Genetic and pharmacological models of cholinergic supersensitivity and affective disorders

Summary Increased muscarinic sensitivity has been associated with altered hormonal states (hypothyroidism and hyperadrenocorticism), chronic administration of muscarinic antagonists or antidepressants with muscarinic actions, selective breeding for anticholinesterase sensitivity, and certain inbred strains of rats and mice. Thus, both genetic and environmental factors may influence muscarinic receptor sensitivity. The reasonably detailed studies on the selectively-bred rats have revealed that the Flinders Sensitive Line (FSL) rats weigh less, are less active, are more sensitive to muscarinic agonists and to stressors, and have higher concentrations of hippocampal and striatal muscarinic receptors than normal, or the selectively-bred, Flinders Resistant Line (FRL) rats. Thus, there are a number of parallels between FSL rats and depressed humans. The FSL rats may be the first animal model of depression to mimic the actual trait of depression, and not just the state.     

Serotonergic and cholinergic interaction in the regulation of pituitary-adrenal function in rats

It has been proposed that the central serotonergic inputs which modulate pituitary-adrenal secretion are mediated by cholinergic neurons. We have tested this hypothesis in intact rats. Male Sprague-Dawley rats were injected with cholinergic and serotonergic agents which enhanced transmitter function and with receptor blocking agents. Agents were injected, singly and in combination, into both unstressed and stressed animals. Since the response to cholinergic agents might be due to changes to vasopressin release, Brattleboro (vasopressin deficient) rats were also injected with cholinergic agents. The level of plasma corticosterone at 1-h post-injection was determined. Results indicate that the serotonin receptor blockade decreased the stimulatory, cholinergic effect of physostigmine. Cholinergic receptor blockers did not significantly reduce the corticosterone rise induced by 5-hydroxytryptophan. These results do not support the hypothesis of cholinergic mediation of serotonergic input. Nicotinic and muscarinic receptors appeared to exert opposing influences on the system. The nicotinic receptor antagonist was able to block the stimulatory effect of physostigmine. The muscarinic receptor antagonist significantly elevated plasma corticosterone levels. No differences were found in the effect of physostigmine on Brattleboro rats as compared to controls. These data are interpreted as suggesting that 1) the acetylcholine-induced stimulation of pituitary-adrenal function is mediated, in part, by serotonergic neurons; and 2) stimulation of nicotinic receptors is facilitatory whereas stimulation of muscarinic receptors is inhibitory to pituitary-adrenal function.     

Effects of antithymic reticuloepithelial cells serum on the levels of circulating thymic factor and on the sensitivity to azathioprine of spleen spontaneous rosette-forming cells

Summary Swiss mice treated with an antithymic reticuloepithelial cells serum (ATRES) showed a drastic and prolonged depression of the serum thymic factor. A similar but less pronounced effect was also observed following the administration of the antithymocyte (ATS) and the antilymphocyte (ALS) sera. Conversely, the azathioprine sensitivity of spleen spontaneous rosette-forming cells was highly modified by the ATRES but not by the ATS or the ALS. The probable mechanisms of such effects are discussed.     

Cholinomimetics produce seizures and brain damage in rats

Microinjections of the cholinergic agonists, carbachol and bethanechol, either into the amygdala or into the dorsal hippocampus produced sustained limbic seizures and brain damage in rats. Systemic administration of pilocarpine in rats resulted in a sequence of convulsive disorders and widespread brain damage as well. Scopolamine prevented the development of convulsive activity and brain damage produced by cholinomimetics. These results suggest that the excessive stimulation of cholinergic muscarinic receptors can lead to limbic seizures and brain damage. It is postulated that muscarinic cholinergic mechanisms are linked to the etiology of temporal lobe epilepsy and epileptic brain damage.     

Ursachen der geschlechtsunterschiedlichen MilchdrÜsengewebsentwickiung bei Ratten

Summary Under the same hormonal conditions, mammary gland growth in adult female rats is more pronounced than in males. Since there are no differences in the glandular development of both sexes, either at birth or at 30 days of life, it is assumed that male rats react less sensitively than female rats in response to a hormonal stimulus with regard to mammary gland growth. It is presumed that androgen influence during the differentiation stage is responsible for the fixation of a decreased sensitivity of the positive feedback-mechanism between estrogens and prolactin secretion in males. Thus changes in sensitivity would be the reason for mammary gland growth in males being smaller than in females under the same hormonal conditions.

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Dieser Arbeit liegen zum Teil die Untersuchungsergebnisse einer SchÜler-Facharbeit von U.Rieser zugrunde.     

