Serotonin (5-HT) release in the dorsal raphé and ventral hippocampus: Raphé control of somatodendritic and terminal 5-HT release

Summary Somatodendritic and terminal release of serotonin (5-HT) was investigated by simultaneously measuring extracellular concentrations of 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the dorsal raphé and ventral hippocampus in freely moving rats. Perfusion of tetrodotoxin (TTX, 1M and 10M) into the dorsal raphé simultaneously decreased dorsal raphé and hippocampal 5-HT release. However, following TTX perfusion into the hippocampus (10M), hippocampal 5-HT release was profoundly reduced but dorsal raphé 5-HT remained unchanged.Systemic injections with the 5-HT_1a agonist, buspirone (1.0–5.0mg/kg, i.p.) decreased 5-HT and 5-HIAA and increased HVA concentrations in the dorsal raphé and in the hippocampus. The decreases in raphé and hippocampal 5-HT induced by systemic buspirone were antagonized in rats pretreated with 1.OmM (–) pindolol, locally perfused into the dorsal raphé. Local dorsal raphé perfusion of (–) pindolol alone (0.01–1.0mM) increased dorsal raphé 5-HT and concomitantly induced a small increase in hippocampal 5-HT. Buspirone perfusion into the dorsal raphé did not change (10 nM, 100nM), or produced a small increase (1.0mM) in raphé 5-HT, without changing hippocampal 5-HT.These data provide evidence that 5-HT release in the dorsal raphé is dependent on the opening of fast activated sodium channels and that dorsal raphé 5-HT_1a receptors control somatodendritic and hippocampal 5-HT release.     

MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning

Several histological and behavioral experiments were conducted to investigate the neurotoxic effects of MK-801 in male mice. Moderate subcutaneous (s.c.) doses of MK-801 (0.5 and 1.0 mg/kg) induced the formation of intracytoplasmic vacuoles in pyramidal neurons in layers III and IV of the posterior cingulate/retrosplenial (PC/RS) cortex in 50% and 100% of the mice from the two respective treatment groups. Electron microscopic analysis of the vacuoles indicated that mitochondria and endoplasmic reticulum are the cellular organelles most prominently involved in this pathomorphological change. Treating mice with a high systemic dose of MK-801 (10 mg/kg s.c. or intraperitoneal (i.p.)) caused selective, irreversible degeneration of a small number of PC/RS cortical neurons. Compared to saline controls, the acquisition performance of mice treated i.p. with 10 mg/kg MK-801 was chronically impaired on a spatial learning task (modified hole board food search task) when tested at several posttreatment intervals (up to at least 5 months), although the groups did not differ on activity or sensorimotor tests conducted 2 weeks posttreatment. In summary, MK-801 caused histopathological changes in the mouse brain similar to those observed in the rat. Furthermore, high dose MK-801 treatment that killed a small number of mouse PC/RS cortical neurons resulted in a chronic acquisition impairment in spatial learning, an effect not previously demonstrated in any species.     

Continuous infusion of rocuronium in a paediatric intensive care unit

Purpose  

To evaluate prospectively the efficacy and dose requirements of rocuronium administered by continuous infusion for neuromuscular blockade in a paediatric ICU population.     

Phospholipase-resistant phosphatidylcholine reduces intra-abdominal adhesions induced by bacterial peritonitis

The majority of intra-abdominal adhesions develop postoperatively or following peritonitis. We have previously shown thatl-phosphatidylcholine reduces postoperative peritoneal adhesions in rats. In the present study, we examined whether adhesion formation after bacterial peritonitis is also reduced byl-phosphatidylcholine or bydl-α-phosphatidylcholine, which is degraded only 50% by phospholipase A₂. Peritonitis was induced in the rat by caecal ligation and double puncture; cecotomy was performed 12, 15, or 18h later. Adhesions were assessed blindly by a scoring system 7 days after cecotomy. When cecotomy was scheduled for 18h after caecal ligation and puncture, the 7-day mortality was 90% (n=20). When cecotomy was performed at 12h, no mortality was seen; however, the adhesion score was low (2.3±0.7). When cecotomy was performed 15h after caecal ligation and puncture, the mortality was 25% and the adhesion score was 4.3±0.9. This figure was reduced significantly by intraperitoneal instillation ofl-phosphatidylcholine ordl-α-phosphatidylcholine for 3 subsequent days. However, the mortality increased byl-phosphatidylcholine (P<0.01), whereas mortality afterdl-α-phosphatidylcholine remained at 30%. We conclude that administration of bothl-phosphatidylcholine anddl-α-phosphatidylcholine decrease adhesion formation after bacterial peritonitis.     

