Tapan K. Banerji

Lithium: Short-term and chronic effects on plasma testosterone and luteinizing hormone concentrations in mice

The effects of short-term and chronic lithium administration on the concentrations of plasma testosterone (T) and luteinizing hormone (LH) were evaluated in C57BL/6 mice, maintained on a fixed photoperiod of LD 14:10 (white lights on at 06:00 h, CST). Lithium chloride was injected intraperitoneally twice daily (at 09:00 and 16:00 h) in groups of adult male mice at a dosage of 2.5 meq/kg for 7 days, and 1.25 meg/kg for 21 days. Circulating levels of T and LH were measured by standard radioimmunoassay (RIA) methods. Plasma T levels showed a significant increase in mice treated with lithium for 7 days as compared to those in saline-injected control animals. However, there was no significant difference in the concentrations of plasma T between chronic (21 days) lithium-treated mice and the matched control. Plasma LH levels remained unchanged following both short-term and chronic lithium treatment.

Circadian and ultradian changes in synaptic vesicle numbers in nerve endings on adrenomedullary noradrenaline cells, and their modifications by pinealectomy and sham operations.

Nerve endings (n = 1,298) on noradrenaline cells in adrenal medullas of male rats (n =117) were investigated by quantitative electron microscopy, with sampling at 8 times during a standardized light:d

Daily Rhythmic Changes in Synaptic Vesicle Contents of Nerve Endings on Adrenomedullary Adrenaline Cells, and Their Modification by Pinealectomy and Sham Operations

Nerve endings on adrenaline cells in male rat adrenal medullas were investigated by quantitative electron microscopy, with sampling at 8 times during a standard light: dark (12:12) photoperiod. Number (N) per unit area of 2 vesicle types (small clear vesicle, SCV; large granular vesicle, LGV) and % of LGV per total vesicle N were determined. Normal (non-operated) animals showed a circadian rhythm (p less than 0.005) in mean SCVN and one with nearly opposite phase relations in % LGVN. Doubly sham-operated animals had a similar rhythm in %LGVN but diminished circadian change in SCVN. Pinealectomized animals had a circadian pattern in SCVN, but this differed from that of normals in having a 2nd peak, a delay or phase shift of the primary peak, and an increased amplitude of the rhythmic changes.

Quantitative Cytological Analysis of Functional Changes in Adrenomedullary Chromaffin Cells in Normal, Sham-Operated, and Pinealectomized Rats in Relation to Time of Day: III. Nuclear Density

Adrenaline (A)‐ and noradrenaline (N)‐cells in juxtacortical and central areas of adrenal medullas of nonoperated, sham‐operated, and pinealectomized male rats (n = 125) were investigated by quantitative electron and light microscopy. Animals were killed at eight time points during a standardized 24‐h, light‐dark (12:12) cycle 14 d after surgery. Diameters of nucleoli (n = 9,600) and the nucleolar margination rate were studied chiefly by light microscopy.

Lithium-induced changes in the plasma and pituitary levels of luteinizing hormone, follicle stimulating hormone and prolactin in rats

Adult male Sprague-Dawley rats, maintained under a controlled photoperiod of LD 14:10 (white lights on at 06:00 h, CST), were injected with lithium chloride and changes in the levels of plasma and pituitary homogenates of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were examined to evaluate the effects of this anti-manic drug on reproductive function. Two groups of rats were injected with lithium chloride intraperitoneally, twice daily at 09:00 and 16:00 h, for 2 and 7 days at a dosage of 2.5 meq/Kg body weight. Plasma and pituitary levels of LH, FSH and PRL were measured by radioimmunoassay. Plasma levels of LH were significantly (P less than 0.05) increased after 2 days of lithium treatment. In contrast, a significant (P less than 0.005) reduction in plasma levels of LH was evident when lithium injections were continued for 7 days. The plasma levels of FSH remained unaffected by lithium treatment by either time period. Lithium administered for 2 days did not bring about any significant alteration in the plasma levels of PRL, although there was a significant (P less than 0.002) reduction in plasma PRL levels after 7 days treatment. The concentrations of pituitary LH, FSH and PRL remained unchanged after 2 and 7 days of lithium treatment.

Effects of Aging on the Activity of Hypothalamic Dopamine-Beta-Hydroxylase during Various Stages of the Estrous Cycle in C57BL/6 Mice

Hypothalamic dopamine-β-hydroxylase (DBH) activity and plasma luteinizing hormone (LH) concentrations were analyzed in female C57BL/6 mice aged 2–4, 7–8, 12–13, and 16–20 months at various times of th

Quantitative Ultrastructural Analysis of Differences in Exocytosis Number in Adrenomedullary Adrenaline Cells of Golden Hamsters Related to Time of Day, Pinealectomy, and Intracellular Region

