Biomedical subjects

D H Overstreet

Publications and source records attributed to D H Overstreet.

At least 37 records · Page 2Linked to original sources

PubMed2000

Combination pharmacotherapy: a mixture of small doses of naltrexone, fluoxetine, and a thyrotropin-releasing hormone analogue reduces alcohol intake in three strains of alcohol-preferring rats.

It is common to treat some diseases with more than one medication simultaneously. Since more than one neurotransmitter system is involved in alcohol-seeking behaviour, then a therapeutic approach that targets more than one system should be more effective in reducing alcohol intake than one addressing a single system. To test this hypothesis, we compared the efficacy of low doses of individual drugs reported to reduce voluntary alcohol drinking to the efficacy of a mixture of these agents at the same low doses in reducing alcohol intake in three strains of alcohol-preferring rats (P, HAD, and Fawn-Hooded). After establishment of a stable baseline for alcohol intake in a continuous access paradigm, each rat received separate single i.p. injections of relatively low doses of either naltrexone (2.0 mg/kg), fluoxetine (1.0 mg/kg), the thyrotropin-releasing hormone analogue TA-0910 (0.2 mg/kg), a mixture of all three drugs, or the vehicle at 09:30. Each rat received all treatments, with an inter-injection washout period of at least 3 days. Alcohol and water intakes were measured at 6 and 24 h, and food intake was measured at 24 h, after the injection. Our results show that individual drugs did not significantly affect food, water, or alcohol intake. However, the mixture significantly reduced alcohol intake in all three strains, but had no effect on food intake. Similar results were obtained when the HAD rats received an oral dose of the individual drugs or the mixture. When P rats were given an i.p. injection of the mixture for 10 consecutive days, there was a continued suppressing effect. These findings show that a combination treatment designed to target simultaneously serotonergic, dopaminergic, and opioidergic systems can reduce alcohol intake, even though the doses of the individual drugs in the mixture are relatively low and ineffective when given singly.

Alcohol Drinking↗

PubMed2000

Rats selectively bred for responsiveness to 5-hydroxytryptamine(1A) receptor stimulation: differences in differential reinforcement of low rate 72-second performance and response to serotonergic drugs.

High (+/-)-8-hydroxy-dipropylaminotetralin HBr (8-OH-DPAT)-sensitive (HDS) rats and low 8-OH-DPAT-sensitive (LDS) rats were selectively bred for differences in sensitivity to the hypothermic effect of the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist 8-OH-DPAT in 30 to 35-day-old rat pups. These rats were trained on the differential reinforcement of low rate 72-s operant schedule. On this schedule, LDS rats had a higher response rate and a lower reinforcement rate than HDS rats. Drugs with primary action on the 5-HT system, 8-OH-DPAT, ketanserin, and fluoxetine, decreased response rate of HDS and LDS rats but increased the reinforcement rate of only the LDS rats. However, a drug with primary action on the norepinephrine system, desipramine, decreased response rate and increased reinforcement rate of HDS and LDS rats, suggesting that norepinephrine function was similar in the two lines of rats. The finding with desipramine indicates that increases in reinforcers on the differential reinforcement of low rate 72-s task are not simply dependent on baseline response or reinforcement rate. We also observed that 8-OH-DPAT engenders a greater hypothermic response in adult (90-day-old) HDS rats than in adult LDS rats. The 5-HT(1A) receptor antagonist WAY-100635 antagonized the hypothermic response. Tissue levels of 8-OH-DPAT from several brain regions in LDS and HDS rats did not differ from each other at either 15- or 30-min postinjection. Because the LDS and HDS rats have different responses to 5-HT-acting drugs, these rats may be useful for studying the role of the serotonergic system in depression.

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

PubMed2000

P rats develop physical dependence on alcohol via voluntary drinking: changes in seizure thresholds, anxiety, and patterns of alcohol drinking.

