Balwant N. Dixit

The effect of Δ1-tetrahydrocannabinol on serotonin metabolism in the rat brain

Abstract Δ1-Tetrahydrocannabinol significantly altered 5-HT metabolism in the rat brain. Whole brain levels of 5-HT were elevated 66% over control 30 minutes after administration of 20 mg/kg of Δ1-THC. The hypothalamus plus midbrain region and cerebellum were most affected and apparently accounted for the overall increase seen in the whole brain levels of 5-HT. Since Δ-THC.did not affect MAO activity, the increase in 5-HT was evidently not due to inhibition of its degradation. However, synthesis rate of 5-HT was significantly reduced (50%) by Δ1-THC. Furthermore, pretreatment with Δ1-THC retarded the rate of reserpine-induced depletion of brain 5-HT. Alteration of the vesicular membrane is suggested as a possible mechanism for the effects of Δ1-THC on 5-HT metabolism.

Behavioral and biochemical effects of chronic Δ9-tetrahydrocannabinol in rats

In an attempt to identify the possible role of brain biogenic amines and adrenocorticotrophic hormone (ACTH) release in the behavioral and physiological effects of Δ9-tetrahydrocannabinol (THC), the time course of drug action was studied. THC (20 mg/kg) was administered daily for 1, 4, 21, or 42 days to Sprague-Dawley rats that were examined for changes in body temperature, food and water intake, rearing and walking activity, compulsive motor routines, and mouse killing. Four hours after the last THC administration the animals were killed and concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in telencephalon, striatum, diencephalon, mesencephalon, and cerebellum, corticosterone in blood plasma, and epinephrine in the adrenal glands were determined. After initial THC administrations a marked hypothermia, anorexia, adipsia, and depression in locomotion were observed, all of which disappeared within 1 week of treatment. The reduced growth rate and decreased rearing activity persisted throughout the 42-day THC treatment. Compulsive motor routines and mouse killing were induced in a significant proportion of rats treated with THC for more than 3 weeks. Level of 5-HT was increased by 16–37% in all brain regions of rats given THC for 21–42 days. Plasma corticosterone was greatly increased after a single THC injection and remained elevated, to a lesser degree, for 42 days. Adrenal epinephrine was decreased after a single THC administration and increased after 42 days. None of the currently investigated biochemical changes correlated with the marked behavioral and physiological changes after initial THC administration to which tolerance develops. The syndrome of compulsive motor routines after prolonged THC treatment might be mediated by elevated brain 5-HT activity.

The effect of Δ1-tetrahydrocannabinol on the uptake of serotonin by rat brain homogenates

Abstract The uptake of 14C-serotonin by rat brain homogenates (synaptosomes) was inhibited by Δ1-tetrahydrocannabinol in concentrations of 1 × 10−7 M and greater. The antidepresdant agent desipramine had the same effect but showed greater potency, with a concentration as low as 1 × 10−8 M being needed to inhibit 14C-serotonin uptake.

CHARACTERIZATION OF (±)-METHADONE UPTAKE BY RAT LUNG

1 By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (±)‐methadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (±)‐methadone against a concentration gradient. 2 This phenomenon was investigated in vitro with rat lung slices incubated in Krebs‐Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio). 3 The principal observations were: (i) Studies on the time‐course of the uptake showed that the T/M ratios of (±)‐methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (±)‐methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.8; (iii) When the concentration of (±)‐methadone in the incubation medium was varied from 0.005 to 0.5 mM, the T/M ratio decreased rapidly suggesting self‐saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly. 4 These results suggested that at low concentrations, (±)‐methadone was transported predominantly by a self‐saturable process while at higher concentrations it was transported by a process of simple diffusion. 5 At low concentrations (0.01 mM) the uptake of (+)‐methadone was higher than that of (‐)‐isomer indicating stereo‐specificity of the uptake process. The uptake of (±)‐methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of O2, lack of glucose, lack of Na+ in the incubation medium, and by exposure of the tissue to high temperature (≅100°C). The uptake was also inhibited by relatively high concentration of iodoacetate (1.0 mM) and of naloxone (1.0 mM). 6 Kinetic analysis of data showed that the diffusion constant for (±)‐methadone was 5.0 (h−1) and the Vmax of the active transport process was 6.5 μmol g−1 h−1.

Role of the renin-angiotensin system in the blood pressure rebound to sodium nitroprusside in the conscious rat.

