Dose-related Depression Research Articles

Dose-related depression of pha-induced stimulation of human lymphocytes by hydrocortisone

Hydrocortisone inhibits PHA-induced lymphocyte stimulation by reducing the number of cells entering G 1-phase and by slowing the volume growth rate during the first 24 h of culture: the kinetics of cellular recruitment is unmodified. This inhibition has a linear log-dose response curve and there is marked intersubject variation in normal adults. Pre-incubation of the cells with hydrocortisone greatly potentiates its inhibitory effect: when added after the start of PHA stimulation, hydrocortisone becomes progressively less effective until it has lost most of its activity by 5 h, even though the cells do not show any microscopic evidence of having entered the G 1-phase at that time. The experiments have elucidated the mode of action of hydrocortisone inhibition on the early stages of PHA-induced lymphocyte stimulation and shown an unexpectedly large intersubject variation in responsiveness that might have therapeutic significance. The methods that have been employed could be adapted for clinical monitoring of the immunosuppressive effect of glucocorticoids in individual patients and for screening synthetic steroids for glucocorticoid activity.

Brain stimulation as a cue for event-related potentials in rat cortex: amphetamine effects.

Slow potential (SP) responses were recorded bilaterally from the frontal cortex of rats with permanently implanted silver-silver chloride electrodes. Trials were presented at variable intervals from 15 to 50 sec and the interval between the pulse cue and onset of the rewarding train was 2 sec. The cue stimulus was a single 0.5 msec monophasic square wave pulse of the same current intensity as rewarding stimulation (100 Hz, 500 msec train). Appropriate current strength was determined by prior testing for self-stimulation. The single pulse by itself failed to evoke an SP response but after repeated pairings, large negative SP responses developed which were bilaterally equal. These responses extinguished rapidly when rewarding stimulation was discontinued. d-Amphetamine (0.125, 0.25 and 0.5 mg/kg, SC) produced a dose-related depression of the SP response to the pulse cue, an effect comparable to that observed using an auditory cue with either food or MFB stimulation reinforcement. The results indicate that frontal cortex SP responses which develop in anticipation of a meaningful event do not require a peripheral sensory cue. Furthermore, amphetamine suppression of these SP responses is not produced via a disruption of the auditory system.

Blockade of amphetamine-induced locomotor activity and stereotypy in rats by spiroperidol but not by an atypical neuroleptic, thioridazine

Amphetamine-induced locomotor activity has been shown to be critically dependent on mesolimbic dopaminergic pathways; it should therefore constitute a sensitive test for “atypical” antischi-zophrenic drugs such as thioridazine which are reputed to block mesolimbic rather than nigrostriatal pathways (unlike “typical” neuroleptics such as spiroperidol which block both). This hypothesis was examined by comparing the ability of thioridazine and spiroperidol to block amphetamine-induced stereotypy (previously shown to depend on nigrostriatal activity) and amphetamine-induced locomotion (reflecting mesolimbic activity). The results were contrary to the hypothesis tested. Although spiroperidol (0.025-0.1 mg/kg) produced a dose-related depression of amphetamine-induced locomotion and stereotypy, thioridazine was without effect even in doses (5.0–20 mg/kg) that were as effective as those of spiroperidol in reducing spontaneous locomotor activity. The results do not support the belief that thioridazine acts selectively on a mesolimbic dopamine system mediating amphetamine-induced locomotion, and raise the possibility that the behavioural effects of low doses of thioridazine depend on other than dopamine receptors.

Effects of dextroamphetamine on event-related slow potentials in rat cortex during a reaction time task

Event-related slow potentials were recorded from two different cortical areas in the rat during an operant reaction time task in which trials were initiated at variable intervals by an auditory warning stimulus. Slow potential responses during the 2-sec period between onset of the warning stimulus and extension of a retractable lever were analyzed. The effects of various doses of d-Amphetamine on the slow potential responses were examined. Surface-negative slow potential responses from the frontal cortex had two components, an early wave which reached maximum amplitude at 200–350 msec after the stimulus and a later wave which began at 650–850 msec. The slow potential response recorded from the visual cortex showed a smaller surface-negative wave which was maximum at 350–1000 msec; following the initial negative wave, the potential gradually shifted positive. d-Amphetamine (0.25, 0.5 and 1.0 mg/kg) caused a dose-related depression of the frontal slow potential responses (indicated by both amplitude and area analysis). Amplitudes and areas of the visual slow potential were not consistently altered. The results of this study indicate that the effects of d-amphetamine on eventrelated slow potentials in the rat are dependent on the cortical area from which they are recorded.

