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Biomedical subjects

E Fride

Publications and source records attributed to E Fride.

At least 37 records · Page 2Linked to original sources
PubMed1996

Developmental aspects of anandamide: ontogeny of response and prenatal exposure.

Recent breakthroughs in cannabinoid research, including the identification of two cannabinoid receptors (CB receptors) and a family of endogenous ligands, the anandamides, may shed new light on the sequelae of pre- and perinatal exposure to cannabinoid receptor ligands and enable the experimental manipulation of the endogenous ligand in the developing organism. In the present study we examined the behavioural response to anandamide (ANA) in developing mice from day 13 into adulthood. We observed that depression of ambulation in an open field and the analgetic response to ANA are not fully developed until adulthood. In a separate set of experiments, we administered five daily injections of ANA (SC, 20 mg/kg) during the last trimester of pregnancy. No effects on birth weight, litter size, sex ratio and eye opening were detected after maternal ANA treatment. Further, no effects on open field performance of the offspring were observed until 4 weeks of age. However, from 40 days of age, a number of differences between the prenatal ANA and control offspring were detected. Thus, the offspring from ANA-treated dams showed impaired responsiveness to a challenge with ANA or delta 0-THC expressed as a lack of immobility in the ring test for catalepsy, hypothermia and analgesia. On the other hand, without challenge, they exhibited a spontaneous decrease in open field activity, catalepsy, hypothermia and a hypoalgetic tendency. These data suggest that exposure to excessive amounts of ANA during gestation alters the functioning of the ANA-CB receptor system. Further experiments investigating responsivity of the immune system suggest an increased inflammatory response to arachidonic acid, and enhanced hypothermic response to lipopolysaccharide in prenatally treated offspring. The results are discussed in relation to other manipulations of the maternal milieu, especially prenatal stress. It is concluded that alterations induced by prenatal exposure to ANA, cannabinoids and other psychotropic drugs or prenatal stress, share common features, but the data also suggest specific effects on the ANA-CB receptor system.

Acute-Phase Reaction↗
PubMed1996

Endogenous cannabinoid ligands--chemical and biological studies.

Arachidonic acid ethanolamide (anandamide) is a brain constituent that binds to the brain cannabinoid receptor (CB1). It produces many of the pharmacological effects caused by delta 9-tetrahydrocannabinol (delta 9-THC) in mice. Anandamide parallels delta 9-THC in its specific interaction with the cannabinoid receptor and in inhibition of adenylate cyclase. Two additional fatty acid ethanolamides that bind to the cannabinoid receptor, homo-gamma-linolenylethanolamide and docostetraenylethanolamide, have been identified in the brain. We believe that the anandamides are involved in the coordination of movement and short term memory. Depression of ambulation in an open field and the analgetic response to anandamide are not fully developed until adulthood, possibly due to an age-related increase in the CB1 receptor concentration. This observation has clinical implications in pediatrics. A second cannabinoid receptor (CB2) is present in the spleen. A monoglyceride, 2-arachidonyl-glycerol which binds to both CB1 and CB2 in transfected cells and inhibits andenylate cyclase in spleen cells was found in the gut. Its role is apparently associated with the immune system. These fatty acids amides and esters represent a new family of chemical modulators in the body.

Animals↗
PubMed1995

Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides.

We have previously shown that the endogenous putative cannabinoid ligand arachidonylethanolamide (anandamide, 20:4, n - 6) induces in vivo and in vitro effects typical of a cannabinoid agonist. We now report that two other endogenous anandamides, docosatetraenylethanolamide (anandamide, 22:4, n - 6) and homo-gamma-linolenylethanolamide (anandamide, 20:3, n - 6), have similar activities. The new anandamides bind to SV40-transformed African green monkey kidney cells transfected with the rat brain cannabinoid receptor cDNA and display K1 values of 253.4 +/- 41.1 and 244.8 +/- 38.7, respectively. The value found for arachidonylethanolamide was 155.1 +/- 13.8 nM. In addition, the new anandamides inhibit prostaglandin E1-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells transfected with the cannabinoid receptor, as well as in N18TG2 mouse neuroblastoma cells that express the cannabinoid receptor naturally. The IC50 values for the inhibition of adenylate cyclase in transfected Chinese hamster ovary-K1 cells were 116.8 +/- 8.7 and 109.3 +/- 8.6 nM for docosatetraenylethanolamide and homo-gamma-linolenylethanolamide, respectively. These values were similar to that obtained with arachidonylethanolamide (100.5 +/- 7.7 nM), but were significantly higher than the IC50 value observed with the plant cannabinoid delta9-tetrahydrocannabinol (9.2 +/- 8.6 nM). The inhibitory effects of the anandamides on adenylate cyclase activity were blocked by pertussis toxin, indicating the involvement of pertussis toxin-sensitive GTP-binding protein(s). In a tetrad of behavioral assays for cannabinoid-like effects, the two new anandamides exerted similar behavioral effects to those observed with delta9-tetrahydrocannabinol and arachidonylethanolamide: inhibition of motor activity in an open field, hypothermia, catalepsy on a ring, and analgesia on a hot plate.

