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G D Schiller

Publications and source records attributed to G D Schiller.

17 recordsLinked to original sources
PubMed1998

Cholinergic/serotonergic interactions in hypothermia: implications for rat models of depression.

This article reviews published reports and presents new evidence that support a number of commonalties between lines of rats selectively bred for differences in cholinergic (muscarinic) and serotonergic (5-HT1A) sensitivity. The Flinders Sensitive Line (FSL) rat, a genetic animal model of depression derived for cholinergic supersensitivity, is more sensitive to both cholinergic and serotonergic agonists, and exhibits exaggerated immobility in the forced swim test relative to the control, Flinders Resistant Line (FRL), rat. Similar exaggerated responses are seen in a line of rats recently selected for increased sensitivity to the 5-HT1A agonist, 8-OH-DPAT (High DPAT Sensitive--HDS), relative to lines selectively bred for either low (Low DPAT Sensitive--LDS) or random (Random DPAT Sensitive--RDS) sensitivity to 8-OH-DPAT. For both the FSL and HDS rats, their exaggerated immobility in the forced swim test is reduced following chronic treatment with antidepressants. The present studies examined further the interaction between cholinergic and serotonergic systems in the above lines. Supersensitive hypothermic responses to 8-OH-DPAT were observed very early (postnatal day 18) in FSL rats, suggesting that both muscarinic and serotonergic supersensitivity are inherent characteristics of these rats. Scopolamine, a muscarinic antagonist, completely blocked the hypothermic effects of the muscarinic agonist oxotremorine in FSL and FRL rats, but had no effect on the hypothermic responses to 8-OH-DPAT, suggesting an independence of muscarinic and 5-HT1A systems. On the other hand, genetic selection of genetically heterogeneous rats for differential hypothermic responses to the muscarinic agonist oxotremorine were accompanied by differential hypothermic responses to 8-OH-DPAT, suggesting an interaction between muscarinic and 5-HT1A systems. Overall, these studies argue for an inherent interaction between muscarinic and 5-HT1A systems, which probably occurs beyond the postsynaptic receptors, possibly at the level of G proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Lymphoid cell infiltration during breast cancer growth: a syngeneic rat model.

The systematic study of potential alterations in lymphoid infiltrates during tumour growth is extremely limited in humans. Therefore, development of a model utilizing a spontaneously arising mammary adenocarcinoma in Dark Agouti rats was adopted for the study of the dynamics of lymphoid cell infiltration during tumour development. Syngeneic rats were inoculated with tumour cell suspensions and the tumours were resected from 5 to 15 days. Serial sections were immunohistochemically stained using a panel of monoclonal antibodies. Irrespective of tumour age, ED2 (macrophages) and W3/25 (CD4)-positive cells were the most prominent cell infiltrates in tumours. There were no significant differences in cell counts for any marker between 8-day and 15-day tumours. However, in 5-day tumours there were significantly fewer macrophages, OX19+ T cells, W3/25+ cells, OX8+ (CD8) cells and OX62+ dendritic cells. Interleukin-2 receptor alpha chain expression was low at all examined stages of tumour growth, indicating a lack of tumour infiltrating lymphocyte (TIL) activation and/or possible TIL anergy. B cell staining was absent in all tumours, negating the possibility of these cells mediating coregulatory signals for TIL activation in the micro-environment of established tumours. The results parallel previous immunohistochemical findings in humans, suggesting that a dysfunctional local immune response in breast cancer may be determined very early during tumour development.

Adenocarcinoma↗
PubMed1992

Immobility-reducing effects of antidepressants in a genetic animal model of depression.

Chronic treatment with the tricyclic antidepressants imipramine (15 mg/kg) and desmethylimipramine (5 mg/kg) significantly reduced the exaggerated immobility normally exhibited by the Flinders Sensitive Line (FSL) rats in the Forced Swim Test. The control group, Flinders Resistant Line (FRL) rats were only slightly affected. In contrast, chronic treatment with the anticholinesterase diisopropyl fluorophosphate at doses known to down regulate muscarinic receptors did not alter swim test immobility in either FSL or FRL rats. Our findings support the validity of the FSL rats as an animal model of depression and suggest that serotonergic and/or noradrenergic, but not cholinergic mechanisms, may underlie the exaggerated immobility of the FSL rats.

Animals↗
PubMed1991

Lack of anxiety in an animal model of depression with cholinergic supersensitivity.

It has been suggested that anxiety and depression are correlated dimensions of behaviour. Consequently, this study investigated the behaviour of the Flinders Sensitive Line, an animal model of depression with cholinergic supersensitivity, in the elevated (+)-maze test of anxiety. The results indicate that anxiety responses (% open/total arm entries) do not differ between the Flinders Sensitive and Flinders Resistant (control) lines of rat (FSL vs. FRL, respectively). Treatment with 1.0 mg/kg of diazepam significantly increased % open/total scores to a similar degree in both lines, further suggesting that the lines do not differ in anxiety. It is concluded that the FSL rat is an animal model of depression without evidence for inherent alteration in anxiety-related behaviour.