The effect of the methionine antagonist l-2-amino-4-methoxy- trans-3-butenoic acid on the growth and metabolism of walker carcinosarcoma in vitro

l-2-Amino-4-methoxy- trans-3-butenoic acid (Ro07–7957) is a structural analogue ot methionine with a potent tumour growth inhibitory activity in vitro. This agent is transported by the methionine carrier system in Walker carcinoma and causes an initial dose-related depression of the acid-soluble pool of methionine. The depression of the incorporation of l-[methyl- 3H]methionine into acid-insoluble material in the presence of Ro07–7957 is greater than that of l-[2- 3H]methionine and l-[4,5( n)- 3H]lysine, suggesting an inhibition of the methylation of macromolecules as well as an inhibition of protein synthesis. There is no effect of the drug on the incorporation of [ 3H]thymidine into acid-insoluble material during the first 24 hr after treatment, while the incorporation of [5- 3H]uridine is stimulated 40 per cent. The ratio of incorporation of l-[2- 3H]methionine to l-[methyl- 14C]methionine into proteins increases with increasing drug concentration, suggesting an inhibition of protein methylation. This effect is more prevalent at 24 hr than after 8 hr of treatment. The specific activity of tRNA methylase using E. coli MRE 600 tRNA as substrate is elevated more than two-fold within 24 hr after treatment, as is also the intracellular level of S-adenosyl- l-methionine (SAM). The effects of this agent on macromolecular metabolism is in some respects similar to that observed with the carcinogen ethionine, and suggests the initial formation of an inhibitor of methylation, which is followed by a later attempt by the cells to maintain homeostasis by production of increased amounts of tRNA methylating enzymes.

Chronic manganese oxide administration to preweanling rats: manganese accumulation and distribution.

Mn accumulation was evaluated in selected tissues of preweanling rats dosed daily with particulate Mn3O4. Significant findings include a high rate of Mn accumulation in the preweanling rat; a Mn dose-related acceleration of postpartum liver iron depletion; a Mn dose-related depression in red blood cells, hematocrit, hemoglobin, body weight, and survival by 21 d postpartum; and a Mn distribution in tissues with liver greater than brain greater than or equal to kidney greater than testes at 18-21 d of age.

Ketamine Acts on the Peripheral Sympathetic Nervous System of Guinea Pigs

The effects of ketamine on the peripheral sympathetic nervous system were studied in vitro by observing the amplitude of the nerve-mediated contraction of the vasa deferentia isolated from guinea pigs. Ketamine dissolved in the perfusate of an organ bath was applied to the tissues for 30 minutes and then washed out with a perfusate lacking ketamine for 90 minutes. Ketamine in concentrations of 10(-8) and 10(-7) g/ml had no effect on contraction induced by hypogastric nerve (preganglionic) stimulation. At 10(-6) g/ml, the drug had no significant effect during application but was associated with increased contractions during washout. At 10(-5) and 10(-4) g/ml, the drug showed a dose-related depression during application and an increase in contractions during washout after a 10(-5) g/ml. Ketamine, 10(-5) g/ml, increased contraction following transmural (postganglionic) stimulation and had a depressant effect at a concentration of 10(-4) g/ml. It is concluded (1) that ketamine has dual effects on the nerve-mediated contraction of the vasa defentia and (2) that cardiovascular responses to ketamine include peripheral effects of ketamine on sympathetic ganglia.

Locomotor depressant action of indole aldoxime and its antagonism by d-amphetamine

The intraperitoneal administration of indole-3-aldehyde oxime (IAO) at doses of 25–150 mg/kg to mice produced hypothermia and profound dose-related depression of locomotor activity. The larger doses induced a state of total tonic immobility. Locomotor depression could best be antagonized by pretreatment with d-amphetamine, whereas apomorphine, clonidine, imipramine and pargyline were ineffective. In view of the possibility of formation of oximes in vivo, the close structural resemblance of IAO to biogenic amines and the effective antagonism of its loco-motor depressant action by d-amphetamine point to a type of chemical compound of possible significance in the central control of motor activity.

