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D H Overstreet

Publications and source records attributed to D H Overstreet.

At least 19 recordsLinked to original sources
PubMed1992

Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism.

The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (greater than 4 g/kg) and preference (greater than 50%) in the FH rats, but low rates of ethanol intake (less than 1.1 g/kg) and preference (less than 20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Maudsley reactive and nonreactive rats differ only in some tasks reflecting emotionality.

The behavior of Maudsley reactive and nonreactive rats, along with that of Wistar controls, was studied using three behavioral tasks which have been associated with emotionality. Consistent with the hypothesis that they are more emotional, the Maudsley reactive rats were more immobile in the forced swim test and spent less time in the open arms of an elevated plus maze than the Maudsley nonreactive or Wistar control rats. However, they learned a two-way active avoidance task just as well as the other two groups. These findings suggest that emotionality is heterogeneous and/or that it is involved to different degrees in the three behavioral tasks.

Animals↗
PubMed1992

The Flinders Sensitive Line exhibits enhanced thermic responsiveness to nicotine relative to the Sprague-Dawley rat.

The Flinders Sensitive Line (FSL) was derived from the Sprague-Dawley rat by selectively breeding animals with heightened sensitivity to an anticholinesterase. The FSL now consistently exhibits enhanced behavioral and physiological responses to muscarinic agonists relative to its progenitor. The authors now report the FSL exhibits enhanced thermic responsiveness to nicotine relative to the Sprague-Dawley rat. The possible relevance of this finding to investigators interested in the disorders of mood is briefly discussed.

Animals↗
PubMed1992

Measurement of temperature in the rat by rectal probe and telemetry yields compatible results.

The change in body temperature of the rat is commonly measured using biotelemetry or the rectal probe. The authors report that the two methods yield qualitatively similar but quantitatively different results in two experiments. In Experiment 1, both methods detected a salicylate-affected reduction in handling-induced hyperthermia. In Experiment 2, both methods were useful in detecting the hypothermia induced by the muscarinic agonist oxotremorine. In both Experiments 1 and 2, measurements of baseline temperature were higher when measured with the rectal probe. Baseline temperature is measured with biotelemetry prior to handling animals, whereas the act of measuring baseline temperature with the rectal probe necessitates handling. The investigators hypothesized that a rise in baseline temperature produced by handling at least partially accounts for the greater hypothermic response obtained in Experiment 2 using measurements obtained with the rectal probe. In Experiment 3, baseline temperature was measured with biotelemetry after animals were handled. Handling produced an increase in baseline temperature. The hypothermic response to oxotremorine was increased when the higher posthandling baseline temperature was used to calculate the hypothermic response of animals. The authors conclude that differences in baseline temperature and hypothermic response obtained with the two methods are related to an effect of handling.

Animals↗
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↗
PubMed1992

Selective breeding for increased cholinergic function: biometrical genetic analysis of muscarinic responses.

Biometric genetic analyses of behavioral and physiologic responses known to be related to muscarinic cholinergic receptors (hypothermia, hypoactivity, inhibited avoidance, and reduced responding for water) were studied in genetic crosses and backcrosses of the Flinders sensitive line (FSL) and Flinders resistant line (FRL) of rats. The FSL rats were more sensitive to the direct muscarinic agonists, arecoline and oxotremorine, and to the indirect agonist, physostigmine, than any other group. The next most sensitive group was the F1 x FSL backcross, followed by the F2, F1, F1 x FRL backcross, and the FRL, in that order. These differences between the genetic groups could be accounted for completely by either solely additive or additive plus dominance genetic factors. When dominance genetic factors contributed to the differences among groups (6 out of 15), the F1 responded like the FRL rats. The variance of the responses measured made it impossible to obtain reliable estimates of the number of genes involved in many instances; when such estimates were possible, several genes (greater than or equal to 3) appeared to be involved. We conclude that muscarinic sensitivity in rats is under genetic control, with the greatest contribution coming from additive genetic factors. Because the FSL rat appears to be a genetic animal model of depression, the finding of several genes influencing muscarinic responses may help account for the difficulties investigators have had in locating a single major gene or biological marker for human depressive disorders.

