Joe Mendels

Effect of lithium on prostaglandin E1 stimulated adenylate cyclase activity of human platelets

Abstract The effect of lithium (Li) on the stimulation of adenylate cyclase by prostaglandin E 1 (PGE 1 ) was examined. In platelet sonicates, Li, as well as sodium (Na), potassium (K), and rubidium (Rb) significantly reduced the PGE 1 -induced stimulation of adenylate cyclase in a dose-dependent manner. The inhibition due to Rb was significantly less than that produced by the other cations; at a high concentration, 64 mM, Li was a more potent inhibitor than the other cations. In intact platelets, only Li reduced the PGE 1 -enhanced accumulation of [ 3 H]cyclic AMP, K and Rb being ineffective. As little as 1 mM Li significantly reduced the stimulatory effect of PGE 1 on [ 3 H]cyclic AMP production in this sytem. The inhibition produced by Li was not blocked by phentolamine, whereas phentolamine did block the inhibition due to norepinephrine (NE). Magnesium enhanced the stimulatory effect of PGE 1 on the production of labeled cyclic AMP in intact platelets and antagonized the inhibition produced by Li on this process. These data show that Li antagonizes PGE 1 − induced stimulation of platelet adenylate cyclase at a site distinct from that at which NE acts.

Platelet adenylate cyclase responses in depression: Implications for a receptor defect

The dose-dependent stimulatory response of prostaglandin E1 (PGE1) on the net synthesis of 3H-adenosine 3′,5′-monophosphate (cyclic AMP) in platelets whose adenine nucleotide pools had been labelled by prior incubation with 3H-adenine was measured. Also, the dose-dependent inhibition produced by norepinephrine (NE) on this stimulatory process was evaluated. Platelets were obtained from eleven moderately depressed male patients and from eight non-depressed normal male control subjects. No difference was noted between the two groups of subjects either in the stimulation produced by PGE1 or in the inhibition caused by NE. Subdividing the patients into different subgroups (e.g., bipolar or unipolar) did not produce any significant differences. This finding suggests that there is no generalized defect in alpha adrenergic responses in depressed male patients.

A method for the determination of sodium, potassium, magnesium and lithium concentrations in erythrocytes.

Abstract A technique for the rapid and accurate estimation of intra-erythrocyte concentrations of Na, K, Li and Mg is described. CoEDTA is used as a marker to estimate plasma trapped in the red cell column ; the use of this compound constitutes a novel departure from other marker substances previously used. Plasma trapping was found to average close to 3% (v/v) of the packed cell column. RBC electrolyte values obtained from healthy control subjects were shown to be in good agreement with values reported in the literature.

Opposite effects of acute and repeated administration of desmethylimipramine on adrenergic responsiveness in rat pineal gland

Abstract The effect of acute and repeated desmethylimipramine (DMI) treatment on catecholamine-stimulated production of adenosine 3, 5-monophosphate (cyclic AMP) in rat pineal gland was studied in vivo . In rats exposed to continuous illumination, the administration of isoproterenol (2μmol/kg) to control animals produced a marked increase in the concentration of cyclic AMP in pineal gland. In contrast, norepinephrine (2μmol/kg) failed to increase the levels of cyclic AMP. After acute treatment with DMI (single injection, 38μmol/kg, i. p.), the isoproterenol-induced rise in cyclic AMP was not significantly different from that measured in control animals. However, acute DMI treatment did allow a significant elevation in the concentration of cyclic AMP in pineal gland in response to norepinephrine. In rats given nine injections of DMI (38μmol/kg, i.p., twice daily) neither isoproterenol nor norepinephrine caused a significant increase in the concentration of cyclic AMP in pineal glands. Although acute treatment with DMI had no significant effect on [ 3 H] dihydroalprenolol binding, chronic treatment with DMI significantly reduced [ 3 H] dihydroalprenolol binding in the pineal gland. The results of this study suggest that while a single administration of DMI can enhance adrenergic responses elicited by norepinephrine, chronic administration of DMI leads to compensatory decreases in receptor density and adrenergic responsiveness.

Radioimmunoassay of imipramine and desmethylimipramine.

Abstract A sensitive radioimmunoassay has been developed for the determination of plasma levels of the tricyclic antidepressants imipramine and desmethylimipramine. Antisera were prepared by immunizing rabbits with N-succinylnortriptyline-bovine serum albumin conjugate. The assay required a preliminary extraction procedure to remove interfering metabolites and separate desmethylimipramine from imipramine. Using 3 H-imipramine as tracer, the radioimmunoassay can measure imipramine and desmethylimipramine levels down to 10 ng/ml using a 0.1 ml plasma sample. Agreement between the radioimmunoassay and a gas-chromatographic assay was excellent for both imipramine (r=0.97) and desmethylimipramine (r=0.99).

