Immunosuppressive Effects of the S-Adenosylhomocysteine Hydrolase Inhibitor, 3-Deazaadenosine

Immunosuppressive effects of 3-deazaadenosine (3-DAA), an inhibitor of S-adenosylhomocysteine hydrolase, were tested in vivo in immune assays against sheep red blood cells (SRBC), involving serum titrations for hemagglutinins and hemolysins, cellular cytotoxicity tests and the direct plaque-forming cell assay. At daily doses up to 100 mg/kg, the compound was suppressive when injected before antigen and the effect appeared to be dose-dependent (ED₅₀ = 52.6 ± 4.9 mg/kg). When doses of 25 mg/kg of 3-DAA were given before antigen, co-injections of 250 mg/kg of L-homocysteine (L-HC) potentiated the suppressive effect, although L-HC alone was inactive. Daily administration of 100 mg/kg of 3-DAA or 250 mg/kg of L-HC alone was not suppressive when given after the antigen; however, in combination they were able to induce suppression. The possible biochemical mechanisms of the suppression, particularly those involving the inhibition of S-adenosylmethionine-dependent methylation reactions, are discussed.     

RADIOPROTECTIVE EFFICACY AND ACUTE TOXICITY OF 5-ANDROSTENEDIOL AFTER SUBCUTANEOUS OR ORAL ADMINISTRATION IN MICE

ABSTRACT

We previously showed that one subcutaneous (sc) injection of 5-androstene-3beta,17beta-diol (AED) stimulated the innate immune system in mice and prevented mortality due to hemopoietic suppression after whole-body ionizing irradiation with gamma rays. In the present study, we tested whether there was any significant toxicity in mice that might hinder development of this steroid for human use. There were no indications of toxicity in chemical analyses of serum after sc doses as high as 4000 mg/kg. At this dose, 2 of 54 mice died when given AED alone. When 4800 mg/kg was given orally, no deaths resulted. The only adverse findings attributed to AED administration were 1) a moderate elevation of granulocytes in abdominal organs and fat after sc injections of 320 mg/kg; and 2) occasional wasting of skin over the injection site in female B6D2F1 but not male C3H/HeN mice. Significant weight loss (6%) was observed after sc injections of 320 mg/kg but not 160 or 80 mg/kg. When male C3H/HeN mice were injected sc with AED at doses of 0–200 mg/kg 24 h before whole body gamma-irradiation (9 Gy), a significant improvement in survival was observed at doses as low as 5 mg/kg. Oral administration of AED produced significant survival enhancement at a dose of 1600 mg/kg. We conclude that the radioprotective efficacy of AED is accompanied by low toxicity.Androst-5-ene-3 beta, 17 beta-diol; Ionizing radiation; Experimental radiation injuries; Toxicity; Clinical chemistry; Histopathology     

The Dose-Dependent Influence of Mechloretamine on the Response to Sheep Erythrocytes in Mice. Comparison of Immunostimulating Properties of Mechloretamine with Levamisole

The effect of the following doses of mechloretamine: 1, 5, 10, 25, 50, 100, 250 and 500 μg^/kg on the immunological response in mice immunized with sheep red blood cells (SRBC) was investigated. the number of plaque forming cells (PFC) to SRBC, the serum hemagglutinins level and the number of lymphocytes forming E or EAC-rosettes were determined. Depending on mechloretamine dose the following effects on the tested parameters were obtained : (i) only stimulating -1 and 5 pg/kg, (ii) stimulating or suppressive according to the test -10-100 pg/kg, (iii) only suppressive -250 and 500 μg/kg. Mechloretamine (5 μg/kg) induced the increase in PFC in comparison with levamisole (2 mg/kg). the difference between the action of mechloretamine and levamisole used in immunostimulating doses on the increased anti-SKBC antibodies or on the E-rosette forming lymphocytes was revealed.     

Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration

The pharmacokinetics of ciprofloxacin was studied in three groups of healthy volunteers comprising a total of 16 males and 16 females (age 21–35 years; body weight 52–80 kg). Single oral doses of 50, 100, 250, 500 and 750 mg were given to fasting subjects. The 250 mg dose was repeated after a breakfast. Intravenous doses of 50, 100 and 200 mg were given by short infusion in a randomized cross-over sequence. Concentrations of the drug in serum and urine were determined by high-performance liquid chromatography and by a microbiological assay. Mean peak concentrations between 0.37±0.49 mg/l (100 mg dose) and 1.97±0.50 (750 mg dose) were measured 60–75 min after oral administration. Twelve hours after 750 mg ciprofloxacin, serum concentrations were 0.15±0.05 mg/l. Taking a breakfast reduced absorption by 15–20% compared to the fasting state, as judged by peak concentrations, AUC and renal excretion. After 200 mg i. v. (20 min infusion period), initial serum concentrations of 4.0±1.2 mg/l were observed which declined 12 h later to 0.070±0.025 mg/l. Mean cumulated recovery of ciprofloxacin from urine over 24 h varied between 25.5% and 33.6% of oral doses and between 53.2% and 57.4% of intravenous doses. Two of the three metabolites seen in the chromatograms were identified as M1 and M3 (oxo-ciprofloxacin). Cumulated renal excretion after an oral 250 mg dose was 1.2±0.4% of M1 and 5.5±1.6% of M3. Bioavailability of oral doses varied from 0.64±0.16 (100 mg) to 0.52±0.11 (500 mg). The AUC was linearly proportional to a single dose of up to 250 mg. Ciprofloxacin was rapidly absorbed and distributed. High distribution volumes were calculated (mean VD_area 186–217 1). The terminal half-life (t₁/2) was 3.1 to 5.4 h. Mean total body clearance was also high (600 to 693 ml/min · 70 kg)). Tolerance of ciprofloxacin was good for all oral doses and for intravenous administration up to 100 mg per dose. Intravenous infusion of 200 mg ciprofloxacin caused transient local irritation.     

Role of the Dopaminergic System of the Brain in the Effects of Glucocorticoid Hormones

The conditioned reinforcement properties of the synthetic glucocorticoid dexamethasone and the possible mechanisms of its action were studied using a conditioned place preference response. On test day 1, male Wistar rats were placed in a two-chamber apparatus and the time spent in each sector was measured for 10 min. Over the next six days, combinations of one of the chambers with administration of agents (reinforcement) were presented using injections of dexamethasone in one sector and injections of physiological saline in the other sector on alternate days. After combinations of dexamethasone (0.25–0.77 mg/kg, i.p.) with the non-preferred sector, rats showed dose-dependent place preference on test day 2; however, when dexamethasone was combined with the initially preferred sector, animals given dexamethasone at a dose of 0.75 mg/kg showed only a slight level of place avoidance. Subthreshold doses of phenamine (0.25 mg/kg) given alone had no effect; however, when given on a background of dexamethasone (0.25 mg/kg), phenamine evoked a place preference response in rats lacking an initial place preference for one sector. Administration of dexamethasone alone (0.25 mg/kg) in these conditions did not induce place preference. Administration of the dopamine D₂ receptor antagonist sulpiride (20 mg/kg) 30 min before combinations of dexamethasone (0.25 mg/kg) with the non-preferred sector completely prevented the acquisition of place preference. Administration of the D₁ dopamine receptor antagonist SCH23390 (0.05 mg/kg) had no effect on the acquisition of conditioned preference. These results provide evidence for the involvement of D₂ receptors in conditioned place preference induced by dexamethasone.     

Suppression of Experimental Allergic Encephalomyelitis by En3638: Dependence

Oral administration of 2, 3 or 4 doses of 100 or 250 mg/kg of EN3638 during the incubation period of experimental allergic encephalomyelitis delayed the onset and reduced the incidence and severity of clinical signs and histological lesions. Five doses of 50 or 100 mg/kg effected virtually complete and permanent suppression of clinical signs even after cessation of therapy, and five doses of 250 mg/kg eliminated histological lesions as well. Optimum results required coverage of the entire incubation period regardless of dose level. These results were obtained only when carbonyl iron was used as the adjuvant for production of EAE. When complete Freund's adjuvant was used, EN3638 delayed the onset but had little or no influence on late-developing clinical signs and histologic lesions after cessation of therapy. The permanence of suppression when carbonyl iron was used is related to the absence of an oil depot. Carbonyl iron is a superior adjuvant for drug suppression studies.     