The effect of l-dopa and propranolol on human CSF cyclic nucleotides

Human CSF cyclic AMP and cyclic GMP have been measured as possible indicators of activity of central neurotransmitter-sensitive adenylate or guanylate cyclase. In an attempt to help to identify the specific neurotransmitter systems of origin of human CSF cyclic AMP and GMP, we studied Parkinson patients with and without l-dopa therapy and schizophrenic patients before and after propranolol therapy. No effect of l-dopa or propranolol was found on CSF cyclic nucleotides. However, Parkinson patients had a 40–50% reduction of CSF cyclic AMP and a 80–90% reduction of CSF cyclic GMP compared with the schizophrenic patients. Implications of this finding are discussed.     

Titration of human brain monoamine oxidase-A and-B by clorgyline andl-deprenil

Summary The interaction of clorgyline andl-deprenil with the-A and-B forms of human brain monoamine oxidase (MAO) has been studied. Both compounds inhibit cerebrocortical MAO in a manner consistent with a suicide inactivation of the enzyme. The interaction of clorgyline with the-A form of the enzyme appears to take place almost entirely at specific binding sites, and the conditions required for this inhibitor to titrate the concentrations of MAO-A have been elucidated.l-Deprenil has also been used to titrate the concentration of the-B form of MAO in cerebrocortical homogenates, but there is a considerable degree of non-specific binding of this compound. The two inhibitors have been used to titrate the concentrations of the two enzyme forms in frontal cortex homogenates from different age groups. There was a significantly higher MAO-B activity for the age range 73–95 years than for the age range 2–63 years. No significant differences between the two age groups were found for MAO-A. The activity of MAO-A in the samples correlated very well with the concentration of this enzyme form. Titration of the B-form of the enzyme withl-deprenil indicated an increased enzyme concentration with age, although other factors, such as the non-specific binding of this compound, could contribute to this effect.     

Effects of enkephalins and two enzyme resistant analogues on monoamine synthesis and metabolism in rat brain

Summary Methionine-enkephalin and leucineenkephalin, administered into the lateral ventricle of intact rats, increased the accumulation of DOPA by a naloxone-sensitive mechanism in different brain regions after inhibition of the aromatic l-amino acid decarboxylase. Because of the rapid enzymatic degradation of both enkephalins large doses (500 g) were required to enhance brain catecholamine synthesis. The two enzyme resistant enkephalin analogues d-Ala²-methionine enkephalin amide (DALA (4–256 g) and FK 33-824 (0.003–1 g) also increased the synthesis of DOPA, dose-dependently and by naloxone-sensitive mechanisms, but at much lower dosage level. The enkephalins markedly enhanced the brain tyrosine concentration but this effect was not antagonized by naloxone, probably because the enzymatic cleavage releases tyrosine from the administered peptides. In contrast, neither DALA nor FK 33-824 increased the brain tyrosine concentration. The formation of 5-HTP and the brain tryptophan concentration were also increased by the enkephalins, although these effects were not blocked by naloxone. The enkephalin analogues, however, enhanced the formation of 5-HTP and the brain tryptophan concentration by naloxonesensitive mechanisms. All four peptides accelerated the disappearance of dopamine, noradrenaline and 5-hydroxytryptamine after inhibition of monoamine synthesis. The results suggest that endogenous enkephalins, through the activation of opiate receptors, are involved in the short-term regulation of central monoaminergic systems.Preliminary data were presented at the Nobel Symposium 42, Principles for the Central Regulation of the Endocrine System, Stockholm, June 8–10, 1978, and at the 4th International Catecholamine Symposium, Asilomar Conference Center, Pacific Grove, California, September 17–22, 1978     

