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Biomedical subjects

A Frazer

Publications and source records attributed to A Frazer.

At least 91 records · Page 5Linked to original sources
PubMed1984

Amish study, V: Lithium-sodium countertransport and catechol O-methyltransferase in pedigrees of bipolar probands.

The authors studied 87 individuals from four large Amish pedigrees to determine the relationship between susceptibility to affective disorders and variation in the measures of two biochemical variables, catechol O-methyltransferase (COMT) and lithium countertransport. Assays were done in duplicate and blind to diagnostic or pedigree status. Data were analyzed separately within families as well as by pooling ill and well subjects across pedigrees. Various statistical analyses yielded no significant differences in lithium measures or COMT activity levels between members diagnosed as having a form of affective disorder and the normal members.

Bipolar Disorder↗
PubMed1984

Pharmacologic mechanisms of action of antidepressants.

In addition to standard types of antidepressants such as the TCAs and MAOIs, there are now newer drugs that have chemical structures and pharmacologic properties quite distinct from those of the original antidepressants. The various classes of antidepressants do have some properties in common, though, particularly an ability to down-regulate central beta-adrenergic receptors after their repeated administration. However, whether all types of antidepressants act through the same mechanism is not known.

Animals↗
PubMed1984

Agonist interactions with beta adrenergic receptors in rat brain.

Agonist interactions with beta adrenergic receptors on membranes prepared from rat brain were examined by measuring agonist inhibition of [125I]iodopindolol binding in the absence or presence of GTP. When rat cerebral cortical membranes were prepared with 1 mM EDTA in the homogenization medium and 2.5 mM MgCl2 was included in the binding reaction, then 250 microM GTP increased the Hill coefficient for isoproterenol from 0.77 to 0.99 and increased the IC50 from 88 to 213 nM. By contrast, I-propranolol competition curves were steep (Hill coefficient = 0.98) and were not affected by GTP. It was inferred from the results of computer-modeling that, in the absence of GTP, isoproterenol bound to two states of the receptor; GTP converted isoproterenol binding to a single low-affinity state. I-Propranolol bound to a single state in the absence or presence of GTP. The effect of GTP on I-epinephrine inhibition of [125I]iodopindolol binding was essentially identical to its effect on isoproterenol inhibition. GTP and GDP were the most potent of all the nucleotides tested. Guanylylimidodiphosphate (1 mM) produced only partial shifts in the isoproterenol competition curves and GMP and ATP were inactive. In membranes prepared from rat hippocampus and hypothalamus, isoproterenol competition curves and GTP effects were qualitatively similar to those observed in cerebral cortex. However, GTP produced only partial shifts of I-isoproterenol competition curves in cerebellum and neostratium. It appears that agonists, but not antagonists, can stabilize a high-affinity ternary complex with the beta adrenergic receptor and the guanine nucleotide binding regulatory protein in membranes prepared from various regions of the rat brain.

Adrenergic beta-Agonists↗
PubMed1984

Determination of selective and nonselective compounds for the 5-HT 1A and 5-HT 1B receptor subtypes in rat frontal cortex.

Recent studies indicate that there are multiple subtypes of the 5-hydroxytryptamine 1 (5-HT1) receptor. Previously, we provided evidence consistent with the finding that multiple states of the 5-HT1 receptor are present when the binding of [3H]-5-HT is measured in the absence of guanine nucleotides. When 1 mM GTP was present in the [3H]-5-HT receptor binding assay, the high affinity state was eliminated. As the presence of multiple states of a receptor complicates the interpretation of the inhibition of [3H]-5-HT binding caused by serotonin agonists and antagonists, we examined the ability of a series of these drugs to compete for 15 nM [3H]-5-HT binding in the presence of 1 mM GTP in the rat frontal cortex. Eight agonists and five antagonists showed selectivity for the two subtypes of the 5-HT1 receptor, whereas three agonists and four antagonists showed the same affinity for these two receptors subtypes. Most of the compounds examined exhibited only a modest 10- to 30-fold degree of selectivity. However, 1-(m-trifluoromethylphenyl) piperazine and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)indole were about 65-fold selective and spiperone was over 100-fold selective for one of the receptor subtypes. The subtype specificity of the selective compounds was determined using either spiperone, a selective 5-HT 1A compound, or 1-(m-trifluoromethylphenyl)piperazine, a selective 5-HT 1B compound, to preferentially inhibit one of the receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Differential actions of serotonin antagonists on two behavioral models of serotonin receptor activation in the rat.