Optimal Conditions for Antitumor Activity of C. Parvum Against the Ascites Form of Sarcoma 180

Single and multiple doses of Corynebacterium parvum (C. parvum) ranging from 0.1-60 mg/kg were tested for antitumor activity against 10⁶ sarcoma 180 cells in male CD1 mice. Determinations were made of the optimal dose and time of treatment needed to produce maximum suppression of the tumor using both median survival time and percent survival to day 90 as endpoints. A dose of 1 mg/kg given 3 days before sarcoma 180 transplant produced complete protection (100% survival). All other treatment regimens produced less of an effect. Single doses of 1, 10 and 60 mglkg had significant antitumor activity when administered either on day 3, 2 or 1 before tumor implant, 0.1 mg/kg protected only when given on day 3. All single doses given 5 or 8 days before and anytime after tumor were ineffective.

Multiple doses were only of advantage over single doses when treatments were after tumor cell inoculation. In vitro cytotoxicity studies demonstrated that both 1 and 60 mg/kg enhanced tumor cell killing by cells isolated from the peritoneal cavity, with the 1 mg/kg dose producing a greater effect. It was concluded that dose and time of administration of C. parvum, in relation to tumor implant, were important in determining optimal antitumor activity against sarcoma 180.     

Oral administration ofl-arginine, a nitric oxide precursor, decreases nociceptive sensitivity in rats

Tail-flick test was used to evaluate the effect of orally administeredl-arginine on nociceptive sensitivity of albino rats, which produced a) analgesia at 30 min postadministration lasting about 1.5 h (100 mg/kg); b) short-term analgesia (50 mg/kg); and c) no analgesic effect (250 mg/kg).d-Arginine (100 mg/kg) did not affect the nociceptive sensitivity. A significant NO increase took place in cerebral cortex at 30 min postadministration ofl-arginine in the given doses. At 1 h postadministration ofl-arginine in doses of 50 and 250 mg/kg, cortical NO content was lower than that in control animals. Analgesic effect ofl-arginine is presumably related to additional synthesis of NO. This effect seems to be not directly produced by NO, but is realized via other transmitter systems. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 11, pp. 498–501, November, 1997     

The effect of disodium 4-chloro-2-iminodibenzoate (CCA) on IgE levels and anaphylactic shock

The effect of disodium 4-chloro-2,2-iminodibenzoate (CCA) on IgE antibody response was examined in C₃H/A and (BALB/c×C57BL/6J) F1 hybrid mice immunized with low doses of ovalbumin (OA) adsorbed on aluminium hydroxide gel. CCA administered orally at the doses of 5 and 50 mg/kg/day reduced IgE antibody production in these mice as determined by PCA test. High doses of CCA (100 mg/kg/day) given from day 7 before immunization of C57BL mice and during 1 week after immunization of mice with OA and Bordetella Pertussis Vaccine reduced the mortality of these mice subjected to anaphylactic shock on day 7 of immunization. CCA treatment was ineffective in anaphylactic shock of C57BL mice immunized with very high dose of OA, known to elicit little or no IgE antibody production but high IgG antibody response.The treatment of OA-immunized Guinea pigs with one oral dose of CCA (100 mg/kg) did not reduce mortality in protracted anaphylactic shock. Our results demonstrate that CCA inhibits IgE production as well as IgE mediated hypersensitivity reactions in mice.     

Effects of Treatment with Amphetamine and Diazepam on Mycobacterium Bovis-Induced Infection in Hamsters