Carcinogenicity of the hair-dye component 2-nitro-p-phenylenediamine: Induction of eosinophilic hepatocellular neoplasms in female B6C3F1 mice

Groups of 50 male and 50 female B6C3F1 mice were given 2-nitro-p-phenylenediamine in the feed at either 2200 or 4400 ppm for 78 wk. Twenty animals of each sex were used as controls. Treatment was followed by a 12–13 wk observation period. There was a dose-related depression of body-weight gain in both sexes. Pigmentation was observed in liver, spleen, intestine and thyroid. Female mice receiving 2-nitro-p-phenylenediamine showed a dose-related increase in the incidence of hepatocellular neoplasms. The majority of these neoplasms were multiple eosinophilic hepatocellular adenomas which were different from the adenomas in control mice. A few female mice given 2-nitro-p-phenylenediamine had foci of cellular alteration in the liver. Neoplasms similar to those induced by 2-nitro-p-phenylenediamine have been reported in mice exposed to two other aromatic amines, 4-chloro-m-phenylenediamine and 4-nitro-o-phenylenediamine. However the latter did not prove to be carcinogenic.

GABA Receptor Control of Parasympathetic Outflow to Heart: Characterization and Brainstem Localization

Blockade of gamma-aminobutyric acid (GABA) receptor function by direct microinjection of the GABA receptor antagonist bicuculline into the nucleus ambiguus of the brainstem produced a marked, dose-related depression of heart rate and blood pressure which was mediated by the vagus nerve. This effect was not obtained in other regions of the brainstem and was reversed by the GABA receptor agonist muscimol. These data indicate that the nucleus ambiguus may be the site of a GABA receptor-mediated inhibition of vagal outflow.

Inhibitory actions of butylated hydroxytoluene on isolated ileal, atrial, and perfused heart preparations

Butylated hydroxytoluene (BHT), in concentrations of 500, 100, and 10 mg/liter (but not 1 mg/liter), significantly depressed methacholine-induced contractions of isolated rat and rabbit ileal preparations. BHT, in concentrations of 500, 100, 10, and 1 mg/liter, significatly ( p < 0.05) depressed the frequency and amplitude (force) of contractions of isolated atrial preparations as compared to controls. Control rat and rabbit atrial beating rates were monitored continously for 120 min (although isolated control atrial preparations continue to beat spontaneously for several hours). BHT at 500 mg/liter terminated spontaneous contractions of isolated rabbit atria after 20 min and after 72 min when tested on rat atria. Although concentrations below 500 mg/liter did not terminate atrial beating activity, they did produce a pronounced concentration-dependent depression of rate and force of atrial contractions. The most pronounced depression of atrial contractions produced by BHT were always seen within the first 30 min (out of a period up to 120 min) of exposure but the depression persisted throughout the exposure period. Similar significant dose-related depressions were seen using the same concentrations in intact perfused rat heart preparations. Additionally, perfused hearts treated with BHT (in concentrations from 1 to 500 mg/liter) showed significant dose-related increases in creatine phosphokinase leakage into the perfusion solutions.

Dopamine-dependent hyperactivity in the rat following manipulation of GABA mechanisms in the region of the nucleus accumbens.

The effect of manipulation of GABA mechanisms in the region of the nucleus accumbens on dopamine-dependent locomotor hyperactivity in the rat has been studied. Two models of hyperactivity were used: (1) the injection of dopamine into the region of the nucleus accumbens in nialamide-pretreated animals and (2) the systemic administration of d-amphetamine. Both GABA and the GABA agonist 3-aminopropane sulphonic acid (3-APS) depressed hyperactivity in a dose-related manner. High concentrations of GABA (greater than 100 micrograms) were required to produce a significant effect and the response was short-lived possibly reflecting the efficient GABA inactivating mechanisms. 3-APS proved to be approximately 10 times more potent as compared to GABA in the dopamine-accumbens hyperactivity model. Conversely GABA receptor antagonism with low doses of either picrotoxin or bicuculline enhanced the mild locomotor response induced by a low dose of dopamine injected into the nucleus accumbens. However such results were difficult to evaluate fairly as higher doses of the GABA antagonists resulted in varying degrees of generalized seizures. Blockade of GABA uptake systems with cis-1, 3-aminocyclohexane carboxylic acid (ACHC), nipecotic acid or beta-alanine within the region of the nucleus accumbens produced dose-related depression of dopamine-dependent hyperactivity in both models. GABA uptake blockade (nipecotic acid) significantly enhanced the GABA-mediated depression of hyperactivity induced by bilateral injection of dopamine into the nucleus accumbens. The results demonstrate an inhibitory action of GABA and drugs facilitating GABA-ergic transmission on dopamine-dependent hyperactivity in the rat. Although open to criticisms of not being able to distinguish between true GABA effects and the results of non-specific neuronal depression the hyperactivity model underlines the potency of the GABA uptake blocking compounds and their possible potential for future clinical use.

