Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicit feeding in the rat

The effects of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on food intake in non-deprived male rats were investigated. Low doses of 8-OH-DPAT (15–60 g/kg) significantly increased food intake, without affecting drinking, grooming, rearing or locomotion. Microstructural analysis of the elicited feeding behaviour revealed that the rate of eating after 8-OH-DPAT treatment was very similar to that previously reported following 16 h food deprivation. Higher drug doses (250–4,000 g/kg) also elicited feeding and caused locomotor stimulation and serotonin-related stereotyped behaviour (i.e. forepaw padding, headweaving, wet dog shakes, flat body posture). When feeding and stereotypy were observed concurrently, response competition was evident and feeding behaviour was fragmented into numerous short eating bouts. As drug-induced stereotypy declined with time, this fragmented pattern of eating was succeeded by long bouts of eating which were similar to those observed at doses of 15–60 g/kg 8-OH-DPAT. The induction of feeding by a serotonin agonist appears paradoxical, since drugs which enhance brain serotonergic activity usually inhibit feeding.     

Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia

Schizophrenia is a highly familial, neurodevelopmental disorder that is associated with several neuropsychiatric, psychological, and neuropathological features. Although pharmacological animal models of dopaminergic and glutamatergic dysfunction have helped advance our understanding of the disease biology, there is a clear need for translational models that capture the neuropathological and functional manifestations associated with the intermediate phenotype and the clinical illness. Neuroimaging of preclinical neurodevelopmental approaches such as methylazoxymethanol acetate (MAM) exposure may afford a powerful translational tool to establish endpoints with greater congruency across animals and humans. Using in vivo volumetric magnetic resonance imaging (MRI), manganese‐enhanced MRI, and diffusion tensor imaging (DTI), we investigated morphological and cytoarchitectural changes of brain structures in MAM‐exposed rats, a neurodevelopmental model of schizophrenia. Compared to saline‐exposed controls, MAM‐exposed rats showed significant enlargement of lateral and third ventricles as well as reduced hippocampal volumes, which is consistent with findings observed in schizophrenia. In addition, DTI revealed that diffusion fractional anisotropy retrieved from corpus callosum and cingulum were significantly decreased in MAM‐exposed rats, suggesting that demyelination occurred in these white‐matter fiber tracts. Imaging findings were confirmed by conducting histological analysis using hematoxylin and eosin and Luxol fast blue stainings. In summary, structural abnormalities resulting from a MAM environmental challenge parallel cerebral pathology observed in schizophrenia. The MAM model incorporating noninvasive imaging techniques may therefore serve as an improved translational research tool for assessing new treatments for schizophrenia. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

The conduct of dental research: the protocol, a guide

BACKGROUND: Research today requires detailed planning to ensure efficient work, to raise funding and to fit into time constraints. AIM: The aim of this article is to provide a broad guidance on the layout and content of a research protocol. METHOD: Years of experience in writing research protocols were used to give guidance on writing, timings, content, layout and successful completion.     

Effects of hydrocortisone and immobilization on tryptophan metabolism in brain and liver of rats of different ages

Hydrocortisone sodium succinate (5 mg/kg i.p.) led to a larger absolute increase in hepatic tryptophan pyrrolase activity in younger (26, 46 and 66 days) than older (107 and 225 days) rats. Activity in control animals was lower in the older rats and there was no obvious correlation between percentage change and age. Responses of male and females were comparable. Consistent with previous findings brain 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) decreased 6 hr after hydrocortisone only at ages when a large absolute increase of pyrrolase activity occurred (26, 46 and 66 days). Brain 5-HT and 5-HIAA levels both before and after hydrocortisone were comparable in males and females. Immobilization led to pyrrolase induction and brain 5-HT changes in 66-day but not in 225-day old rats. Studies with different hydrocortisone preparations showed that the soluble succinate salt caused a more rapid increase of pyrrolase activity than the insoluble acetate salt or free base and a more marked brain 5-HT decrease. Results are discussed in relation to the suggested association between liver tryptophan pyrrolase activity and the subsequent changes in brain 5-HT and 5-HIAA.     