This research analyzed differences mainly in the incidence of exocytotic figures in adrenaline cells (A ‐ cells) in pinealectomized (PX), sham‐operated (SPX), and non‐operated (NO) adult male golden hamsters, with the aim of determining whether these parameters change with the time of day and following pinealectomy, and whether intracellular regional differences exist in such changes. Animals acclimated to a standardized light: dark (LD) 12:12 photoperiod were sacrificed at 11 h after the onset of light (L‐11h) and 1 h after the onset of darkness (D‐1h) (8 animals/group/time) at 28 days postoperation. The adrenal medullas were examined and analyzed morphometrically by electron microscopy. The number of exocytoses per unit length (NEL) and the exocytosis index (a rough index of the number of exocytoses per cell) were measured in PF (perivascular‐space‐facing) and non‐PF plasma membranes. NEL increased from L‐11h (NO: 0.040 ± 0.010, X̄± SE) to D‐1h (0.078 ± 0.012) in all three experimental groups (ANOVA: P < 0.005), showing over fourfold higher levels in PF than in non‐PF membranes. NEL in PF membranes in PX animals showed higher levels than those in NO and SPX animals (P < 0.025), but in non‐PF membranes, no differences owing to time of day or surgery were seen. Exocytosis indices were (1) higher at D‐lh than at L‐llh in all three experimental groups (P < 0.005), (2) similar in PF and non‐PF membranes in control groups, and (3) higher in PF membranes in the PX group than in either non‐PF membranes or PF membranes in control groups. In conclusion, the exocytosis number in A cells changes in relation to time of day, rising in early dark phase, and its rise following pinealectomy can be seen only in PF membranes.

Hypothalamic dopamine-β-hydroxylase activity: Fluctuations with time of day and their modifications by intracranial surgery, adrenalectomy, and pinealectomy

Hypothalamic and plasma dopamine-β-hydroxylase (DBH, EC 1.14.2.1) activities were measured by a coupled radioenzymatic method. Animals representing five experimental groups (intact controls, adrenalectomized, pinealectomized, adrenalectomized + pinealectomized, doubly sham-operated) were killed and sampled at 8 times through the 24-hr daily cycle, 15 days postoperation, and at 50–52 days of age. Hypothalamic DBH in intact control animals had statistically significant fluctuations in relation to time of day. These changes were lost or dampened in groups that had had intracranial surgery and were characteristically shifted by adrenalectomy, either alone or with pinealectomy. Plasma DBH fluctuations in the same animals resembled those in hypothalamus in some features (e.g., peak near mid-dark; shift in daily maxima and minima after adrenalectomy) and differed in others (e.g., no effect of intracranial surgery or of sham operation; adrenalectomized + pinealectomized animals resembled the solely pinealectomized). Although temporal patterns in hypothalamic DBH activity thus differed in the experimental animal groups, the daily means of hypothalamic DBH activity were similar.

Effects of lithium on the pituitary-gonadal axis in the rat: Evidence for dose-dependent changes in plasma gonadotropin and testosterone levels

The purpose of the present study was to examine the effects of lithium, a drug which is now used rather widely in the treatment of acute mania and the prophylaxis of manic-depressive bipolar disorders, on the pituitary-gonadal function in the laboratory rat. Sexually adult male rats, maintained under standardized laboratory conditions (LD 14: 10; lights on at 06:00 h, CST), were injected (ip) with lithium chloride both acutely for 1 day and chronically for 5 days, and by utilizing a low and high dose. For the low dose, lithium was injected twice daily (at 10:00 and 15:00 h) at 2.5 meg/Kg for 1 and 5 days, whereas in the high dose groups, also receiving lithium twice daily and at the same hours, the dosages were 5 meq/Kg for 1 day and 3.5 meq/Kg for 5 days. Animals were sacrificed 4 hours after the last lithium (or saline) injections. Plasma and pituitary levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and plasma levels of testosterone (T) were measured by radioimmunoassay (RIA). The administration of the low dose led to a significantly higher (P less than 0.001) plasma FSH, but unaltered plasma LH, levels after 5 days. In contrast, the high dose lithium led to significant suppressions of plasma LH (P less than 0.02; on day 5) and FSH (P less than 0.001; on both day 1 and 5) levels. The levels of plasma T also showed a significant reduction following the low dose (P less than 0.02; on day 5), as well as the high dose lithium treatment, as evident after both 1 (P less than 0.02) and 5 (P less than 0.02) days. Regardless of the dosage, or the duration of treatment, pituitary gonadotropin levels remained unaltered following lithium. The results of our present experiments suggest that lithium administration, either acutely or on a chronic basis, might be associated with significant adverse effects on the pituitary-testicular axis. Furthermore, since some of the hormonal changes were evident when plasma lithium concentration was within the therapeutic range, our data may have potential clinical implications.

Acute lithium treatment suppresses the proestrous LH surge in mice: chronic lithium leads to constant diestrus

Although the therapeutic usefulness of lithium in manic-depressive psychosis is now well-established, a number of basic and clinical studies in recent years have shown that the administration of this anti-manic drug produces a wide range of adverse endocrine and metabolic effects. The present study was undertaken in order to examine (a) what effects acute lithium administration might have on the preovulatory surge of luteinizing hormone (LH) during proestrus, and (b) whether chronic lithium administration has any adverse effect on the estrous cycle in C57BL/6 mice. Acute injections of lithium on the day of proestrus (at 10.00, 16.00 and 18.00 h; LD 14:10; lights on at 05.00 h CST) at a dosage of 5 mEq/kg b. wt. led to a significant (P less than 0.01) suppression of the LH surge that normally occurs in the evening of proestrus at 21.00 h. Chronic administration of lithium, on the other hand, resulted in a complete disruption in the regularity of the estrous cycle. This was characterized by an increasing number of mice showing a continuous diestrous vaginal smear during the first week of exposure to lithium, after which all of the lithium-treated mice completely stopped cycling and entered into constant diestrus. These results represent for the first time that lithium has significant adverse effects on the reproductive function in the female, especially in regard to the proestrous LH surge and estrous cyclicity in mice. Since these adverse effects were manifested under conditions when plasma lithium concentrations were within or around the therapeutic range, our results provide important conceptual information concerning possible adverse effects of lithium on the reproductive function in the human female.