Lasting effects of acute dehydration and post-weaning undernourishment on cortical spreading depression in adult rats

Summary Acute dehydration (D) early in life made adult rats less susceptible to cortical spreading depression (SD) than control (C) rats. Post weaning undernourished (U) rats tended to be more susceptible than controls. The association of D and U (DU group) made rats more susceptible to SD than U-rats. It is suggested that this association gives rise to a more complex pathological state than that which would result from the summation of the effects of its components.This work was supported by the Brazilian agencies CNPq and CAPES and by the Federal University of Pernambuco. The suggestions of Dr. T. P. Hicks, which contributed to improve the English text, are very much appreciated.     

The behavior of the homozygous and heterozygous sub-types of rats which are genetically-selected for diabetes insipidus: A comparison with Long Evans and Wistar stocks

Several aspects of spontaneous and conditioned behavior (food and water intake, locomotion and emotionality, passive and active avoidance acquisition and retention) of standard (albino and pigmented) rats, and rats heterozygous (HEDI) and homozygous (HODI) for diabetes insipidus, are reviewed. As would be expected, HODI rats have been repeatedly found to consume far more fluid than either HEDI or control rats. Pigmented rats appear to be more active than albinos. HODI rats exhibit less marked emotional responses than do control rats, among which the pigmented ones exhibit the highest emotionality. Light aversion is more evident in albino than in pigmented rats. No differences are found among HEDI, HODI and normal Long Evans rats. It is quite difficult to provide a clear-cut statement concerning inter-strain differences in passive avoidance behavior, possibly because of the variety of techniques employed. In any case, HODI rats do not perform worse than normal controls do. In one-way active avoidance paradigms, pigmented rats perform better than albinos, and the performance of HODI rats does not differ from that of controls. In two-way avoidance paradigms, albinos appear to outperform pigmented rats. Once again, there are no obvious differences between HODI and control animals.In addition to indicating that HODI rats may actually be less emotional than the other groups of rats reviewed here, the studies described once again fail to confirm the previously alleged functions of vasopressin in memory consolidation.     

The behavior of the homozygous and heterozygous sub-types of rats which are genetically-selected for diabetes insipidus: a comparison with Long Evans and Wistar stocks

Several aspects of spontaneous and conditioned behavior (food and water intake, locomotion and emotionality, passive and active avoidance acquisition and retention) of standard (albino and pigmented) rats, and rats heterozygous (HEDI) and homozygous (HODI) for diabetes insipidus, are reviewed. As would be expected, HODI rats have been repeatedly found to consume far more fluid than either HEDI or control rats. Pigmented rats appear to be more active than albinos. HODI rats exhibit less marked emotional responses than do control rats, among which the pigmented ones exhibit the highest emotionality. Light aversion is more evident in albino than in pigmented rats. No differences are found among HEDI, HODI and normal Long Evans rats. It is quite difficult to provide a clear-cut statement concerning inter-strain differences in passive avoidance behavior, possibly because of the variety of techniques employed. In any case, HODI rats do not perform worse than normal controls do. In one-way active avoidance paradigms, pigmented rats perform better than albinos, and the performance of HODI rats does not differ from that of controls. In two-way avoidance paradigms, albinos appear to outperform pigmented rats. Once again, there are no obvious differences between HODI and control animals. In addition to indicating that HODI rats may actually be less emotional than the other groups of rats reviewed here, the studies described once again fail to confirm the previously alleged functions of vasopressin in memory consolidation.     

Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition

Summary Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.     

Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition

Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.     

Graft-versus-host reaction and lymphoid organs in normally fed and protein-deprived rats.

Lymph node graft-versus-host reaction (GVHR) induced by parental splenic lymphocytes inoculated into hind foot pads of F-1 hybrid rats is correlated with the state of the thymus and the spleen of the recipients. This may explain the depression of the reaction after protracted protein deprivation. Furthermore, GVHR provokes mainly in normal rats a reduction of thymus and spleen possibly due to a T-cell transfer to the grafted area.     

Mechanical responses of the isolated cervix of the day-22 pregnant rat to field stimulation.

Field stimulation of isolated, spirally-cut cervix from day-22 pregnant rats produced contractions which could be inhibited by tetrodotoxin or hyoscine and potentiated by propranolol. The rat cervix would appear to receive both cholinergic and noradrenergic innervations whose transmitters activate muscarinic cholinoceptors and beta-adrenoceptors respectively.     