Animals↗
PubMed1991

Early development of muscarinic supersensitivity in a genetic animal model of depression.

Adult Flinders-Sensitive Line (FSL) rats are significantly more sensitive to the behavioral and physiologic effects of muscarinic agonists than are control, Flinders-Resistant Line (FRL) rats; therefore, they resemble humans with depressive disorders. The present study examined the sensitivity of prepubertal and pubertal FSL and FRL rats to the hypothermic and locomotor inhibitory effects of the muscarinic agonist, oxotremorine, and compared these findings to the regional development of muscarinic receptor binding in similarly aged rats. The FSL rats were significantly more sensitive (-1.85 degrees +/- 0.2 degrees C) than the FRL rats (-0.65 degrees +/- 0.15 degrees C) to the hypothermic effect of 0.25 mumol/kg of oxotremorine at the earliest age tested (18 days postpartum) and became progressively more sensitive throughout the period of testing (FSL -2.8 degrees +/- 0.24 degrees C versus FRL -0.5 degrees +/- 0.16 degrees C at 61 days postpartum, data represent the mean +/- SEM of pooled male and female). Significant increases in muscarinic receptor number in FSL rat brain were observed only in older (61 days postpartum) rats. These results are consistent with the suggestion that the FSL rat is a genetic animal model of depression, but also indicate that the differences in muscarinic sensitivity cannot be accounted for exclusively by differences in the number, per se, of muscarinic receptors.

Aging↗
PubMed1990

gamma-Aminobutyric acidA receptor regulation in culture: altered allosteric interactions following prolonged exposure to benzodiazepines, barbiturates, and methylxanthines.

In previous reports, we have described the use of primary neuronal cultures derived from chick brain to study the regulation of the gamma-aminobutyric acidA (GABAA) receptor complex. Chronic exposure of cultures to GABA, benzodiazepines, or methylxanthines results in decreased enhancement of [3H]flunitrazepam binding by GABA, consistent with an allosteric uncoupling of GABA and benzodiazepine recognition sites of the GABAA receptor. In the present communication, we extend our studies of the pharmacology of benzodiazepine- and methylxanthine-induced uncoupling of GABA/benzodiazepine recognition site interactions and present evidence to show that certain barbiturates (barbital and pentobarbital) also induce uncoupling. Chronic exposure to flurazepam (a high efficacy benzodiazepine) elicits no change in the number of benzodiazepine binding sites or the affinity of benzodiazepine binding in the absence of GABA. Whereas flurazepam and theophylline decrease coupling, Ro15-1788 (a low efficacy benzodiazepine) inhibits flurazepam-induced but not theophylline-induced uncoupling, suggesting that theophylline and flurazepam act through separate receptors. Flurazepam-induced uncoupling is not prevented by SR-95531 or picrotoxin (specific inhibitors of GABA action) and, therefore, is not an indirect effect mediated by endogenous GABA. The onset of flurazepam-induced uncoupling (EC50 approximately 1 microM) exhibits a t 1/2 of about 18 hr, in general agreement with the half-time for receptor turnover. Uncoupling is reversible following washout and recovery at 37 degrees. These results are discussed in terms of mechanisms of GABAA receptor regulation in response to chronic exposure to functionally homologous or heterologous ligands.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Antidepressant effects of rolipram in a genetic animal model of depression: cholinergic supersensitivity and weight gain.

The effects of rolipram, a new generation antidepressant which is a selective inhibitor of phosphodiesterase, on the selectively bred Flinders Sensitive Line (FSL) of rats, a genetic animal model of depression, was studied. Acutely, rolipram produced comparable decreases in temperature and activity in the FSL and the Flinders Resistant Line (FRL) rats. Upon chronic treatment there was a trend for rolipram to counteract the shock-induced suppression of activity in the FSL rats, suggesting an antidepressant-like effect. However, both groups gained a significant amount of weight, which appeared to be associated with polydipsia and polyuria. In addition, both groups were significantly more affected by the muscarinic agonist, oxotremorine, than their vehicle-treated counterparts. Thus, the FSL rats, which are genetically supersensitive to cholinergic agonists, are even more sensitive following chronic treatment with rolipram. These unexpected findings suggest that rolipram may not be appropriate as an antidepressant for humans because of undesirable side effects.

Albuterol↗
PubMed1988

Chronic caffeine or theophylline exposure reduces gamma-aminobutyric acid/benzodiazepine receptor site interactions.