Effects of nicotine on cardiac prostaglandin and platelet thromboxane synthesis.

1 Rabbit hearts were perfused with a solution containing [14C]-arachidonic acid (AA) and various concentrations of nicotine (3 x 10(-8) to 3 x 10(-5) M). The venous effluent was collected and extracted for lipid acid material, which was subsequently subjected to thin layer radiochromatography. 2 Human platelets were incubated with nicotine (10(-8) to 10(-4) M), in the absence or presence of unlabelled AA. The amount of smooth muscle stimulating activity resulting from 30s of incubation was tested on a rabbit aortic strip. 3 In hearts perfused with [14C]-AA; nicotine induced a dose-related depression of the release of [14C]-6-keto-prostaglandin F1alpha, and a parallel increase of [14C]-prostaglandin E2. 4 Nicotine neither induced synthesis of thromboxane in human platelets, nor affected the platelet synthesis of thromboxane induced by AA. 5 It is suggested that nicotine affects the metabolism of prostaglandin endoperoxides in the heart by inhibiting their conversion to prostacyclin and facilitating, directly or indirectly, the formation of prostaglandin E2.

The effect of contrast media on the isolated perfused canine heart.

The intravascular injection of contrast medium produces a rise of ventricular filling pressure which may reflect blood volume expansion, a negative inotropic effect on the myocardium, and/or a decrease in ventricular diastolic compliance. This phenomenon was studied by randomly infusing three substances, Renografin-76, 1% saline and 38% sucrose, into the aortic root of the isolated perfused canine heart. The preparation was modified by having an inflated ballon within the left ventricular cavity so that the end diastolic ventricular volume and afterload were fixed. A dose-related depression of left ventricular systolic pressure and peak dP/dt due to contrast media occurred, without a significant change in the left ventricular diastolic pressure. This decrease in ventricular contractility due to Renografin-76 could not be attributed entirely to either a saline or an osmotic effect. No significant changes were observed in left ventricular diastolic compliance. Sucrose was found to exhibit a marked positive inotropic effect.

Effects of 1,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole[difenamizole] on a conditioned avoidance response

The effect of l,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole[difenamizole], an analgesic synthesized by the present authors, on the performance of a conditioned avoidance was compared with that of analgesic doses of morphine, aminopyrine, chlorpromazine and chlordiazepoxide in rats. Experiments were conducted in a two-compartment rat shuttle-box system using 20-trial sessions and a 5-sec conditioned stimulus-unconditioned stimulus interval. Difenamizole (100–400 mg/kg, p.o.) increased significantly the number of avoidance failures, decreased the number of fecal boluses excreted, and prolonged response latency times. Aminopyrine (100–400 mg/kg, p.o.) produced a dose-related prolongation in response latency time, but the effect of this drug on the percentage avoidance was less than that produced by difenamizole at low doses. The avoidance behaviour was hardly influenced by analgesic doses of morphine (10–40 mg/kg, p.o.) and chlordiazepoxide (10–40 mg/kg, P.O.). Chlorpromazine (5–20 mg/kg, p.o.) produced a dose-related depression in percentage avoidance and a doserelated prolongation in response latency time. The effect of difenamizole on conditioned avoidance performance was similar to that produced by chlorpromazine.

Lidocaine, monoethylglycinexylidide, and isolated human uterine muscle.

The effects of lidocaine and its primary metabolite monoethylglycinexylidide (MEGX) on isolated human muscle strips from non-gravid and gravid uteri were evaluated. No differences between the effects of lidocaine and those of MEGX on gravid and non-gravid muscle strips were observed. Lidocaine produced significant (P less than 0.01) dose-related depression of uterine contractility, although significant pharamacologic depression occurred only at lidocaine concentrations in excess of 25 microgram/ml. MEGX produced no consistent changes in any of the responses measured.