Detection of varicella zoster virus DNA in human tissue by standard and nested polymerase chain reaction

Results and conclusion The sensitivity of the PCR assay was determined with cloned VZV DNA. About 200 copies of the target sequence were necessary for detectable amplification by standard PCR and less than 20 copies by nested PCR. Out of 24 human trigeminal ganglia five tested positive for VZV DNA by standard PCR (21%), in eleven cases VZV DNA was detectable using nested PCR (46%). Sequences specific for VZV could be detected in PMBC from children with acute varicella up to six days after the onset of rash by standard (one child) or nested (three children) PCR. This confirms that at the time of haematogenous spread before and during the rash viral DNA can be found within the mononuclear cells. Thus the use of nested primers enhances the sensitivity of the assay and allows the detection of only a few genomic copies of viruses in human tissues.     

Depression and antidepressants: molecular and cellular aspects

Clinical depression is viewed as a physical and psychic disease process having a neuropathological basis, although a clear understanding of its ethiopathology is still missing. The observation that depressive symptoms are influenced by pharmacological manipulation of monoamines led to the hypothesis that depression results from reduced availability or functional deficiency of monoaminergic transmitters in some cerebral regions. However, there are limitations to current monoamine theories related to mood disorders. Recently, a growing body of experimental data has showed that other classes of endogenous compounds, such as neuropeptides and amino acids, may play a significant role in the pathophysiology of affective disorders. With the development of neuroscience, neuronal networks and intracellular pathways have been identified and characterized, describing the existence of the interaction between monoamines and receptors in turn able to modulate the expression of intracellular proteins and neurotrophic factors, suggesting that depression/antidepressants may be intermingled with neurogenesis/neurodegenerative processes.     

Graft-versus-host reaction and lymphoid organs in normally fed and protein-deprived rats

Summary Lymph node graft-versus-host reaction (GVHR) induced by parental splenic lymphocytes inoculated into hind foot pads of F-1 hybrid rats is correlated with the state of the thymus and the spleen of the recipients. This may explain the depression of the reaction after protracted protein deprivation. Furthermore, GVHR provokes mainly in normal rats a reduction of thymus and spleen possibly due to a T-cell transfer to the grafted area.I thank Mrs.M. Cl. Gonzalez and Mr.D. Soulas (C.N.R.S.) for their skilled technical assistance.     

Plasma enteroglucagon, peptide YY and gastrin in rats deprived of luminal nutrition, and after urogastrone-EGF administration. A proliferative role for PYY in the intestinal epithelium?

Intestinal tissue mass was significantly reduced throughout the gastrointestinal tract (p less than 0.001) of intravenously fed (TPN) rats. Urogastrone-epidermal growth factor, (URO-EGF), reversed these changes. Although plasma enteroglucagon and gastrin levels showed a small increase with URO-EGF, this was far less than the gut tissue weight change, suggesting that it was unlikely that they were involved in modulating the proliferative response of the intestine to URO-EGF. Peptide tyrosine tyrosine (PYY) levels were however significantly increased by URO-EGF, indicating that PYY may possibly have a role in the modulation of intestinal cell proliferation.     

Inhibitory effect of atropine on the isoprenaline-induced increase in vasopressin plasma concentration in rats

The isoprenaline-induced increase in plasma levels of vasopressin in conscious rats was reduced by intravenous and intracerebroventricular applications of atropine. It is concluded that central neurons with muscarinic receptors contribute to the isoprenaline-induced vasopressin release.     

Inhibitory effect of atropine on the isoprenaline-induced increase in vasopressin plasma concentration in rats

Summary The isoprenaline-induced increase in plasma levels of vasopressin in conscious rats was reduced by intravenous and intracerebroventricular applications of atropine. It is concluded that central neurons with muscarinic receptors contribute to the isoprenaline-induced vasopressin release.     

The influence of hypertension upon the normal cardiovascular responses to hemorrhagic hypotension and shock

The data suggest that rats genetically inbred to be hypertensive (SHR) are less able to compensate for hemorrhage and shock than their normotensive controls (WKY). Two reasons for this genetic dysfunction are: 1) SHRs seem to depend more on innervated alpha 1 than noninnervated alpha 2 adrenoreceptors for vasoconstriction; and 2) the vascular smooth muscle hypertrophy noted in SHRs may interfere with effective vasoconstriction.     

Depressor effects of muscarinic and non-muscarinic mediation induced by lateral hypothalamic stimulation in the cat

Transient sympathetically-mediated depressor effects were induced by stimulation of a small locus in the lateral hypothalamic peri-fornical region, medial to the fields of Forel. The ganglionic blocking agent, atropine methyl nitrate (ATMN), was used to show that muscarinic as well as non-muscarinic sympathetic ganglion receptor neurotransmission was involved. Evidence is presented that stimulation of this LH site co-activates a number of mechanisms and that depending on which of these are activated, the ganglionic blocking agent ATMN may either block, reverse or potentiate the depressor effect.