Intravenous infusions of sodium nitroprusside (SNP) at doses of 20, 40 or 80 micrograms/kg min-1 for 30 min produced dose-related decrements in blood pressure in conscious rats fitted with indwelling aortic and vena caval catheters. Immediately upon termination of SNP infusions, blood pressure rebounded to levels which were significantly above pre-SNP control values. The following evidence indicates that the rebound increase in blood pressure was due to increased activity of the renin-angiotensin system: (1) plasma renin activity was increased approximately four-fold by SNP, (2) rebound did not occur in nephrectomized rats, (3) rebound was markedly attenuated in animals treated with an angiotensin converting enzyme inhibitor, SQ14225, (D-3-mercapto-2-methylpropanoyl-L-proline) and (4) beta-adrenergic receptor blockade with propranolol reduced the rebound response. In addition, the magnitude of the rebound following SNP infusions was directly related to the dose of SNP infused. These results are consistent with the hypothesis that renin accumulates during SNP infusion more rapidly than it is metabolized. Consequently, the accumulated renin elicits a hypertensive response when SNP treatment is withdrawn.

Effect of ethanol on the oxidative metabolism of tryptamine by rat liver homogenate.

1 The effect of a wide range of ethanol concentrations (v/v) on indoleacetic acid (IAA) formation from the oxidative deamination of tryptamine was studied in vitro, in rat whole liver homogenate. 2 IAA production was inhibited progressively by ethanol in concentrations between 0.01% to 0.2%, but the inhibition declined when the ethanol concentration was increased further to 6%. 3 Ethanol‐induced inhibition of IAA formation was only partially reversed by excess aldehyde dehydrogenase, whereas reductions in IAA formation were completely prevented by pyrazole or ethanol (6% and 10%) itself. 4 Excess nicotinamide adenine dinucleotide failed to alter the inhibitory effect of ethanol and no evidence was obtained for inhibition of monoamine oxidase by ethanol or its metabolite, acetaldehyde. 5 We conclude that ethanol indirectly inhibits IAA production as a result of oxidation of ethanol by alcohol dehydrogenase, during which the oxidative metabolism of tryptamine is shifted towards the reductive pathway, thus favouring the formation of tryptophol in place of IAA.

Cardiovascular effects of chronic reserpine administration in mongrel dogs

Abstract Twenty-four mongrel dogs received small oral doses of reserpine daily for 12–13 months. Chronic administration of low doses of reserpine did not induce significant alterations in arterial blood pressures; however, there was a gradual, significant decrease in heart rate. Studies on autonomic function revealed a certain degree of impairment of cardiovascular reflexes and sympathetic tone. Hypotensive response to hexamethonium was inhibited in reserpine-treated dogs. At the termination of the study, left ventricular work was significantly lower and cardiac output decreased in the reserpine-treated group under pentobarbital anesthesia. Although the right ventricular contractile force and rate of tension development were significantly greater in the reserpine-treated group, the stroke volumes were not. Greater pressor responses obtained to intravenous administration of epinephrine and norepinephrine in the reserpine group were due to a greater elevation of total peripheral resistance rather than cardiac output. It is concluded that the efficiency of the right ventricular myocardium was attenuated in the dogs treated with reserpine.

Pharmacologic implications of alterations in the metabolism of chloramphenicol

Abstract In the present study, it was shown that in rats the glucuronide conjugation of chloramphenicol was reduced by 18- to 24-hr fasting and by pretreatment with o - and p -toluic acids. This was reflected in the increased availability of chloramphenicol to produce liver microsomal enzyme inhibition. Eighteen- to 24-hr fasting and administration of o - and p -toluic acids delayed the disappearance of chloramphenicol from the plasma and from the liver and reduced the levels of chloramphenicol glucuronide in the plasma and in the liver tissue. These changes in the inactivation profile were accompanied by potentiation of chloramphenicol-induced prolongation of hexobarbital sleeping time. In fasted rats, glucose administration antagonized the changes observed in chloramphenicol metabolism and its effect on hexobarbital sleeping time. Pretreatment with o -toluamide, which is not conjugated with glucuronic acid, did not have a significant effect on glucuronide conjugation of chloramphenicol. It was also shown that thiamphenicol-induced inhibition of liver microsomal enzymes in vivo , measured in terms of its effect on the prolongation of hexobarbital sleeping time, was not affected either by fasting or by administration of o - and p -toluic acids. Thiamphenicol, an analog of chloramphenicol, is not metabolized by glucuronide conjugation, but is excreted unchanged. These observations indicate that the potentiation of chloramphenicol-induced prolongation of hexobarbital sleeping time in fasted and in o - or p -toluic acid-treated rats was due to the availability of higher amounts of chloramphenicol producing a greater degree of microsomal inhibition.