59Fe uptake method to differentiate between proliferation-dependent and nondependent cytotoxic agents

The 24-hr incorporation of 59 Fe into circulating red blood cells was measured in mice 24, 48, 72 and 96 hr after treatment with cytarabine, methotrexate, vinblastine, cyclophosphamide, and busulfan to determine whether these agents acted on proliferating cells or on resting cells. Cytarabine and methotrexate, which are proliferation-dependent agents, reduced 59 Fe uptake 24 and 48 hr but not 72 and 96 hr after drug treatment. On the other hand, cyclophosphamide and busulfan, which are proliferation-nondependent agents, reduced 59 Fe uptake at each of these time periods. Vinblastine, which attacks proliferating cells more sensitively than nonproliferating cells, lowered 59 Fe uptake severely at 24 and 48 hr, slightly at 72 hr, and not at all at 96 hr. When a single dose (75 to 300 mg/kg) of cytarabine was given, no dose-related depression of 59 Fe uptake was found 48 hr after drug treatment but when the same doses were given as three divided doses, dose-related depression of 59 Fe was observed 48 hr after cytarabine. At 72 hr after the administration of three divided doses of 50 mg/kg, no depression of 59 Fe uptake was found but when an initial dose of 50 mg/kg was given 12 hr prior to the three divided doses, 59 Fe incorporation was reduced by 65%. These studies indicate that the 59 Fe uptake method can be used to determine whether the cytotoxic agents act only on proliferating cells or on nonproliferating cells as well.

Central vagal control of fentanyl-induced bradycardia during halothane anesthesia.

Six mongrel dogs were used to investigate the mechanism of action of fentanyl-induced bradycardia. With controlled acid-base balance and temperature, and under 1.0 to 1.2 percent endtidal halothane anesthesia, 5 and microgram/kg of IV fentanyl citrate were given sequentially 1 hour apart and heart rate (HR) followed for 60 minutes. A dose-related depression of HR followed both injections. One week later the same dogs were studied similarly, except that bilateral cervical vagotomies were performed before fentanyl was given. The decrease in HR was at most 10 percent of the decrease in HR observed in the innervated dogs. Serum fentanyl levels were comparable. The data indicate the majority of the chronotropic action of fentanyl involves vagal efferent impulses from the central nervous system.

Intraperitoneal and intracranial cholecystokinin depress operant responding for food

Intraperitoneal injection of 20 I.D.U./kg of cholecystokinin (CCK), a gut hormone, depressed food intake in female rats as measured by an operant response for food. The effect was maximal thirty min after the injection and lasted 60–90 min. Intracranial injection of 0.05, 0.10, or 0.20 I.D.U. of CCK into the lateral ventricle of female rats, produced a dose-related depression of food-rewarded lever pressing. In this case, however, the effect was not observed during the first thirty min, but became apparent thereafter. The results are discussed in terms of possible receptors for CCK within the brain.

Effects of intrahypothalamic 6-hydroxydopamine on central thermoregulatory responses to (+)- and (-)-norepinephrine and dopamine

Tntracerebral injection of 0.01 or 0.015 to 0.1 μmol of both the (+)- and (-)- cnantiomers of norepinephrine (NE) and dopamine (DA) into the preoptic-anterior hypothalamic region (PO/AH) of awake cats caused dose-related depressions of rectal temperature. After local denervation of the preoptic-anterior hypothalamic region (PO/AH) with 6-hydroxydopamine (6-OHDA), hypothermie receptor sensitivity to (-)-NE increased (supersensitivity) whereas sensitivity to (+)-NE remained virtually unchanged and that to DA decreased (subsensitivity). These demonstrations of central pharmacologie (hypothermie) receptor supersensitivity and stereoselectivity are qualitatively similar to pharmacological drug-receptor interactions observed in peripheral adrenergic neuroeffector tissues. Drug-induced reductions in rectal temperature were accompanied by physiologically and temporally related reductions in heart rate, in shivering and. less regularly, by peripheral vasodilation. The differential responses to DA. (+)- and (-)-NE are discussed in relationship to their possible modes of hypothermie receptor interaction.