BACKGROUND: It has been proposed that the alcohol-preferring P rat meets many of the criteria for an animal model of alcoholism. However, the development of alcohol dependence has not been explored in rats that self-administer ethanol for less than 15-20 weeks. The present study investigated the development of physical dependence upon alcohol after 2-6 weeks of voluntary alcohol intake. Changes in bicuculline-induced seizure thresholds, microstructure of alcohol drinking, and anxiety-related behavior were used as indices of alcohol dependence. In addition, we evaluated the microstructure of alcohol drinking associated with the development of physical dependence upon alcohol. METHODS: Alcohol (10% ethanol solution) was measured in graduated drinking tubes with both alcohol and water available continuously. Microstructure of alcohol intake was monitored by a computerized drinkometer. Physical dependence upon alcohol was determined by measuring bicuculline-induced seizure thresholds after alcohol withdrawal. Anxiety-related behavior of P rats after alcohol withdrawal was determined by the social interaction and elevated plus maze tests. RESULTS: Initial alcohol intake in the alcohol-preferring P rat was relatively modest (3.9 +/- 0.4 g/kg/day). Four days of forced alcohol exposure (initiation) followed by 6 weeks of voluntary drinking resulted in an increase of alcohol intake to 5.5 +/- 0.2 g/kg/day. Ethanol self-administration for 6 weeks, but not for 2 or 4 weeks, produced a significant reduction (30%; p < 0.05) in bicuculline-induced seizure thresholds during alcohol withdrawal. Alterations in the microstructure of alcohol intake (i.e., 90% increase in the size of alcohol drinking bouts compared to the baseline [p < 0.001] with no change in bout frequency) were associated with the development of alcohol dependence. Termination of alcohol intake after 6 weeks of voluntary alcohol consumption resulted in increased anxiety according to both the social interaction and elevated plus maze tests. CONCLUSIONS: The results of this study indicate that 6 weeks of voluntary alcohol intake are sufficient for the development of physical dependence upon alcohol in the alcohol-preferring P rats as measured by susceptibility to bicuculline-induced seizures. This time is much shorter than the 15-20 weeks reported earlier. Development of physical dependence to alcohol was associated with an increase in daily alcohol intake (40% over the baseline), an increase in alcohol intake during each drinking bout (90% over the baseline), and elevated anxiety during alcohol withdrawal.

Alcohol Drinking↗

PubMed1999

The flinders sensitive line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17beta-estradiol.

The possible link between estrogen and serotonin (5-HT) in depression was investigated using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rats, in comparison to control Flinders Resistant Line rats. The mRNA levels of the estrogen receptor (ER) alpha and beta subtypes and the 5-HT(1A) and 5-HT(2A) receptors were analyzed in several limbic-related areas of ovariectomized FSL and FRL rats treated with 17beta-estradiol (0.15 microg/g) or vehicle. The FSL animals were shown to express significantly lower levels of the 5-HT(2A) receptor transcripts in the perirhinal cortex, piriform cortex, and medial anterodorsal amygdala and higher levels in the CA 2-3 region of the hippocampus. The only significant difference between the rat lines in ER mRNA expression was found in the medial posterodorsal amygdala, where the FSL rats showed lower ERalpha expression levels. Overall, estradiol treatment increased 5-HT(2A) and decreased 5-HT(1A) receptor mRNA levels in several of the examined regions of both lines. Thus, in many areas, estradiol was found to regulate the 5-HT receptor mRNA expression in the opposite direction to the alterations found in the FSL rats. These findings further support the implication of 5-HT receptors, in particular the 5-HT(2A) subtype, in the etiology of affective disorders. Moreover, the ability of estradiol to regulate the expression of the 5-HT(1A) and 5-HT(2A) receptor genes might account for the reported influence of gonadal hormones in mood and depression.

Animals↗

PubMed1999

Alterations in neuropeptide Y levels and Y1 binding sites in the Flinders Sensitive Line rats, a genetic animal model of depression.

Previously, we observed specific alterations of neuropeptide Y (NPY) and Y1 receptor mRNA expression in discrete regions of the Flinders Sensitive Line rats (FSL), an animal model of depression. In order to clarify the correlation between mRNA expression and protein content, radioimmunoassay and receptor autoradiography were currently performed. In the FSL rats, NPY-like immunoreactivity (NPY-LI) was decreased in the hippocampal CA region, while Y1 binding sites were increased; NPY-LI was increased in the arcuate nucleus. Fluoxetine treatment elevated NPY-LI in the arcuate and anterior cingulate cortex and increased Y1 binding sites in the medial amygdala and occipital cortex in both strains. No differences were found regarding the Y2 binding sites. The results demonstrate a good correlation between NPY peptide and mRNA expression, and sustain the possible involvement of NPY and Y1 receptors in depression.

