Effect of chronic clozapine administration on [3H]MK801-binding sites in the rat brain: a side-preference action in cortical areas.

We studied modifications in [3H]MK801-binding sites in the rat brain after chronic clozapine. We found a 20-30% reduction of [3H]MK801-binding sites in the anterior cingulate, frontoparietal motor and frontoparietal somatosensory cortices on the left side but none on the right. We also demonstrated a 20% bilateral increase of N-methyl-D-aspartate (NMDA) receptors in the dentate gyrus of the hippocampus. No changes were found in the prefrontal cortex, caudate-putamen, nucleus accumbens, hippocampus or olfactory tubercle.

Differences between morning and afternoon hormonal responses to D-fenfluramine in healthy humans.

The prolactin (PRL) and cortisol responses to oral D-fenfluramine (30 mg) and placebo were measured in seven healthy subjects (two women and five men) in the morning and in the afternoon. As compared to placebo, D-fenfluramine significantly increased plasma PRL levels in both the morning and the afternoon, with no significant circadian difference. On the contrary, D-fenfluramine significantly enhanced plasma cortisol levels in the afternoon, but not in the morning. These data suggest that the time of the day at which the D-fenfluramine challenge test is carried out may be an important variable in determining the glucocorticoid response to the 5-HT releasing agent in humans.

Effect of different types of stressors on peptide messenger ribonucleic acids in the hypothalamic paraventricular nucleus.

Using in situ hybridization we have studied the effects of different types of stressors, such as ether, immobilization, cold and swimming, on the expression of several peptide messenger ribonucleic acids (mRNAs) in the hypothalamic paraventricular nucleus of adult male rats. Paraventricular nucleus sections were hybridized using synthetic oligonucleotide probes complementary to mRNA for corticotropin-releasing hormone, neurotensin, enkephalin and thyrotropin-releasing hormone. A clear upregulation of neurotensin mRNA was seen after ether and, to a lesser extent, after immobilization stress, whereas after the two other stressors neurotensin mRNA was undetectable, as in control rats. An increase in enkephalin mRNA was observed in a selective region of the dorsal part of the medioparvocellular subdivision of the paraventricular nucleus only after ether and immobilization stress. No significant changes were seen in corticotropin-releasing hormone and thyrotropin-releasing hormone mRNA levels in any of the experimental paradigms. The present results show selective changes for various peptide mRNAs in the paraventricular nucleus after various types of stress. Significant effects could be demonstrated only on neurotensin and enkephalin mRNA after ether and immobilization stress. This suggests that adaptive changes in the rate of synthesis, processing and transport of the peptide may develop over a longer period of time.

CGRP-like immunoreactivity in A11 dopamine neurons projecting to the spinal cord and a note on CGRP-CCK cross-reactivity.

Using the indirect immunofluorescence technique and double labelling procedures combined with retrograde tracing it could be demonstrated that the A11 dopamine cell group, located at the border between the diencephalon and mesencephalon of the rat brain and some of which project to the spinal cord, contains calcitonin gene-related peptide (CGRP)-like immunoreactivity. Thus, another catecholamine group in the rat brain has been shown to have a coexisting peptide. One of the CGRP antisera used in the present study also stained cholecystokinin (CCK) containing neurons in various brain areas. Absorption and displacement experiments using immunohistochemistry and radioimmunoassay showed that this cross-reactivity was confined to the C-terminal portion of the peptide molecule. Therefore, the present results suggest that CGRP antisera used for immunohistochemistry and radioimmunoassay should be tested for possible cross-reactivity with CCK.

Failure of single electroconvulsive shock to affect daytime melatonin production in rats.

It has been reported that, in the rat, different types of stressful procedures increase daytime melatonin production. Electroconvulsive shock (ECS) has been shown not to affect daytime pineal melatonin in rats killed 9 hr after its administration. It is possible that the long-lasting interval between the ECS administration and the sacrifice of the animals obscured an effect of the stressful procedure. In the present study, the effects of acute ECS on daytime melatonin production were evaluated in both ECS- and sham-treated rats killed 30, 60, 120, and 240 min after treatment. As compared with the sham-treated animals, rats receiving acute ECS (80 mA, 0.5 sec) did not show any significant difference in either pineal or serum melatonin levels at any time point after treatment. These data indicate that single ECS does not affect daytime melatonin production in the rat and suggest that the pineal gland may respond differently to the various stressful procedures.

Physical exercise at night blunts the nocturnal increase of plasma melatonin levels in healthy humans.

The effects of physical exercise on nighttime melatonin secretion have never been investigated in humans. For this purpose, plasma melatonin levels were measured at different times during the day and the night in seven healthy men (aged 26-33 yrs), both in resting condition and before and after a physical exercise performed between 10.40 and 11.00 p.m.. The exercise consisted in bicycling on a bicycle ergometer at 50% of the personal maximal work capacity (MWC) for 10 min, followed by other 10 min of bicycling at 80% of the MWC. The results clearly showed that physical stress at night significantly blunts the nocturnal increase in plasma melatonin levels (group X time interaction: p less than 0.00001; two-way ANOVA with repeated measures). These findings, taken together with the data of the literature, suggest that the response of the pineal gland to provocative stimuli may depend on its level of activity when the stimulus is applied.

Preliminary observations on the suppression of nocturnal plasma melatonin levels by short-term administration of diazepam in humans.

Several studies suggest that GABAergic mechanisms may be involved in the modulation of melatonin secretion. However, conflicting results have been reported in animal studies; in humans the issue has not been widely investigated. In the present study, using a double-blind design, six healthy men received orally, at midnight, 10 mg of diazepam, a GABAergic agent, or placebo, on two different occasions 1 week apart. Blood samples were collected, in the dark, immediately before the drug administration, and at 12:30, 1, 2, 3, and 4 AM. Serum melatonin was measured by a radioimmunological method with [125I]melatonin as a tracer. Two-way ANOVA with repeated measurements disclosed a significant effect for treatment (P less than 0.01), for time (P less than 0.0004), and for treatment X time interaction (P less than 0.05). Following diazepam administration, serum melatonin levels observed at 2, 3, and 4 AM were significantly lower than the corresponding values following placebo (P less than 0.002 at 2 and 4 AM; P less than 0.03 at 3 AM [Students' paired t test]). These results show that nocturnal blood melatonin levels may be suppressed by the acute administration of a GABAergic agent, suggesting that GABA may be involved in the modulation of pineal activity in man.