Adenylyl Cyclases↗
PubMed1995

Anandamides: tolerance and cross-tolerance to delta 9-tetrahydrocannabinol.

In this study we examined whether tolerance develops to chronic exposure to anandamides [20:4, n-6 (ANA) and 20:3, n-6 (HLEA)] two of the recently discovered endogenous cannabinoid receptor ligands in brain. Tolerance to ANA and cross-tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was examined in female Sabra or C57BL/6 mice which had received daily injections (i.p.) of low (0.001-1 mg/kg) or high doses (20 mg/kg) of ANA or HLEA for 2 weeks. Twenty four h after the last injection, the mice were challenged with 20 mg/kg ANA or delta 9-THC. Animals were subjected to a series of tests frequently used to assess cannabinoid-induced effects. The results indicated that the high dose, but not the low doses of anandamides produced tolerance to ANA and cross-tolerance to delta 9-THC for motor activity in an open field, catalepsy on a ring, hypothermia and analgesia on a hot plate. One week after the last ANA treatment, tolerance was not present anymore. No tolerance to ANA was observed for reduced defecation in the open field, a measure of intestinal hypomotility. This phenomenon may possibly be attributed to a difference between activities produced through different types of cannabinoid receptors.

Animals↗
PubMed1995

Low doses of anandamides inhibit pharmacological effects of delta 9-tetrahydrocannabinol.

It has been shown previously that the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide 20:4, n-6) induces in vivo and in vivo effects typical of a cannabinoid partial agonist. We now report that the synthetic docosahexaenylethanolamide (anandamide 22:6, n-3) shows similar activities. In addition we show that these two anandamides, under certain experimental conditions, antagonize the effects of delta 9-THC both in vivo and in vitro. Thus a significant decrease in the potency of delta 9-THC-induced inhibition of adenylate cyclase was observed in N18TG2 neuroblastoma cells that were pretreated with low concentrations of anandamides. At these low concentrations of anandamides had no effect when applied alone. In vivo, Sabra or ICR mice were subjected to a tetrad of tests, designed to detect cannabinoid-induced effects. Mice pretreated (i.p.) with 10 mg/kg of delta 9-THC received injections with anandamides. Only low doses (0.0001-0.1 mg/kg) of the anandamides, which had no effects when administered alone, partially or fully inhibited the THC-induced effects. These findings suggest that the inhibition of delta 9-THC-induced effects by low doses of anandamides may be due to partial agonistic effects of these materials. It is possible that low doses of the anandamides are capable of activating a Gs protein mediated signaling pathway, or may cause an allosteric modulation of the cannabinoid receptor.

Animals↗
PubMed1993

Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent.

Anandamide (arachidonylethanolamide) is a brain constituent which binds to the cannabinoid receptor. We now report the first in vivo examination of this ligand. Anandamide administered i.p. in mice, caused lowering of activity in an immobility and in an open field test, and produced hypothermia and analgesia. These effects parallel those caused by psychotropic cannabinoids.

Amides↗
PubMed1993

Immunocompetence in the long sleep and short sleep mouse lines: baseline versus primed responses.

Two lines of mice which were selectively bred for high (Long Sleep; LS) and low (Short Sleep; SS) reactivities to a sedative dose of ethanol, are also differentiated by agents that act at the GABAA-receptor complex. Since this supramolecular complex may also modulate immune function, measures of immunity have been examined in these lines. In the present study the immune responsiveness before and after an allogeneic priming stimulus was investigated. Lower mitogen-induced T-cell proliferation, mixed leukocyte reaction, and cytotoxic T lymphocyte activity were found in unprimed LS compared to unprimed SS mice. In contrast, the LS line exhibited a marked augmentation of these responses after priming, while the SS mice appeared unresponsive to this challenge. Addition of splenocytes or cell-free splenic cultures from primed mice to cultures from unprimed mice suggested that differences in priming-induced cell-to-cell interactions, rather than the release of a soluble helper factor(s) into the medium, are responsible for the marked augmentation of the secondary response in LS, compared to SS mice. Fewer T-helper and T-suppressor/cytotoxic cells were found in LS compared to SS mice, and this was unaffected by priming. These results extend previous findings demonstrating a higher natural killer cell activity and rate of tumor rejection in LS mice and suggest that these lines may be useful in studying the regulatory role of the GABAA complex in immune function.

