Withdrawal-like behaviour induced by inhibitors of biogenic amine reuptake in rats treated chronically with Δ 9-tetrahydrocannabinol

The effects of the biogenic amine reuptake inhibitors fluoxetine, clomipramine and imipramine on the behaviour of rats after chronic treatment with ⁹ tetrahydrocannabinol ( ⁹-THC) for 5 and 10 days were examined. Rats with permanently in-dwelling IV cannulae were injected twice daily with doses of ⁹-THC (2–6 mg/kg). ⁹-THC treatment reduced the rate of body weight gain and induced the typical biphasic modifications of behaviour. Tolerance developed to both of these effects. On days 6 and 11 of the experiment, rats were injected IP with 15 mg/kg imipramine HCl, clomipramine HCl or fluoxetine HCl, and behaviour, consisting of writhes, backward kicks, jumps and wet shakes, was observed for the next 30 min. Each of the amine reuptake inhibitors induced changes in behaviour, the severity of which appeared to correlate with their ability to inhibit the reuptake of 5-hydroxytryptamine (5-HT). It is suggested that tryptaminergic mechanisms are involved in the production of a withdrawal-like behaviour after chronic ⁹-THC treatment.     

Accuracy in coronary graft flow measurement

A blood flow calibration apparatus is described for use with electromagnetic flow probes. It is an automatic gravity-flow system, which provides a constant level and therefore constant flow at any preset rate. On several occasions, the use of this device has helped to determine whether flow probes require simple adjustment, factory repair, or replacement. Using this system, a systematic error in the manufacturer's "precalibration" averaging +22% (range, 9 to 50%) has been discovered, and appropriate corrections have been made. The accuracy of these corrections has been confirmed by a rapid, in vivo method of calibration, which also is described and which can be carried out during the conduct of aortocoronary bypass operation. It is recommended that all groups measuring coronary graft flow become familiar with their electromagnetic flowmeter and probes by means such as those described, in the interest of accurate flow measurement after bypass operation.     

2-Nitroimidazole potentiation of nitrosourea induced cytotoxicity in subcutaneous implants of rat 9L brain tumor cells

Summary To determine if the 2-nitroimidazole (2-NI) and the nitrosourea (NU) in a brain tumor chemopotentiation trial should be selected on the basis of known structure-activity relationships (electron affinity, lipophilicity, alkylating activity, carbamoylating activity), s.c. implants of rat 9L brain tumor cells were treated with combinations of misonidazole (MISO) or etanidazole (SR-2508) administered under oxic and hypoxic conditions, and BCNU, CCNU or chlorozotocin (CLZ) administered under oxic conditions. Cell kill was assessed by an in vivo to in vitro colony formation assay. To mimic the preincubation effect, the 2-NI was injected i.p., and 30min later the tumor was clamped. After 2hr, the clamp was released, and the NU administered immediately. MISO (2.5 mmole/kg) and SR-2508 (3.75 mmole/kg) reached the same peak tumor concentration in 30 min. Both 2-NIs were metabolized at the same rate in the clamped tumors; however, metabolism of the 2-NIs by hypoxic cells over the 2hr clamping period did not produce any measurable s.c. 9L cell kill. The relative effectiveness of the NUs for killing oxic s.c. 9L tumor cells was: BCNU > CCNU > CLZ. Clamping the tumor prior to NU administration did not change the NU cytotoxicity. No potentiation of the NU cytotoxicity by the 2-NIs was observed in oxic tumors. Although metabolism of MISO by hypoxic cells did not result in potentiation of CLZ cytotoxicity at any dose, it resulted in potentiation of BCNU cytotoxicity at all doses and CCNU cytotoxicity at high doses. Metabolism of SR-2508 by hypoxic cells did not result in potentiation of BCNU, CCNU or CLZ cytotoxicity at any dose. These in situ data indicate that, 1) MISO is superior to SR-2508 for potentiating NU cytotoxicity, and 2) the NU in a brain tumor chemopotentiation trial should be selected on the basis that it is the most effective potentiable NU against a particular type of brain tumor.     