Abstract

Tuberculosis is an example of an infection with an intracellular bacterium in which sensitivity is determined mainly by the host response. Macrophages are the architectural and functional units of the granulomas described in tuberculosis. Treatment with amphetamine (AMPH) and diazepam has been reported to decrease macrophage activity The present experiment was undertaken to investigate the effects of AMPH and/or diazepam given alone or in combination on hamster resistance to Mycobacterium bovis. The effects of these treatments on serum Cortisol levels were also studied. Adult hamsters were treated i.p. with AMPH (group E₁ = 1.0 or 2.0 mg/kg/day), with AMPH (group E₂ = 1.0 or 2.0 mg/kg/day) plus diazepam (2.0 mg/kg/day), with diazepam (group E3 = 2.0 mg/kg/day), or with control vehicles (1.0 ml/kg/day) for 40 days. Six days after the beginning of the treatments, the animals received identical inoculum concentrations of M. bovis. Hamsters treated with AMPH plus diazepam exhibited: 1) increased weight loss; 2) increased mortality; 3) increased scores of M. bovis colony forming units (CFU) isolated from liver, lung and spleen; 4) increased granuloma areas measured in the liver, lung and spleen. These effects were not induced by AMPH (1.0 or 2.0 mg/kg/day) given alone and were produced by diazepam (2.0 mg/kg/day) treatment per se. Furthermore, AMPH (2.0 mg/kg/day) and diazepam (2.0 mg/kg/day) given alone or in combination for 20 days increased the serum levels of Cortisol in relation to control hamsters, with the effect being higher in the animals treated with both drugs. The present data, which demonstrate an impaired defense against M. bovis in hamsters treated with AMPH plus diazepam or with diazepam alone, were tentatively explained on the basis of a direct and/or indirect action of the drugs on macrophage/lymphocyte activity. In the former case, the effects may be related to stimulation of peripheral benzodiazepine receptor sites (PBR) present on macrophages/lymphocytes and/or to a direct effect of ACTH on immune cells, while in the latter they may be mediated by Cortisol via PBR and ACTH stimulation of the adrenals.     

Effects of cocaine on the immune system of Balb/C mice

Cocaine was given to Balb/C mice by intramuscular injection to assess the effects of the drug on their immune system. An injection of 5 mg/kg of cocaine 24 hr before assay suppressed phagocytic activity of peritoneal macrophages and decreased the numbers of thymocytes and white blood cells in a dose-dependent manner. The suppression appeared to be reversible. Tumor-implanted mice received 10 consecutive days of injections of smaller doses of cocaine (0.05, 0.25, or 5 mg/kg), also resulting in a dose-dependent suppression of phagocytosis 24 hr after the last injection. Cocaine decreased the number of plaque-forming cells when 5 mg/kg of cocaine was injected on the day of immunization but no inhibition was detected if the drug was given later. The size of tumors appeared to be increased in mice injected with cocaine for 10 consecutive days in comparison to the control mice. The effects were concentration dependent. Our study showed that cocaine had general suppressive effects on the mouse immune system.     

The Differential Sensitivity of Rat Peripheul Blood T Cells to Immunosuppressants: Cyclophosphamidb and Dbxametmsone

Abstract

Peripheral blood T cells from rats given a single oral dose of dexamethasone (DMS) or cyclophosphamide (CY) exhibited a differential sensitivity to these compounds as measured by lymphoproliferation in the presence of concanavalin A (Con A) or phytohemagglutinin (PHA). Con A-responsive cells (T_{con A} were found to be resistant to the effects of DMS, while the PHA-responsive population (T ^PHA showed a dose-dependent suppression at dose levels of 0.35 and 1.00 mg/kg. DMS did not alter serum antibody production against sheep erythrocytes at the dosage level which produced a significant depression of the PHA response. Animals treated with CY showed enhanced Con A-mediated lymphoproliferation at a dose of 15 mg/kg and marked suppression at 45 mg/kg. The PHA-mediated response, however, exhibited only a dose-dependent suppression at both dosage levels. CY had no effect on the antibody response at doses that enhance Con A lymphoproliferation. These results suggest that T helper cells and T suppressor cells are not T_PHA cells.     

Inhibition of postpyrogenic increase of phagocytic and killing activity of neutrophils by nonsteroid antiinflammatory drugs

Acetylsalicylic acid (300 mg/kg), mefenamic acid (30 mg/kg) or indomethacin (20 mg/kg) given orally in the doses preventing the postpyrogenic fever, inhibited the stimulatory effect of LPS on phagocytic and killing activity of neutrophils. The dose of acetylsalicylic acid that did not eliminate fever in rabbits (100 mg/kg), had no suppressive effect upon fever-stimulated killing activity of neutrophils. The drugs administered twice a day to normothermic animals did not evoke any suppressive changes in the activity of neutrophils.     