Animals↗
PubMed1992

Immunoenhancing effects of alprazolam, a benzodiazepine receptor agonist.

The effects of alprazolam (ALP), a triazolobenzodiazepine with high affinity for "central" benzodiazepine receptors, were examined on several parameters of immune function in mice. NK, MLR, and mitogen-induced lymphocyte proliferation were all significantly increased 2 hr after administration of low doses (0.02-1.0 mg/kg) of ALP. Twenty four hr later, similar but less robust immunoenhancing effects were observed. These measures of immune functions were not affected by higher doses of ALP (5-10 mg/kg). The immunoenhancing effects of ALP did not appear related to serum corticosterone levels. These and other findings demonstrate that the GABA/benzodiazepine receptor chloride channel complex can bidirectionally modulate immune function.

Alprazolam↗
PubMed1991

Inhibition of calcium mobilization is an early event in opiate-induced immunosuppression.

Morphine administered as a subcutaneous implant inhibits the initial increase in cytoplasmic free-calcium [Ca2+]i induced by mitogens in mouse splenocytes. This effect was not reproduced by incubation of splenocytes with morphine (10(-8)-10(-4) M). Analysis of splenocyte subpopulations demonstrates that this effect was manifest in both B and T cells. However, within T cell subpopulations, CD4+ but not CD8+ cells were affected. Adrenalectomy abolished this effect of morphine in CD4+ T but not CD4-, CD8- spleen cells (most likely Thy 1.2- B cells). Moreover, simultaneous administration of the opiate antagonist naltrexone blocked the effect of morphine in CD4-, CD8- spleen cells, but not in CD4+ T cells. These data indicate that the effects of morphine on mitogen-stimulated increase in [Ca2+]i may be mediated through distinct glucocorticoid-dependent and -independent mechanisms. The morphine-induced inhibition of an increase in [Ca2+]i in immune cells reported here may be an early event mediating opiate-induced immunosuppression.

Animals↗
PubMed1990

Strain-dependent association between immune function and paw preference in mice.

The relationship between immune function and the preferred direction of behavioral asymmetry was examined in several mouse strains. Mixed leukocyte reaction, natural killer cell activity, cytotoxic T lymphocyte response and lymphoproliferation in response to mitogens were investigated in animals with left or right paw preference. From the 7 strains and substrains examined, it appeared that differences in immune function between left and right pawed mice, when present, vary in directionality. Thus, in C3H/HeJ and 129/J, left pawed mice had higher immune responses than right pawed mice, whereas in C3H/HeNCr MTV- and BALB/cJ animals, the reverse was found. In C3H/HeNCr MTV+, C57BL/6J and Collin's heterogenous control population for the high/low asymmetry lines, no differences between animals with left or right paw preference were found. The statistical significance of these differences were not uniform for all the immune parameters studied. These data indicate that the association between immune function and preference for using the left versus right paw is a strain-dependent phenomenon and may suggest that the inconsistent evidence for an association between immune deficiency and left-handedness could be due to genetic heterogeneity among subpopulations.

Animals↗
PubMed1990

Morphine-induced immune alterations in vivo.

The high incidence of human immunodeficiency virus (HIV) seropositivity among drug abusers prompted us to examine in an animal model the effects of morphine on aspects of the immune system that may be specifically related to HIV infection. We now report a robust, sustained elevation in the ratio of CD4+/CD8+ cells in the spleen and thymus of mice chronically treated with morphine. Since CD4+ cells have been reported to be target cells for HIV, these alterations, in concert with a marked cellular atrophy that appears to be restricted to organs of the immune system, suggest that opiates may serve as cofactors in altering the immune status of the host and thus contribute to the increased susceptibility to HIV infection and eventual development of AIDS in opiate abusers.

Animals↗
PubMed1990

Immunoenhancing effects of alprazolam in mice.

The GABA/benzodiazepine receptor chloride channel complex has been proposed to play a modulatory role in immune function. The effects of alprazolam, a triazolobenzodiazepine with high affinity for "central" benzodiazepine receptors, were examined on several parameters of immune function in mice. Natural killer cell activity, mixed leukocyte reactivity and mitogen-induced lymphocyte proliferation were all significantly increased two hr after administration of low doses (0.02-1.0 mg/kg) of alprazolam. Twenty four hr later, similar but less robust immunoenhancing effects were observed. Higher doses of alprazolam (5-10 mg/kg) did not affect these measures of immune function. The immunoenhancing effects of alprazolam did not appear related to corticosterone levels. In contrast, vehicle injection caused a profound suppression of these immune parameters two hr later, which was no longer apparent 24 hr later. This immunosuppression appeared to correlate with a concurrent rise in serum corticosterone levels. These data support the hypothesis that the GABA/benzodiazepine receptor chloride channel complex modulates immune function. Use of low doses of alprazolam may be of potential clinical importance when immunoenhancement is required.