Effect of tetrakis-μ-3,5-diisopropylsalicylatodiaquodicopper(II) on the status of reduced glutathione in freshly isolated hepatocytes

Effects of different concentrations of tetrakis--3,5-diisopropylsalicylatodiaquodicopper(II) (Cu(II)₂(3,5-DIPS)₄(H₂O)₂) on the reduced status of glutathione (GSH), the major nonprotein thiol in tissues, were investigated using freshly isolated hepatocytes. Cu(II)₂(3,5-DIPS)₄ below 100 M did not have any significant effects on either the GSH content or viability of the hepatocytes, but at 150–250 M it decreased both parameters after 1 h of incubation. The decrease in cellular GSH was not followed by an increase in the oxidized form of GSH (GSSG) in the cell suspension. The addition of deferoxamine with Cu(II)₂(3,5-DIPS)₄ to the hepatocyte suspension prevented depletion in GSH content and loss of cell viability by Cu(II)₂(3,5-DIPS)₄. Both GSH depletion and loss of cell viability were found to be Cu(II)₂(3,5-DIPS)₄ dose dependent. From these results, it appears that Cu(II)₂(3,5-DIPS)₄ penetrated the cell membrane and acted by decreasing the GSH level by forming a copper-glutathione complex.     

Cardiac function in congenital hypothyroidism: Impairment and response to L-T4 therapy

Summary Electrocardiograms (heart rate, QRS voltage, QRS axis in the frontal plane, Q-Tc interval), echocardiograms [left ventricular fractional shortening (LVFS); preejection period (PEP); PEP/left ventricular ejection time (PEP/LVET) ratio; end-diastolic left ventricular free wall and interventricular septum thickness; presence of pericardial effusion], and thyrotropin (TSH), thyroxine (T₄), and triiodothyronine (T₃) serum levels were evaluated before and 1 week, 1 and 2 months after the start ofl-thyroxine (L-T₄) therapy in 11 infants with congenital hypothyroidism (CH), aged 16–59 days when first seen.Before the start of therapy, infants with CH had significantly lower QRS complexes and LVFS and significantly higher values for Q-Tc, PEP, and PEP/LVET than normal infants of the same age. The QTc interval, PEP and PEP/LVET ratio of infants with CH were significantly greater before than 1 week after L-T₄ therapy, and LVFS was significantly lower before than 1 month after L-T₄ therapy. Four of the infants with CH had small pericardial effusions, which disappeared within the first week of therapy.QRS axis in the frontal plane, Q-Tc interval, and PEP were negatively correlated with logT₄ and logT₃ serum levels. PEP/LVET ratios were negatively correlated with logT₄ serum values. The QRS voltage values were positively correlated with logT₄ and logT₃ serum values. The frontal-plane QRS axis, Q-Tc interval, and PEP/LVET ratio were positively correlated with logTSH serum levels. The QRS voltages were negatively correlated with TSH serum levels.Our data show that before therapy infants with CH have the same functional, but not morphological, abnormalities as older hypothyroid ones and that one third of them have small pericardial effusions. L-T₄ therapy rapidly reverses these changes.     

Pain syndromes in HIV infection

Pain causes considerable disability and discomfort in HIV (Human Immunodeficiency Virus) infected individuals. A large number of patients infected with HIV suffer from one or more pain-related syndromes. Pain is under-reported and suboptimally managed in these patients. An outline of the different pain syndromes, including headache, oral cavity pain, chest pain, abdominal pain, anorectal pain, musculoskeletal pain and peripheral neuropathic pain, and their aetiologies are discussed. Current pain management modalities, including non-narcotic and narcotic analgesics, tricyclic antidepressants, anticonvulsants, physical therapy and psychological techniques, are outlined. Treatment should be based on the same principles applied to the management of cancer-related pain. A multi-disciplinary, comprehensive approach to pain management will assist these individuals to achieve improved levels of comfort, function and quality of life in this ultimately terminal illness.