Skin test suppression by antihistamines and the development of subsensitivity

The suppression of skin test reactivity by single doses of six antihistamines was measured before and after a period of daily antihistamine ingestion in 18 subjects. Single doses of hydroxyzine, 50 mg; chlorpheniramine, 16 mg; and promethazine, 50 mg; induced significant suppression of skin test reactivity at 2 hr, whereas the suppression produced by tripelennamine, 100 mg; diphenhydramine, 50 mg; and cyproheptadine, 16 mg; did not differ significantly from that produced by placebo. After 3 wk of treatment with hydroxyzine, 75 mg per day, the suppressive effect of hydroxyzine as well as the five clinically unrelated antihistamines was significantly reduced. Although the response to chlorpheniramine was also reduced after chronic treatment with chlorpheniramine, 24 mg per day, the difference was not statistically significant. We conclude that antihistamines in the doses used differ greatly in their suppressive effect on skin test reactivity. The antihistamine producing the most skin test suppression, hydroxyzine, when it was taken daily for 3 wk, caused the development of partial tolerance not only to its own effect but to those of clinically unrelated antihistamines.     

Anti-inflammatory potential of dichloromethane leaf extracts of Eucalyptus globulus (Labill) and Senna didymobotrya (Fresenius) in mice

BackgroundInflammation is an immune response characterized by swelling, redness, pain and heat. Inflammation is mainly managed using conventional medicines that are associated with many side effects. Plant-based remedies are considerably better alternative therapies for they have fewer side effects.ObjectiveThis study aimed at determining the anti-inflammatory potential of dichloromethane (DCM) leaf extracts of Eucalyptus globulus and Senna didymobotrya in mice.MethodsFresh leaves of these plants were harvested from Embu County, Kenya. Quantitative phytochemical analysis was done using Gas Chromatography-Mass Spectrometry (GC-MS). Anti-inflammatory test comprised nine groups of five animals each: normal, negative, positive controls and 6 experimental groups. Inflammation was induced with Carrageenan. One hour post-treatment, the different groups were intraperitoneally administered with the reference drug, diclofenac, 3% DMSO and six DCM leaf extracts at doses of 25, 50, 100, 150, 200 and 250mg/kgbw.ResultsGC-MS results revealed α-phellandrene, camphene, terpinolene, and limonene among others. Anti-inflammatory effects showed that extract doses of 100,150,200 and 250mg/kg bw significantly reduced the inflamed paw. Doses of 200 and 250mg/kgbw in both plants were more potent and compared with diclofenac. E. globulus extract dose of 250mg kg bw reduced inflamed paw in the 1^st, 2^nd, 3^rd and 4^th hours, by 2.27,6.52,9.09 and 10.90% respectively while S.didymobotrya at similar dose ranges, inflamed paw reduced by 2.41, 5.43, 8.31 and 9.05% respectively.ConclusionE. globulus and S. didymobotrya have potent anti-inflammatory activities, attributed to their constituent phytochemicals. This study confirms the traditional use of these plants in treating inflammation.     

Acute effects of vitamin B6 and fixed combinations of vitamin B1, B6, B12 on nociceptive activity evoked in the rat thalamus: Dose-response relationship and combinations with morphine and paracetamol

Summary Nociceptive activity was elicited in neurones of the thalamus by supramaximal electrical stimulation of afferent C fibres in the sural nerve of rats under urethane anesthesia. The fixed combination of vitamin B₁, B₆, B₁₂ (Neurobion^®) as well as of vitamin B₆ administered by i.p. injection dose-dependently reduced the evoked nociceptive activity. The ED₅₀ of Neurobion^® is 4.6 ml/kg (at 100 min after injection) and that of vitamin B₆ is 189mg/kg (at 90 min after injection). The minimum effective doses of Neurobion^® and vitamin B₆ are 0.5 ml/kg and 40 mg/kg, respectively. When Neurobion^® or vitamin B₆ were given at their minimum effective doses, and the minimum effective doses of morphine (0.025 mg/kg) or paracetamol (5 mg/kg) were injected i.v. 80 min later, i.e., when the maximum effect of higher doses of Neurobion^® or vitamin B₆was about to develop, no supraadditive effect developed. It is concluded that the antinociceptive effect caused by a single injection of Neurobion^® is largely due to vitamin B₆. Vitamin B₁₂ may contribute to this effect, whereas vitamin B₁ alone exhibited only a slight effect on nociception. Moreover, it appears that Neurobion^® produces its antinociceptive effect after a single injection and after repeated administration during several days by different mechanisms so that the effect of analgesic agents is not enhanced following a single injection of Neurobion^® but may be enhanced after repeated administration of the compound.     