Amygdala↗

PubMed1999

Increased catecholamine levels in specific brain regions of a rat model of depression: normalization by chronic antidepressant treatment.

Alterations in catecholamine levels and neurotransmission have been shown in depressive disorders. However, the exact sites of alterations and the relation between these alterations to the etiology of the disease and the effectiveness of antidepressant therapy are poorly understood. In this study, catecholamine levels and metabolism were measured in specific brain regions of a genetic rat model of depression [Flinders Sensitive Line (FSL) rats], and compared to normal Sprague-Dawley rats. Norepinephrine levels were found to be two to threefold higher in the nucleus accumbens, prefrontal cortex, hippocampus and median raphe nucleus of FSL rats as compared with control Sprague-Dawley rats. Dopamine levels were sixfold higher in the nucleus accumbens and twofold higher in the striatum, hippocampus and hypothalamus of FSL rats as compared with control Sprague-Dawley rats. After chronic treatment with the antidepressant desipramine, the immobility score in a swim test, as a measure of a behavioral deficit, as well as catecholamine levels of the FSL rats became normalized, but these parameters in the control rats did not change. The results indicate that the behavioral deficits expressed in the FSL model for depression correlate with increased catecholamine levels in specific brain sites, and further suggest the FSL rats as a model for elucidation of the molecular mechanism of clinically used antidepressant drugs.

Adrenergic Uptake Inhibitors↗

PubMed1999

Antidepressant effects of nicotine in an animal model of depression.

Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg s.c.) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the alpha4beta2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the alpha7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders.

Alkaloids↗

PubMed1999

Antidepressant effect of ingested nicotine in female rats of Flinders resistant and sensitive lines.

Both major depression and depressive symptoms are associated with a high rate of nicotine dependence, and a history of major depression has an adverse impact on smoking cessation. The main objective of this study was to investigate whether continuous ingestion of nicotine affects indices of depressive behavior in the rat. We compared cholinergic- and serotonergic-hypersensitive Flinders Sensitive Line rats (FSL), a genetic animal model of depression, with their control counterparts, Flinders Resistant Line rats (FRL). Female rats of both lines were allowed access to a solution of nicotine bitartrate (100 microg/mL) in tap water for 14 days. Subsequent behavioral testing revealed striking effects of continuous ingestion of nicotine on depressive-like behavior of both lines. FSL and FRL rats that ingested nicotine for 14 days displayed less immobility in the 10-min forced-swim test (an index of depressive-like behavior) relative to the animals of both lines that were not exposed to nicotine or exposed to nicotine for shorter periods of time. This finding indicates that ingested nicotine has antidepressant properties that are independent of the genetic difference between FSL and FRL female rats. Animal studies on nicotine ingestion and withdrawal may become an important source of insights into the comorbidity of depression and nicotine self-administration.

Animals↗

PubMed1999

Ontogeny of muscarinic cholinergic supersensitivity in the Flinders Sensitive Line rat.

The present study examined the ontogeny of muscarinic sensitivity in the Flinders Sensitive Line (FSL) rat, a model for human depression that was selectively bred for increased cholinergic function. In most cases, the FSL rats were more sensitive to the muscarinic agonists, oxotremorine and oxotremorine-M. early postnatally [13 days postpartum (P13)], suggesting that muscarinic supersensitivity is an inherent characteristic of FSL rats. The emergence of increased sensitivity to muscarinic agonists in FSL rats did not correlate with either the emergence of subsensitivity to the muscarinic antagonist, scopolamine, at P60 or with increased muscarinic (M1 or M2) receptor density. Relative to FRL rats, FSL rats did not exhibit increases in muscarinic receptor binding until P32 in the striatum and hippocampus and P120 in the hypothalamus. These results are consistent with the suggestions that (a) muscarinic supersensitivity, which appears early in development, may be associated with depressive disorders, and (b) the differences in muscarinic sensitivity early postnatally cannot be accounted for by an increase in the number of muscarinic receptors, per se.