Analysis of Variance↗
PubMed1992

Ethanol and complement hemolytic activity of selectively bred hypercholinergic rats.

Depression and alcoholism are associated with impaired immune responses. Complement proteins and fragments participate in the induction and modulation of both specific and non-specific immune reactions. This study examined the effect of prolonged ethanol ingestion on complement CH50 levels in two strains of rats, the Flinders Resistant Line (FRL) and the Flinders Sensitive Line (FSL), that differ in cholinergic sensitivity and depressive tendencies. Chronic ethanol exposure given as either the source of drinking fluid or as a liquid diet had a significant inhibition on mean CH50 unit responses in both FSL (41-48%) and FRL (23-24%) rats. The difference in group response to ethanol was confirmed by a significant interaction of ethanol treatment versus group in the two-way ANOVA. The FSL rats appear to be more easily affected than FRLs. Genetic differences in the neurotransmitter systems, therefore, may play a role in susceptibility to immunosuppression resulting from ethanol exposure.

Alcoholism↗
PubMed1991

Diurnal rhythm of core body temperature is phase advanced in a rodent model of depression.

We examined the diurnal rhythm of core body temperature in a strain of rats with an upregulated central muscarinic receptor system. The Flinders-Sensitive Line (FSL) was derived by selectively breeding rats for sensitivity to cholinergic agonists. When compared to control rats, the FSL rats showed a remarkably strong phase advance of the acrophase in body temperature during a standard light-dark schedule. Some patients with some types of depression also show phase advances in a number of circadian rhythms, including temperature. Our finding of a phase advance in a rodent model with a known upregulated muscarinic receptor system is compatible with both the phase advance and the muscarinic overdrive theories of depression. These findings also further validate the usefulness of the FSL rats in the study of depression.

Animals↗
PubMed1991

Clinical and biochemical aspects of depressive disorders: II. Transmitter/receptor theories.

The present document is the second of three parts in a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various receptor/transmitter theories of depressive disorders are discussed in this section. Specifically, data supporting noradrenergic, serotonergic, cholinergic, dopaminergic, GABAergic, and peptidergic theories, as well as interactions between noradrenergic and serotonergic, or cholinergic and catecholaminergic systems are presented. Problems with the data and future directions for research are also discussed. A previous publication, Part I of this review, dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders. A future publication, Part III of this review, discusses treatments for depression and some of the controversies in this field.

Animals↗
PubMed1991

Dopamine sensitivity in rats selectively bred for increases in cholinergic function.

Because of the extensive literature demonstrating an interaction between cholinergic and dopaminergic systems, the Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats, selectively bred for differences in cholinergic function, were tested for differences in dopamine sensitivity. Large differences in sensitivity to dopamine agonists were detected, but the direction depended upon the function: The FSL rats were supersensitive to the hypothermic effects of dopamine agonists, but were subsensitive to the stereotypy-inducing effects. Measurement of dopamine receptors by either standard binding techniques or autoradiography failed to demonstrate any receptor differences in the FSL and FRL rats. Behavioural studies with dopamine antagonists were less clear-cut, but suggested that the FSL rats might be more sensitive to their catalepsy-inducing effects. These findings indicate that the changes in dopamine sensitivity which accompany cholinergic supersensitivity are function-dependent, but are not associated with parallel changes in dopamine receptor concentration.

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

Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats.