Ligand binding studies have identified certain serotonin (5-HT) antagonists with selective affinity for 5-HT2 receptors and other serotonin antagonists with affinity for both 5-HT1 and 5-HT2 receptors. This study compared the actions of ketanserin and pipamperone, selective 5-HT2 receptor antagonists, with metergoline and methysergide, nonselective 5-HT antagonists, on two behavioral responses in rats that are produced by the activation of 5-HT receptors: 1) the head shake response and 2) the 5-HT syndrome. Both the selective and the nonselective 5-HT antagonists blocked the head shake response produced by 5-hydroxy-L-tryptophan. The order of relative potency was: metergoline greater than ketanserin greater than pipamperone greater than methysergide. All four antagonists also blocked the head shake response produced by the 5-HT agonist quipazine. In contrast, the symptoms of the 5-HT syndrome produced by 5-methoxy-N,N-dimethyltryptamine were blocked by pretreatment with the nonselective 5-HT receptor antagonists but not by the 5-HT2 receptor antagonists. The differential actions of 5-HT antagonists on these behavioral responses suggest that different 5-HT receptors are involved in the head shake response and the 5-HT syndrome. That the order of relative potency for these drugs to block the head shake response was the same as their reported affinity for the 5-HT2 receptor suggests that the 5-HT2 receptor is involved in the head shake response. In contrast, the ability of 5-HT antagonists with affinity for the 5-HT1 receptor to block the 5-HT syndrome and the inability of 5-HT2 receptor antagonists to block the syndrome suggests that this behavioral response probably involves the activation of 5-HT1 receptors.

Animals↗
PubMed1984

Multiple states of the 5-hydroxytryptamine1 receptor as indicated by the effects of GTP on [3H]5-hydroxytryptamine binding in rat frontal cortex.

In several monoamine receptor systems, agonist but not antagonist binding is found to be associated with both a high- and a low-affinity state of the receptor. Guanine nucleotides, like GTP, can eliminate the high-affinity receptor state such that only the low-affinity state of the receptor is present. Since [3H]5-hydroxytryptamine ([3H]5-HT) is an agonist, its binding may also be associated with multiple states of a receptor. To evaluate this, the binding of [3H]5-HT to rat frontal cortical membranes was measured in the absence and presence of GTP. Three different types of binding experiments were performed: (a) saturation experiments, (b) dissociation experiments, and (c) competition experiments with 5-hydroxytryptamine (5-HT) agonists. When all three types of binding experiments were carried out in the absence of GTP, results from either graphical representations or computer analysis of the data indicated that a two-component model of binding described the data better than a single-component model. By contrast, in the presence of GTP, a one-component model adequately described the data obtained from either saturation or dissociation experiments. Competition of [3H]5-HT (15 nM) binding by three 5-HT agonists (5-methoxytryptamine, 5-HT, and d-lysergic acid diethylamide) was adequately described by a single-component system in the presence of GTP as well, even though all three agonists produced biphasic inhibition curves in the absence of the guanine nucleotide. These experimental results are consistent with the idea that the binding of [3H]5-HT in the absence of GTP is associated with multiple receptor states. Since the presence of multiple states can confound the interpretation of inhibition curves of [3H]5-HT binding caused by agonists, it is important to eliminate the high-affinity state of the receptor by including GTP in the binding assay.

Animals↗
PubMed1983

The effect of antidepressant drugs on regional cerebral glucose utilization in the rat.

The 2-deoxyglucose (2-DG) technique is a potentially powerful method for assessing the effect of centrally acting drugs on local neuronal function in the brain. Since little is established on the effect of antidepressant drugs on local functional activity throughout the brain, we have employed this technique to study the effects of desmethylimipramine (DMI), a tricyclic antidepressant, and assessing the effect of centrally acting drugs on local neuronal function in the brain. Since little is established on the effect of antidepressant drugs on local functional activity throughout the brain, we have employed this technique to study the effects of desmethylimipramine (DMI), a tricyclic antidepressant, and assessing the effect of centrally acting drugs on local neuronal function in the brain. Since little is established on the effect of antidepressant drugs on local functional activity throughout the brain, we have employed this technique to study the effects of desmethylimipramine (DMI), a tricyclic antidepressant, and phenelzine, a monoamine oxidase inhibitor used clinically as an antidepressant, on local glucose utilization. The drugs were administered either as an acute dose, or repeatedly for 7 days, or chronically for 28 days. The local metabolic rate of glucose was determined in 30 regions of rat brain. Acute DMI increased glucose utilization in 11 regions whereas, in contrast, chronic DMI decreased glucose utilization in 7 regions of rat brain. Many of the areas affected are those of the telencephalon and diencephalon that receive prominent noradrenergic innervation. This is consistent with the notion that acute DMI treatment leads to enhanced and chronic DMI treatment leads to reduced noradrenergic functioning in the CNS. In contrast to these effects with DMI, phenelzine had little effects on glucose utilization either after acute or chronic dosing.