Animals↗

PubMed1999

Chronic fluoxetine in tests of anxiety in rat lines selectively bred for differential 5-HT1A receptor function.

Selective breeding for high and low sensitivity to the hypothermic response induced by the 5-HT1A receptor agonist 8- OH-DPAT has established two lines of rat (HDS and LDS, respectively) whose behavior differs in a model of depression and in the social interaction test of anxiety. The HDS line has a higher level of anxiety and, furthermore, does not display the usual anxiogenic response to intrahippocampal administration of 8-OH-DPAT. It was therefore hypothesized that this line of rat might be a useful model of high trait anxiety with a susceptibility to depression. We thus investigated whether chronic treatment with fluoxetine would result in an anxiolytic effect in the social interaction test in the LDS and HDS lines of rat. In both lines, acute fluoxetine (10 mg/kg) produced an anxiogenic effect in the social interaction test; when rats were tested 24 h after 14 days of fluoxetine treatment there were no anxiolytic effects in either line. In the social interaction test, chronic fluoxetine treatment did not change either the anxiogenic effect of 8-OH-DPAT (100 ng) injected bilaterally into the dorsal hippocampus in the LDS line or the lack of response in the HDS line. In the elevated plus-maze, chronic fluoxetine treatment resulted in a significant anxiogenic effect in the HDS line, but was without effect in the LDS line. Intrahippocampal 8-OH-DPAT was without effect in the plus-maze in either line. These results suggest that chronic treatment with fluoxetine did not modify the hippocampal 5-HT1A receptor in either line. The anxiogenic effects observed in the plus-maze in the HDS line after chronic fluoxetine might relate to line differences in 5-HT1A receptors in other brain regions.

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

PubMed1999

Links between multiple chemical sensitivity and asthma in a rat model of cholinergic hypersensitivity: a brief review.

Individuals with multiple chemical sensitivity (MCS) also commonly report symptoms of asthma, but, as far as we have been able to determine, no one has yet suggested that an abnormal cholinergic system may provide the link between asthma and MCS. The present brief review provides evidence for such a link by summarizing recent findings in a genetic animal model of cholinergic hyperresponsiveness. The Flinders Sensitive Line (FSL) rats were developed by selective breeding for increased responses to an anticholinesterase agent similar to commonly used organophosphate pesticides. Relative to their control line, the Flinders Resistant Line (FRL) rats, the FSL rats are more sensitive to drugs that stimulate acetylcholine receptors, alcohol, diazepam, and drugs that have a selective effect on dopamine or serotonin receptors. These findings raise the possibility that the FSL rats may resemble individuals with MCS. Hyperresponsiveness of the airways is a hallmark of asthma. The procedure known as whole-body plethysmography, where breathing can be monitored in freely moving animals, was employed to study the FSL and FRL rats. The FSL rats exhibited a greater index of bronchoconstriction than the FRL rats in response to both a cholinergic agonist and an allergen challenge. Thus, the FSL rats are more sensitive both to a variety of drugs unrelated to the cholinergic system and to cholinergic- and allergen-induced bronchoconstriction. An abnormal cholinergic system may therefore contribute to both MCS and asthma.

Animals↗

PubMed1999

Suppression of alcohol intake by chronic naloxone treatment in P rats: tolerance development and elevation of opiate receptor binding.