The Flinders Sensitive Line (FSL) of rats has been selectively bred to have increased sensitivity to cholinergic agonists. However, these rats exhibit altered responsiveness to a number of noncholinergic agents, such as apomorphine, buspirone and ethanol. This study compared the FSL and control Flinders Resistant Line (FRL) rats in terms of their hyperthermic response to the phencyclidine (PCP) receptor agonist, MK-801 (0.2 mg/kg SC) and their MK-801 binding characteristics. We have found that FSL rats react with a delayed hyperthermia, having a significantly lower hyperthermia for the first 120 min of observation. Thereafter the response does not differ in FSL and FRL rats. Both groups had similar affinities and numbers of [3H]MK-801 binding sites in the hippocampus/cerebral cortex. Pretreatment with scopolamine (1 mg/kg SC) failed to affect MK-801-induced hyperthermia in either line of rats. These findings suggest that selective breeding of FSL rats attenuated the secondary mechanisms involved in the PCP receptor-mediated hyperthermic response. However, by itself cholinergic supersensitivity does not appear to be a major factor in the blunted responsiveness of FSL rats to MK-801.

Animals↗
PubMed1991

Effects of calcium channel inhibitors on the hypothermic response to oxotremorine in normo and hypercholinergic rats.

The Flinders Sensitive Line of rats (FSL) has been selectively bred to have increased sensitivity to cholinergic drugs. Typically, these rats react with twice as great a hypothermic effect to muscarinic agonists such as oxotremorine, as do similarly bred Flinders Resistant Line rats (FRL). We compared the effects of three chemically different calcium channel inhibitors (diltiazem, nicardipine and verapamil) on the hypothermia induced in FRL and FSL rats by oxotremorine (0.2 mg kg-1 s.c.). Each drug was injected i.p. in a dose of 20 mumol kg-1 30 min before oxotremorine. Methylatropine (2 mg kg-1 s.c.) was administered 15 min before oxotremorine to block the peripheral effects of the agonist. The hypothermic effect of oxotremorine in FSL rats was antagonized by nicardipine and diltiazem. In contrast, verapamil failed to influence the hypothermic response in FSL rats. Verapamil significantly (P less than 0.05) augmented oxotremorine hypothermia in FRL rats. Diltiazem and nicardipine were without effect on oxotremorine-induced hypothermia in FRL rats. There were no significant changes in temperature in separate groups of FRL and FSL rats treated with calcium channel inhibitors alone.

Animals↗
PubMed1991

Drug-induced reductions in ethanol intake in alcohol preferring and Fawn-Hooded rats.

The ethanol intake of Fawn-Hooded rats, a serotonin deficient strain, was examined under a two bottle choice between ethanol (10%) and tap water. The Fawn-Hooded rats drank as much ethanol as the alcohol preferring strain of rats (approximately 6 times that of the control Wistar rats), but drank more fluid and ate more. In general, direct and indirect serotonin agonists, reduced ethanol intake to a smaller degree in the Fawn-Hooded rats compared to the P rats. In contrast the centrally acting antimuscarinic scopolamine reduced ethanol intake to a similar degree in the two strains.

Alcohol Drinking↗
PubMed1991

Alterations in the hypothalamic-pituitary-adrenal axis in a proposed animal model of depression with genetic muscarinic supersensitivity.

Rats from the Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL), which have been bred for differences in sensitivity to cholinergic agonists, were killed by decapitation under quiet, nonstressful conditions and the concentrations of corticotropin-releasing factor (CRF) in various brain regions, the concentrations of CRF receptors in the anterior pituitary, and plasma ACTH and corticosterone concentrations were determined. A first study revealed that the cholinergically hypersensitive FSL rats exhibited lower concentrations of CRF in the median eminence, locus ceruleus, and prefrontal cortex, but no such changes in some 13 other brain regions. In this first study, the FSL rats had significantly lower plasma ACTH concentrations. However, there were no differences in plasma corticosterone concentrations between the two groups. A second study confirmed the results of the first study and revealed that the density of anterior pituitary CRF receptor binding sites was elevated in the FSL rats. The observed pattern of alterations in these measures of HPA axis activity suggest that the cholinergically supersensitive FSL rats may possess diminished HPA activity.

Adrenocorticotropic Hormone↗
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↗