Animals↗
PubMed1983

Continuous light paradoxically reduces catecholamine-induced melatonin production.

Exposure of rats to continuous light for 14 days reduced the stimulation of melatonin content in the pineal gland produced by either isoproterenol administration or exposure to darkness. Since continuous light has been reported to enhance many intermediate biochemical events leading to the synthesis of melatonin, these results demonstrate the importance of examining the endproduct of an organ when evaluating the physiological significance of biochemical changes in model biological systems.

Animals↗
PubMed1983

Plasma and erythrocyte electrolytes in affective disorders.

Plasma and erythrocyte sodium (Na+), total and free (ultrafiltrable) plasma magnesium (Mg2+) as well as erythrocyte magnesium were measured in patients with affective disorders and in healthy control subjects. Depressed and manic patients had higher total plasma Mg2+ than did hospitalized healthy control subjects, but concentrations of ultrafiltrable Mg2+ did not differ. Although erythrocyte Mg2+ was significantly elevated in the depressed subjects in comparison with that found in the non-hospitalized healthy controls, this difference was not seen between the depressives and the hospitalized healthy controls. Depressed, manic or healthy control subjects did not differ with respect to either plasma or erythrocyte.

Adult↗
PubMed1982

Prevention of the serotonin syndrome in rats by repeated administration of monoamine oxidase inhibitors but not tricyclic antidepressants.

The serotonin syndrome, a behavioral response produced by the activation of serotonin receptors, and 3H-serotonin binding were examined after repeated treatment of rats with different types of antidepressant drugs. The serotonin syndrome was produced by the direct-acting serotonin receptor agonists 5-methoxy-N,N-dimethyltryptamine (5-MeDMT) or d-lysergic acid diethylamide (LSD). Repeated, but not acute treatment of rats with monoamine oxidase inhibitors (nialamide, pargyline, and phenelzine) prevented the serotonin syndrome in response to either 5-MeDMT or LSD and also reduced 3H-serotonin binding in the brain stem and spinal cord. Pretreatment of rats with p-chlorophenylalanine blocked the ability of nialamide treatment to inhibit the serotonin syndrome caused by 5-MeDMT. By contrast, neither the serotonin syndrome or 3H-serotonin binding was affected significantly by the repeated administration of tricyclic antidepressants (amitriptyline, desmethylimipramine, and chlorimipramine) or iprindole. Repeated monoamine oxidase inhibitor treatments may prevent the serotonin syndrome by causing a reduction of 3H-serotonin receptor binding sites in the brain stem and/or spinal cord.

Animals↗
PubMed1982

Effect of treatment of rats with antidepressants on melatonin concentrations in the pineal gland and serum.

The effect of administration of antidepressant drugs to rats on catecholamine-induced rises in the concentration of melatonin in the pineal gland and serum was studied. Increases in melatonin levels were produced by either the exogenous administration of different doses of L-isoproterenol or by exposure of rats to darkness. Repeated administration of either desmethylimipramine or nialamide reduced significantly the elevation in melatonin concentrations in the pineal gland produced by either L-isoproterenol or darkness. The rise in serum melatonin seen at night was also blunted significantly in rats treated repeatedly with these drugs. By contrast, the concentration of melatonin in either the pineal gland or serum was not reduced in rats given desmethylimipramine or nialamide acutely. In fact, daytime concentrations of melatonin both in the gland and in serum were significantly increased after either acute or repeated treatment with nialamide. The nialamide-induced increase in daytime concentrations of melatonin in the pineal gland was prevented if the rats were treated with propranolol. The diminished hormonal responsiveness produced by the repeated administration of antidepressants occurred at a time when the binding of [3H]dihydroalprenolol to pineal gland homogenates was reduced. Thus, a hormonal response to catecholamines regulated via beta adrenergic receptor activation is reduced by repeated antidepressant treatments in conjunction with the development of beta adrenergic receptor subsensitivity.

Animals↗
PubMed1981

Electrical stimulation of sympathetic nerves increases the concentration of cyclic AMP in rat pineal gland.

Electrical stimulation of the superior cervical ganglia causes a rapid increase in the concentration of cyclic AMP in the pineal gland of rats. This effect is dependent upon the frequency, voltage, and duration of the stimulus and is markedly potentiated by pretreating the animals with desmethylimipramine. The increase in cyclic AMP is blocked by prior treatment of the rats with reserpine, bretylium, or propanolol but not with phentolamine. These results provide direct evidence that electrical stimulation of sympathetic nerves increases cyclic AMP in a target organ through the release of norepinephrine from presynaptic terminals acting on postsynaptic beta-adrenergic receptors.

Animals↗