Regional and subcellular changes in the concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat brain caused by hydrocortisone,DL-α-methyltryptophan l-kynurenine and immobilization

1. In agreement with previous findings on whole brain, the intraperitoneal injection of hydrocortisone, DL-α-methyltryptophan or L-kynurenine decreased the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) in different regions of the rat brain.2. Hydrocortisone caused similar decreases in the concentrations of both 5-HT and 5-HIAA, suggesting decreased 5-HT synthesis.3. Changes in the concentration of 5-HIAA after hydrocortisone corresponded significantly to those after α-methyltryptophan. Changes in the concentration of 5-HT did not correspond, possibly due to falsely high 5-HT values because of interfering material derived from α-methyltryptophan.4. In general, kynurenine caused larger decreases in the concentration of 5-HT than in the concentration of 5-HIAA.5. In agreement with previous findings with whole brain, immobilization of rats for 5 h decreased the concentration of 5-HT and increased that of 5-HIAA in most brain regions.6. The order of the percentage decreases in the concentrations of 5-HIAA 6 h after hydrocortisone injection was, in decreasing order: hypothalamus, striatum, cerebellum, mid-brain, pons + medulla and cortex. The percentage increases after immobilization for 5 h were in the reverse order.7. The differences between the percentage decreases in the concentration of 5-HIAA after hydrocortisone and the percentage increases after immobilization were very similar in all regions except the hypothalamus. This is consistent with immobilization stress increasing the firing rate of 5-hydroxytryptaminergic neurones similarly in different regions.8. During the first 3 h of immobilization the concentrations of 5-HIAA in the hypothalamus and in the rest of the brain increased approximately in parallel. Between 3 and 5 h, 5-HIAA returned to control concentrations in the hypothalamus while continuing to rise in the rest of the brain.9. Relative changes in the concentration of 5-HT in particulate and supernatant fractions after the various treatments were comparable except 2 h after kynurenine injection when the concentration 5-HT fell in the particulate but not in the supernatant fraction. The concentration of 5-HT did fall in the latter, though more slowly than in the former fraction, suggesting a concentration of amine synthesizing organelles in particulate material.     

Effect of d-amphetamine on tryptophan and other aromatic amino acids in brain.

The investigation examined the mechanism of the increase in brain tryptophan concentration of rats treated with d-amphetamine. Certain well recognised influences upon brain tryptophan have been excluded as responsible. Thus, the effect is not associated with changes in the plasma concentrations of NEFA or free tryptophan. It is probably not due to a tryptophan-specific mechanism, because amphetamine increases the ratio of brain/plasma concentrations not only of tryptophan but also of tyrosine and phenylalanine. The concentration ratios for liver/plasma also rose, as did the liver tryptophan concentration, but these changes were less striking than for brain. Both alpha- and beta-adrenergic blocking drugs opposed the changes in brain, but in different ways. Thus, after treatment of rats with phentolamine, amphetamine decreased the plasma concentrations of the three aromatic amino acids; however, as the brain concentrations were little altered, the brain/plasma concentration ratios rose. Propranolol (and the dopamine blocker pimozide) opposed the increases of the ratios, so that the brain concentrations again altered little. The increased brain/plasma ratios resulting from the administration of amphetamine were associated with hyperthermia. Propranolol, pimozide and the diabetogenic drug streptozotocin opposed the changes in both plasma and brain; phentolamine affected neither. Despite the increase in brain tryptophan caused by amphetamine this drug had relatively little concurrent effect on 5HT synthesis. Experiments with adrenergic blockers suggest that the small rise of plasma insulin after the injection of amphetamine into rats did not cause the brain changes; these are probably a consequence of hyperthermia. The findings with streptozotocin suggest that the hyperthermic effect of amphetamine is manifested only in states of normal insulin secretion.     

Plasma and Brain Amino Acids in Fulminant Hepatic Failure and their Relationship to Hepatic Encephalopathy

Amino acid concentrations were determined in plasma, whole blood, cerebrospinal fluid and brain tissue of 45 patients with grade 3 or 4 coma due to fulminant hepatic failure. The concentration of 15 of the 19 amino acids determined were significantly increased in blood and the, increases were greatest for the amino acids concerned with neurotransmitter metabolism. There was no correlation, however, between the plasma concentration of these amino acids and changes in the grade of hepatic coma. The plasma concentrations of the branched chain amino acids were normal except in those patients who subsequently recovered in whom levels were slightly decreased. Phenylalanine, tyrosine and methionine were among the 15 out of 18 amino acids which were significantly increased in cerebrospinal fluid and among the 15 out of 21 amino acids which were significantly increased in the brain. The increase in tryptophan was associated with a significant elevation in brain 5-hyroxyindoleacetic acid concentration suggesting an increase in 5-hydroxytryptamine turnover in hepatic coma. Brain to plasma ratios of most amino acids in hepatic coma patients were similar to control subjects suggesting that plasma concentration is the main factor controlling the cerebral concentration. However, for the branched chain amino acids, cerebrospinal fluid and brain concentrations were increased when plasma concentrations were normal suggesting an increase in brain uptake.