Effects of drugs of abuse on acquisition of behavioral chains in squirrel monkeys

The acute effects of various drugs of abuse on the acquisition of chains of behavior were assessed in squirrel monkeys trained to respond on three keys for food. Each new session the monkeys acquired a different four-response chain by responding sequentially on three keys in the presence of four different stimuli. Incorrect responses inactivated the keys and darkened the chamber for 10 s (time-out). Dose-effect curves were obtained by administering the drugs intramuscularly before the session and recording their effects on the rate and accuracy of responding. Cocaine,d-amphetamine, and ⁹-tetrahydrocannabinol all decreased the accuracy and rate of responding within the dose range of 0.56–3 mg/kg. The highest dose of morphine tested (3 mg/kg) produced parallel decreases in the accuracy and rate of responding in some monkeys but had no effect at lower doses. These drugs decreased within-session accuracy though clearly acquisition did occur, but high doses of caffeine (30 and 56 mg/kg) prevented acquisition and recovery of performance and, furthermore, at 30 mg/kg these effects were observed in the absence of decreases in the rate of responding. The drugs of abuse tested all produced dose-related decreases in both the accuracy and rate of responding, and the decreases in accuracy were primarily observed only at doses that also decreased response rates. Therefore, based on these results from nonhuman primates each of these drugs has the potential to alter learning particularly when doses that disrupt other behaviors are administered.     

Increase in ω3 (Peripheral-Type Benzodiazepine) binding site densities in different types of human brain tumours

Summary The density of ₃ (peripheral type benzodiazepine) binding sites, a marker of reactive and tumoural cells, has been measured in different types of human brain tumours; ₃ sites were quantified autoradiographically in sections from biopsy or autopsy specimens labelled with the specific radioligand³H-PK 11195. Compared to normal brain parenchyma, up to 12-fold increase in ₃ site densities were found in appparently viable areas of high grade astrocytoma and glioblastoma specimens, whereas more limited increases (2 to 3-fold) in this marker were observed in areas of necrosis. Low grade gliomas (astrocytomas) and meningiomas exhibited only moderate increases (2 to 3-fold) in this autoradiographic marker. Metastases of lung or kidney origin were characterized by greatly elevated (up to 20-fold) ₃ site densities as compared to normal brain parenchyma. In every case, there was a good spatial correspondence between the histopathological limits of the tumour and the anatomical location of the increase in ₃ site densities. These results suggest that ₃ site densities in human brain tumours reflect their proliferative activity and point to a possible future usefulness of positron or gamma-ray emitting ₃ site ligands for the clinical investigation and detection of human brain proliferative diseases.     

High-speed black blood imaging of vessel stenosis in the presence of pulsatile flow.

Stenosis phantoms were created to study the ability of "black blood" methods to image a vessel stenosis in the presence of pulsatile flow. Black blood images were acquired with a modified TurboFLASH (fast low-angle shot) method that eliminates flow signal by applying a set of prepulses before segmented data acquisition. With this high-speed approach, imaging can be completed within 16 seconds. This technique was compared with conventional spin-echo black blood, gradient-echo black blood, and gradient-echo bright blood methods. Loss of flow signal, which extended beyond the site of the stenosis, was seen on the gradient-echo bright blood images. The pattern of signal loss varied with the type of stenosis. Flow voids were achieved with spin-echo black blood imaging; however, substantial ghosting artifacts were seen. With gradient-echo black blood imaging, it was difficult to eliminate all flow signal, particularly for in-plane flow. The modified TurboFLASH method produced high-quality black blood images in a fraction of the time needed for spin-echo imaging. It showed no ghosting artifacts even in the presence of pulsatile flow.     

Rigid immobilization alters matrix organization in the injured rat medial collateral ligament.

The effects of mobilization on matrix reorganization and density after ligament injury were studied in rat medial collateral ligaments using scanning electron microscopy (SEM). Both medial collateral ligaments of 14 Sprague-Dawley rats were sharply incised transversely at their midpoint. A 1.14-mm threaded Kirschner wire was driven through the tibia and into the femur of the right leg (through the knee) to immobilize that knee at 90 degrees of flexion. Four additional rats were used as controls. The right medial collateral ligament of the control rats was exposed in the same manner as the experimental rats and the wound closed without damaging the ligament. Rats were sacrificed on the 7th and 14th days postinjury and the ligaments evaluated by SEM. The electron micrographs from this study demonstrated that early on, the tissue at the injury site is disorganized on a gross scale with large bundles of poorly organized matrix. Large "defects" were present between bundles in the substance of the ligament and appeared as holes in the ligament around the injury site. As healing progressed, the matrix in the mobilized specimens appeared to bridge the injury site more rapidly and completely with fewer "defects" and thus higher density than the immobilized specimens.     

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

The influences of 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.     

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.     

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.