GABA_B agonists were assessed in either CB₁ (–/–) mice or wild type mice treated with the CB₁ antagonist SR 141716.Results Memory deficits resulting from 10 mg/kg ⁹-THC in the Morris water maze were completely reversed by bicuculline, though unaffected by CGP 36742. Bicuculline also blocked the disruptive effects of ⁹-THC in the T-maze, but failed to alter non-mnemonic effects of ⁹-THC. Although CB₁ (–/–) mice exhibited supersensitivity to muscimol-induced water maze deficits compared with wild type control mice, muscimol elicited virtually identical effects in SR 141716-treated and vehicle-treated wild type mice.Conclusions This is the first demonstration of which we are aware showing that GABA_A receptors may play a necessary role in ⁹-THC-induced memory impairment in whole animals.     

Action of cannabidiol on the anxiety and other effects produced by δ9-THC in normal subjects

The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ⁹-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ⁹-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ⁹-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ⁹-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ⁹-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ⁹-TCH. This antagonism does not appear to be caused by a general block of ⁹-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ⁹-TCH.These results suggest that the effects of CBD, as opposed to those of ⁹-TCH, might be involved in the antagonism of effects between the two cannabinoids.With a fellowship from Capesfrom CNP_q     

Comparison of cloned and pharmacologically defined rat tissue α1-adrenoceptor subtypes

Multiple ₁-adrenoceptor subtypes have been defined by pharmacological and receptor cloning techniques, but the precise alignment of cloned and pharmacologically-defined subtypes is still unclear. We have compared the affinities of 8 subtype-selective compounds at three cloned ₁-adrenoceptor subtypes (rat _1B, bovine _1C rat _1A/D) with those previously determined by the same methods in rat spleen, cerebral cortex, and kidney (Naunyn-Schmiedeberg's Arch. Pharmacol. 348: 385–395, 1993). Among all compounds tested to date at cloned ₁-adrenoceptor subtypes (+)-tamsulosin appears to be the most selective with a rank order of potency _1C > _{1A/D 1B}. Affinities for the _1A-selective 5-methyl-urapidil, methoxamine, oxymetazoline, phentolamine and (–)- and (+)-tamsulosin and for noradrenaline and SDZ NVI-085 at the splenic _1B-adrenoceptors and at their low affinity sites in cerebral cortex and kidney correlated best with those at the cloned _1B-adrenoceptor. Affinities of these drugs at their high affinity sites in cerebral cortex (pharmacologically-defined _1A-adrenoceptor) were matched best by those at the cloned _1C-adrenoceptor. Rat kidney appears to contain two chloroethylclonidine-resistant ₁-adrenoceptor subtypes one of which is similar to the cloned at _1C- and one to the cloned _1A/D-adrenoceptor. We conclude that the cloned _1B-adrenoceptor is the genetic correlate of the pharmacologically-defined _1B-adrenoceptor. An ₁-adrenoceptor subtype corresponding to the cloned _1A/D-adrenoceptor appears to exist in rat kidney. Among cloned ₁-adrenoceptor subtypes, the bovine _1C-adrenoceptor bears the closest resemblance to the pharmacologically-defined _1A-adrenoceptor in rat cortex and to one of the chloroethylclonidine-insensitive subtypes in rat kidney.     

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.     

Metabolism and autoradiographic distribution of Δ8- and Δ9 tetrahydrocannabinol in some organs of the monkey callithrix jacchus

Summary Metabolism and autoradiographic distribution of the two isomeric tetrahydrocannabinols, (2,4-¹⁴C)-⁸-THC and (2,4-¹⁴C)-⁹-THC), were studied in the marmoset Callithrix jacchus. Of the two cannabinoids, ⁸-THC had a slower initial rate of biotransformation to the psychopharmacologically more potent 11-hydroxylated metabolite. This may explain the minor psychopharmacological activity of the ⁸-isomer. In glandular tissues an accumulation of unchanged ⁹-THC was observed.Autoradiography revealed characteristic label distributions in some organs 30 min after the administration of the drugs. This labelling pattern was found to be changed after a 6-hr incorporation period. The autoradiographic distribution of ⁸- and ⁹-THC appeared to be identical.     

Antiproliferative and cytotoxic effects of some σ<Subscript>2</Subscript> agonists and σ<Subscript>1</Subscript> antagonists in tumour cell lines

To establish the activity of ligands at ₁ and ₂ receptor, we chose two tumour cell lines, the human SK-N-SH neuroblastoma and the rat C6 glioma lines, which express ₂ receptors at a high density and ₁ receptors in their high-affinity or low-affinity state. We tested the ₂ receptor agonist PB28 and the ₂ antagonist AC927, and (+)-pentazocine and NE100 as agonist and antagonist, respectively, at ₁ receptors, with regard to antiproliferative and cytotoxic effects. In addition, 1,3-di(2-tolyl)guanidine (DTG) and haloperidol were tested as reference compounds displaying nearly equipotent affinity (₂>₁ and ₁>₂, respectively). In both SK-N-SH and C6 cells, PB28 and NE100 displayed the most potent results both in antiproliferative and cytotoxic assay while AC927 and (+)-pentazocine were inactive in both assays. The cytotoxic and antiproliferative effects of DTG and haloperidol reflected their ₁ antagonist activity and ₂ agonist activity. Moreover, our results in the tumour cell lines correlated well with those for ₂ activity found previously in a functional assay in the guinea-pig bladder. These findings establish a new model for evaluating both ₂ and ₁ receptor activity of ligands, which could be useful for developing new ligands having mixed ₂ agonist/₁ antagonist activity as potential antineoplastic agents.     