Methylxanthines, such as caffeine and theophylline, are adenosine receptor antagonists that exert dramatic effects upon the behavior of vertebrate animals by increasing attentiveness, anxiety, and convulsive activity. Benzodiazepines, such as flunitrazepam, generally exert behavioral effects that are opposite to those of methylxanthines. We report the finding that chronic exposure of embryonic brain neurons to caffeine or theophylline reduces the ability of gamma-aminobutyric acid (GABA) to potentiate the binding of [3H]flunitrazepam to the GABA/benzodiazepine receptor. This theophylline-induced "uncoupling" of GABA- and benzodiazepine-binding site allosteric interactions is blocked by chloroadenosine, an adenosine receptor agonist, indicating that the chronic effects of theophylline are mediated by a site that resembles an adenosine receptor. We speculate that adverse central nervous system effects of long-term exposure to methylxanthines such as in caffeine-containing beverages or theophylline-containing medications may be exerted by a cell-mediated modification of the GABAA receptor.

Allosteric Regulation↗
PubMed1984

Selective breeding for differences in cholinergic function: pre- and postsynaptic mechanisms involved in sensitivity to the anticholinesterase, DFP.

To determine the contribution of presynaptic cholinergic mechanisms to the increased sensitivity of a genetically selected line of Sprague-Dawley rats (Flinders S-line) to the anticholinesterase, diisopropyl fluorophosphate (DFP), rats were sacrificed by focused microwave irradiation of the head 1 min after a pulse injection of deuterium-labeled choline into the tail vein. The S-line rats exhibited higher concentrations of labeled acetylcholine (ACh) in the cortex than the rats bred for resistance to DFP (Flinders R-line). To determine the contribution of postsynaptic cholinergic mechanisms the concentration of brain muscarinic ACh receptors (mAChR) was determined. The S-line rats exhibited higher concentrations of striatal and hippocampal mAChR than the R-line rats. Thus, both pre- and postsynaptic cholinergic mechanisms may contribute to the increased sensitivity to DFP but their relative importance varies with brain region: increased ACh synthesis in the cortex and increased concentrations of mAChR in the striatum and hippocampus.

Acetylcholine↗
PubMed1977

Failure of cycloheximide to alter rate of recovery of temperature following acute DFP treatment.

Cycloheximide, 400 microgram intraventricularly 4 h after a 1 mg/kg i.m. injection of the irreversible anticholinesterase DFP, failed to alter the rate of recovery of temperature to normal. Tolerance to the hypothermic effects of DFP developed at the same rate in cycloheximide-treated rats. These findings suggest that neither recovery from the acute effects of DFP nor tolerance to its chronic effects depends on protein synthesis.

Animals↗
PubMed1977

Development and disappearance of subsensitivity to pilocarpine following a single administration of the irreversible anticholinesterase angent, DFP.

The present study examined the possibility that subsensitivity to pilocarpine might occur following a single injection of the irreversible anticholinesterase agent, DFP. In one experiment male Sprague-Dawley rats were trained to drink from experimental drinking chambers for 1/2 h per day. After establishment of baselines, pilocarpine hydrochloride (8 mg/kg) was injected i.p. 5 min before the drinking session. One week later DFP or the arachis oil vehicle (1 mg/kg) was injected intramuscularly and injections of pilocarpine were given at varying times thereafter. The suppression of water intake by this dose of pilocarpine was unaffected by pretreatment with arachis oil, but was markedly attenuated by pretreatment with DFP. This subsensitivity was first observed on the second day but had largely disappeared by the 14th day. DFP was found to have comparable effects on water intake and brain acetylcholinesterase activity when the injections were separated by 20 days. In a second experiment the hypothermic effects of pilocarpine were found to be reduced in rats acutely treated with DFP. These data establish that subsensitivity to pilocarpine occurs following a single administration of DFP. This subsensitivity could reflect a reduced sensitivity of postsynaptic receptors to acetylcholine, which may partially account for the behavioural recovery of the rats while acetylcholinesterase activity is still markedly depressed.

Acetylcholinesterase↗
PubMed1975

Dipsogenic effects of intra and extracellular thirst stimuli before and after chronic DFP treatment.

The water intake of rats was observed following subcutaneous administration of intra and extracellular thirst stimuli (hypertonic saline, polyethylene glycol, angiotensin, and isoproterenol) before and after chronic treatment with the anticholinesterase agent, diisopropyl fluorophosphate (DFP), and its arachis oil vehicle. Only hypertonic saline and isoproterenol reliably increased water intake in both groups prior to chronic treatment. After chronic treatment hypertonic saline produced the same degree of water intake in the DFP-treated and control animals, but isoproterenol appeared to produce a greater degree of water intake in the DFP-treated than in the control rats. These results suggest that there are no gross disturbances in the mechanisms underlying intra and extracellular thirst stimuli following the development of tolerance to DFP.

Angiotensin II↗