Expressive characteristics of anxiety in depressed men and women

This study was aimed at identifying the expressive, movement, and social behaviors associated with anxiety in the syndrome of major depression. The sample consisted of 97 hospitalized male and female depressed patients. Expressive and social behaviors were evaluated prior to treatment in a structured videotaped interview. Anxiety was measured using a multi-vantaged approach including doctors rating, nurses rating, patient self-report, and a separate video rating. Results indicate that anxiety was significantly associated with agitation, distressed facial expression, bodily discomfort, and poor social interaction in both sexes. Men and women differed in certain respects: anxiety was highly related to motor retardation in women only, and to hostility in men only. Differences in the pattern of expressive behavior between high and low anxious, depressed patients were clearly significant, and several were large enough to serve as clinical indicators. These findings help to characterize the expressive features of anxiety in the context of severe depression, and add to the growing literature on sex differences in depression.

Effects of intracellular lithium on epinephrine-induced accumulation of cyclic AMP in skeletal muscle.

Abstract The effects of lithium and of magnesium ions on adenosine 3,5-monophosphate (cyclic AMP) accumulation in isolated rat hemidiaphragms were investigated. Magnesium ions caused a small but significant increase in the basal concentration of cyclic AMP, whereas lithium ions had no effect. However, pretreatment of tissues with LiCl caused a significant dose-dependent reduction in the effect of epinephrine on the concentration of cyclic AMP. Magnesium ions enhanced the rise in tissue cyclic AMP caused by epinephrine, but this stimulatory effect of magnesium ions was reduced in tissues that had been pretreated with LiCl. It was concluded that lithium ions act at an intracellular site to inhibit hormone-induced accumulation of the cyclic nucleotide and was proposed that magnesium and lithium ions act at different cellular locations to produce their effects on hormone-induced cyclic AMP accumulation.

Metabolic and electrolyte changes produced by lithium ions in the isolated rat diaphragm.

Abstract The effects of lithium ions on glucose metabolism and the tissue content of monovalent cations were studied in rat hemidiaphragms incubated in vitro . The entrance of lithium ions into the cell was associated with an increase in the rate of glucose utilization and glycogen synthesis. As lithium was taken up by the tissue, there was a concomitant loss of potassium. The loss of potassium could not account for the stimulation of glucose metabolism produced by lithium and it was concluded that lithium ions per se increased glucose uptake and particularly glycogen synthesis. Preincubation of hemidiaphragms in media containing different concentrations of lithium ions resulted in an increase in the rate of glycogen synthesis during a subsequent incubation in the absence of lithium. The stimulation of glycogen formation was directly related to the tissue content of lithium. Lithium ions did not significantly alter the cyclic AMP content of the tissues under conditions at which the rate of glucose metabolism was markedly enhanced.

The lithium ratio as a guide to patient compliance

Abstract Noncomplannce with medication regimens not only reduces the benefits of proper therapy to the patient, but also complicates the clinicians appraisal of response to therapy. The magnitude of this problem is evident from a review of 50 compliance studies. One-quarter to one-half of all patients failed to comply adequately with medication orders.1 Noncompliance is not inherent in any particular personality, ethnic, or socioeconomic group.2 Psychiatric patients may pose a particular problem because their illness itself may interfere with their capacity to cooperate with pharmacotherapy. This makes medication compliance a major variable in assessing the response to psychoactive drugs such as the lithium ion (Li+). With regard to Li+, a partial solution to this problem has been the ability to measure the plasma concentration of the cation. However, because absorption of Li+ from the gastrointestinal tract is rapid, a patient who takes only a few doses of lithium prior to seeing his physician may appear to have “therapeutic” plasma concentrations of Li+ while still being noncompliant. For this reason, measurement of plasma Li+ concentration may not always give an accurate assessment of whether or not a patient has adhered to the prescribed regimen. The present investigation was designed to determine if the measurement of Li+ in another body compartment might provide the physician with a parameter that would enable him to more accurately assess the compliance of his patients. Since the erythrocyte (RBC) behaves pharmacokinetically as a tissue compartment separate from plasma,3 we examined whether the erythrocyte concentration of Li+ might be used as an indicator of patient compliance.

The effect of lithium carbonate on self-stimulating behavior in the rat☆

Abstract The effect of lithium on self-stimulatory behavior in rats with electrodes implanted in the medial forebrain bundle was studied. No alteration in the rate of self-stimulatory behavior was found.