Electrophysiological and electrochemical analysis of the secretion of ATP and noradrenaline from the sympathetic nerves in rat tail artery: effects of α2-adrenoceptor agonists and antagonists and noradrenaline reuptake blockers

Summary The aim of this study was to investigate whether or not nerve impulses release ATP and noradrenaline in parallel from the sympathetic nerve terminals of the rat tail artery. The extracellularly recorded excitatory junction current (EJC) was used to study, pulse by pulse, the release of ATP. An electrochemical method was used to study online the nerve stimulation-induced rise in the extracellular concentration of endogenous noradrenaline at the probe, a carbon fibre electrode (CF). This parameter, which does not directly represent noradrenaline release, but reflects release minus clearance, has been termed [NA]_CF. The effects of a number of pharmacological agents on the EJCs were examined both at 0.1 and 2 Hz, and the effects on the EJC response to 100 pulses at 2 Hz compared with that on the [NA]_CF response. Clonidine and xylazine were used as ₂-agonists, yohimbine and idazoxan as ₂-antagonists and desipramine and cocaine as blockers of noradrenaline reuptake. Most of these agents had unwanted side effects, especially at higher concentrations. However, clonidine and xylazine depressed at lower concentrations the EJC and [NA]_CF responses to about the same extent; these effects were partially or completely reversed by yohimbine. Yohimbine or idazoxan did not affect the EJCs at 0.1 Hz but enhanced the EJC and [NA]_CF responses to 100 pulses at 2 Hz to the same extent. All effects of desipramine (1 M) seemed explainable as a result of block of noradrenaline reuptake, while cocaine (10 M) in addition exerted an unspecific depressant (probably local anesthetic) effect. Under control conditions, both agents depressed the EJC but dramatically enhanced the [NA]_CF response to 100 pulses at 2 Hz. Addition of yohimbine prevented the depressant effect of desipramine on the EJCs completely and reduced that of cocaine, but increased their effects on the [NA]_CF response. These results are compatible with the view that ATP and noradrenaline are released in parallel from the sympathetic nerve terminals of this tissue. The different, and under some conditions even opposite, effects of desipramine or cocaine on the EJC and [NA]_CF responses are explainable in terms of the known post-secretory effects of these agents. Send offprint requests to M. Msghina at the above address     

Relationship of metabolism of 2′-, 3′- and 5′-adenine nucleotides to presynaptic inhibition of transmitter release in rat vas deferens

Summary In the isolated rat vas deferens stimulated at 0.2 Hz, a series of 2, 3-, and 5-substituted adenine nucleotides all inhibited the twitch responses, their actions being potentiated by the nucleoside transport inhibitors, HNBTGR, NBMPR and dipyridamole.The metabolism of these nucleotides was examined utilising HPLC analysis of the bathing medium after exposure to 30 M nucleoside or nucleotide for 5 min. 5-AMP, 5-ADP, 5-ATP, and NAD⁺ were all partially hydrolysed to adenosine, the relative extent of this being 5-AMP>5-ADP=5-ATPNAD⁺. However, the other nucleotides examined were not detectably converted to adenosine or to adenosine deamination products.These results indicate that the 2-, 3- and 5-substituted nucleotides studied act at a P₁-purinoceptor in rat vas deferens to inhibit neurotransmission and, with the exception of 5-AMP, 5-ADP, 5-ATP and NAD⁺, all appear to act directly at this receptor. However, the 5-adenine nucleotides (AMP, ADP and ATP) and NAD⁺ all appear to act at least partially indirectly subsequent to their hydrolysis to adenosine.Abbreviations. The following abbreviations are used ADA adenosine deaminase (EC 3.5.4.4) - 5-ADP adenosine 5-diphosphate - 2,5-ADP adenosine 2,5-diphosphate - 3 5-ADP, adenosine 3,5-diphosphate - 2-, 3 or 5-AMP adenosine 2-, 3-, or 5-monophosphate - 5-ATP adenosine 5-triphosphate - cNADP⁺ -nicotinamide dinucleotide 2,3-cyclic monophosphate - CoA coenzyme A - HNBTGR 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine - NAD⁺ -nicotinamide adenine dinucleotide - NADP⁺ -nicotinamide adenine dinucleotide phosphate - NBMPR 6-(4-nitrobenzylthio)-purine riboside     

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.