Effects of Bromocriptine Treatment on Immune Responses and 3–Methylcholanthrene-Induced Tumorigenesis in Rats

Abstract

Seven-week-old male Sprague-Dawley rats were given a single injection of 1.5 mg of 3–methylcholanthrene (3MC) to induce in situ fibrosarcomas. the rats were also treated with the dopamine agonist bromocriptine (BCR) from two days prior to 14 days after 3MC treatment and again for 14 consecutive days beginning at week 5. Tumor incidence was markedly increased and latency decreased in BCR-3MC rats compared to 3MC controls. Natural killer (NK) cell cytotoxicity responses and production of interleukin 2 (IL2) was enhanced at two weeks in rats treated with only BCR. Natural killer cell activity was suppressed at two weeks in rats treated with only 3MC. This effect was reversed by BCR treatment. Rats treated with 3MC and BCR had suppressed NK cell responses and production of IL2 and interferon-γ (IFN) at 12 weeks.

In another study, rats injected with 1, 3 or 5 mg/kg BCR for 14 consecutive days had increased NK cell activity and IL2 production at all doses and increased IFN production at the two high doses. Antibody (IgG) responses to an injected antigen and delayed-type hypersensitivity reactions were not affected by BCR treatment. Animals treated with the two high doses of BCR had decreased serum prolactin (PRL) levels. Serum growth hormone (GH) concentrations were markedly increased in the group treated with 3 mg/kg BCR.

These data suggest that BCR enhances 3MC-induced tumorigenesis. the mechanism of this effect is apparently not mediated by suppression of the immune system since BCR-treated rats had selectively enhanced immune function. Enhancement of immune responses by BCR has not been previously reported.     

Radioprotective efficacy and acute toxicity of 5-androstenediol after subcutaneous or oral administration in mice

We previously showed that one subcutaneous (sc) injection of 5-androstene-3beta,17beta-diol (AED) stimulated the innate immune system in mice and prevented mortality due to hemopoietic suppression after whole-body ionizing irradiation with gamma rays. In the present study, we tested whether there was any significant toxicity in mice that might hinder development of this steroid for human use. There were no indications of toxicity in chemical analyses of serum after sc doses as high as 4000 mg/kg. At this dose, 2 of 54 mice died when given AED alone. When 4800 mg/kg was given orally, no deaths resulted. The only adverse findings attributed to AED administration were 1) a moderate elevation of granulocytes in abdominal organs and fat after sc injections of 320 mg/kg; and 2) occasional wasting of skin over the injection site in female B6D2F1 but not male C3H/HeN mice. Significant weight loss (6%) was observed after sc injections of 320 mg/kg but not 160 or 80 mg/kg. When male C3H/HeN mice were injected sc with AED at doses of 0-200 mg/kg 24 h before whole body gamma-irradiation (9 Gy), a significant improvement in survival was observed at doses as low as 5 mg/kg. Oral administration of AED produced significant survival enhancement at a dose of 1600 mg/kg. We conclude that the radioprotective efficacy of AED is accompanied by low toxicity.Androst-5-ene-3 beta, 17 beta-diol; Ionizing radiation; Experimental radiation injuries; Toxicity; Clinical chemistry; Histopathology     

Effects of apomorphine and haloperidol on response suppression learning of young chicks

In four experiments, the effects of augmenting or blocking dopamine receptor activity on response suppression learning of Colburn X Colburn chicks were determined. In each experiment, 4-day-old chicks were trained to key peck for heat reward and then tested for response suppression learning by using either a response-contingent punishment or an extinction-punishment task. Before response suppression testing, different groups of chicks were injected ip with apomorphine (1.0, 2.0, or 4.0 mg/kg) either alone or after pretreatment with haloperidol (0.5 or 1.0 mg/kg). Regardless of the response suppression task used, chicks injected with apomorphine had difficulty inhibiting their responding; whereas, chicks injected with haloperidol, either alone or before apomorphine treatment, responded on fewer trials than saline-treated chicks. During extinction testing, 4-day-old chicks given only apomorphine showed the typical suppressive effect of punishment on responding rather than the paradoxical punishment-induced increase in responding found in normal 1-day-old chicks. These results indicate that activation of dopamine receptors retards response suppression learning of the 4-day-old chick, but functional changes in central dopaminergic mechanisms are not primarily responsible for the normal age-dependent improvement in response suppression learning of the young chick.