Adjuvants, Immunologic↗
PubMed1990

Immune function in lines of mice selected for high or low degrees of behavioral asymmetry.

Cerebral lateralization has been suggested to play a regulatory role in immune function. In this study, several measures of immune function were evaluated in mice selectively bred for either a strong (HI) or weak (LO) degree of behavioral asymmetry (paw preference) and compared to an unselected control population (HET). Both HI and LO animals had fewer spleen cells but higher degrees of [3H]thymidine incorporation into DNA (on a per cell basis) than HET mice. However, only HI mice had lower immune functions compared to HET controls manifest as reduced mixed leukocyte reaction (MLR), cytotoxic T lymphocyte (CTL) activity, and natural killer (NK) cell activity. These findings indicate that although both extremes in the degree of paw preference may be associated with deviations from the norm, a high degree of behavioral lateralization is associated with decreased immune responsiveness in this animal model.

Animals↗
PubMed1990

Opiate-induced inhibition of calcium flux in immune cells.

Administration of morphine as a subcutaneous implant inhibits the initial influx of calcium (Ca2+) induced by mitogens in mouse splenocytes. This effect was not reproduced by incubation of splenocytes with morphine (10(-8)-10(-4)M). Within T cell subpopulations, CD4+, but not CD8+ cells were affected. Adrenalectomy abolished this effect of morphine in CD4+ but not B cells. Moreover, simultaneous administration of the opiate antagonist naltrexone blocked the effect of morphine in B cells, but not in CD4+ cells. These data indicate that inhibition of Ca2+ influx by morphine may be mediated through distinct glucocorticoid-dependent and independent mechanisms. The morphine-induced inhibition of Ca2+ influx in immune cells reported here may be an early event mediating opiate-induced immunosuppression.

Adrenalectomy↗
PubMed1989

Mitochondrial protein synthesis may be involved in long-term memory formation.

The hypothesis that two qualitatively different stages of cerebral protein synthesis (PS) are required for the formation of long-term memory (LTM) for an active-avoidance task was investigated in rats. Cytoplasmic PS was inhibited with anisomycin (ANI-5.0 mg subcutaneously). When ANI was injected at 15 min pre- and 30 min posttraining, so that cerebral PS was inhibited by 90% for 2 hours starting just before training. LTM formation was prevented. When ANI was given after training, it was not effective. Mitochondrial PS was inhibited with chloramphenicol (CAP-1.5 mg intracisternally). Inhibition occurred 40 min after the injection. CAP interfered with LTM formation only when injected between 15 and 55 min after training. From these data it was concluded that two stages of PS are required for the formation of LTM. The first one takes place in the cytoplasm, starts with the commencement of training and is independent of newly synthesized mRNA. The second stage takes place in mitochondria starting approximately 25 min after training and is dependent upon newly formed mRNA.

Animals↗
PubMed1989

Alterations in behavioral and striatal dopamine asymmetries induced by prenatal stress.

We investigated the effects of maternal noise and light stress, randomly applied throughout pregnancy, on the development of behavioral and neurochemical asymmetries in the rat offspring. This form of maternal stress resulted in a rightward positioning of the tail of both sexes soon after birth as opposed to the leftward bias in controls. At adulthood, prenatally stressed offspring showed a change in directional bias compared to controls with a preponderance of left turns after amphetamine. In the males, this was expressed as a reduction in directional preference, while in females a reversal occurred of their dominant turning direction from right (controls) to left. We also observed a reduction in dopamine turnover rates in the left corpora striata of stressed offspring of both sexes. Again, in the females, this change was particularly marked and resulted in a reversal towards the right hemisphere. The findings from this study are consistent with the possibility that the alterations in cerebral asymmetries induced by prenatal stress may underly the decrease in the ability of the offspring to cope with anxiety provoking situations.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Prenatal stress increases anxiety related behavior and alters cerebral lateralization of dopamine activity.

Effects of unpredictable (random) prenatal stress on the level of anxiety and cerebral lateralization of dopamine turnover rates were studied in rats. The observation of a decrease in the amount of time spent in the open arms of a "plus-maze" supported earlier findings of an increased fearfulness to stressful situations in the offspring in adulthood. We also observed elevated rates of dopamine turnover in the right prefrontal cortex and reduced dopamine activity in the right nucleus accumbens and left corpus striatum of the prenatally stressed animals. This resulted in directional shifts of left-right differences in dopamine activity in all 3 areas. These findings indicate that prenatal stress induces permanent alterations in dopaminergic activity and in cerebral asymmetry. We suggest that the changes in cerebral lateralization of dopamine function may underly the increase in reactivity to anxiety-provoking situations in prenatally stressed offspring.

Animals↗