BACKGROUND: This study was planned to determine the feasibility of using a slow release naloxone preparation to treat alcoholism, because compliance with medication is a significant problem in alcoholics. METHODS: Experiments were performed in alcohol-preferring P rats maintained either on continuous access or on limited access (1 hr/day) to alcohol with water and food provided ad libitum. Naloxone (Nx) was administered either by twice daily subcutaneous injections or by slow release (1.1 mg/kg/hr) osmotic minipump. In limited access experiments, Nx was injected immediately before access to alcohol. RESULTS: An initial experiment estimated the dose-effect curve for Nx subcutaneous suppression on alcohol intake. Nx (2.5-20 mg/kg) had a stronger effect during the first 2 hr after injection (ED50 = 2.1 mg/kg); however, the effect was more modest on 24-hr consumption. Similar results were found with chronic Nx treatment. Low doses of Nx (0.5 and 2.0 mg/kg) injected immediately before limited access to alcohol produced almost complete suppression of alcohol intake for at least 14 consecutive days. However, 14 days of treatment with 26 mg/kg/day by minipump or injection produced an initial 50% suppression of 24-hr alcohol intake with the gradual development of tolerance. An acute challenge with Nx immediately after the pumps were scheduled to be empty provided additional evidence of tolerance development in chronically Nx-treated rats. Brain micro-opiate receptors, estimated autoradiographically by using the ligand [3H][D-Ala2,N-Me-Phe4, Gly-ol5][tyrosyl-3,5-3H]-enkephalin, showed that rats chronically exposed to Nx and showing tolerance to Nx suppression of drinking exhibited 17% to 250% increases in [3H][D-Ala2,N-Me-Phe4, Gly-ol5][tyrosyl-3,5-3H]-enkephalin binding. CONCLUSIONS: High doses of Nx are required to suppress continuous access alcohol consumption in P rats, and tolerance develops to the ethanol consumption-suppressing effect of Nx that may be related to increases in micro-opiate receptors.

Alcohol Drinking↗

PubMed1998

Altered gene expression for catecholamine biosynthetic enzymes and stress response in rat genetic model of depression.

Although stress is a major contributory factor in the development of depression, the relationship between stress and depression is still unclear. In this study, we evaluated basal mRNA levels of several genes involved in neurotransmitter biosynthesis and the effect of stress in Flinder's Sensitive Line (FSL), a genetic rat model of depression. In adrenals, basal levels of tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT) and GTP cyclohydrolase I (GTPCH) mRNAs were markedly elevated in FSL rats compared to the control strain. As opposed to control strain, immobilization stress (IMO) to FSL rats, did not further raise DBH, PNMT or GTPCH mRNAs and had relatively mild effect on TH. In contrast to enzymes involved in catecholamine biosynthesis, basal NPY and its response to IMO were unchanged in FSL rats. In the brain, the two major dopaminergic nuclei displayed differences. In substantia nigra, TH mRNA levels were similar in both strains, and elevated by IMO only in FSL rats. In ventral tegmental area in FSL rats, TH mRNA was 2-fold higher than in the control strain and not further elevated by IMO. These high basal mRNA levels and abnormal response to stress in several catecholaminergic cell types in FSL rats may be related to the manifestations of depression.

Animals↗

PubMed1998

Alterations in neuropeptide Y and Y1 receptor mRNA expression in brains from an animal model of depression: region specific adaptation after fluoxetine treatment.

To investigate the possible link between neuropeptide Y (NPY) and depression, we analyzed NPY and its receptors in different limbic-related regions in the Flinder sensitive line (FSL), a genetic animal model of depression. In situ hybridization histochemistry was used to measure mRNA expression levels of NPY and NPY receptors, Y1 and Y2, in the FSL as compared to the control Flinder resistant Line rats (FRL). In the FSL rats, NPY mRNA expression levels were significantly decreased in the nucleus accumbens and CA regions, but increased in the arcuate nucleus and anterior cingulate cortex. Y1 receptor mRNA expression was decreased in different cortical regions (retrosplenial, anterior cingulate, and occipital) and in the hippocampal dentate gyrus. Y2 mRNA expression levels did not differ between FSL and FRL animals. The effect of the antidepressant drug fluoxetine (a serotonin reuptake inhibitor) in the two rat strains was also studied. There was an increase of the NPY mRNA hybridization signal in the arcuate nucleus of both strains following the antidepressant treatment (10 micromol/kg; daily for 14 days). However, in other brain regions, fluoxetine administration caused a differential effect on the induction of NPY-related genes in the two rat strains: in the CA region and dentate gyrus NPY mRNA expression was increased in the FSL, but decreased in the FRL. In contrast, Y1 mRNA levels tended to be decreased by fluoxetine in the nucleus accumbens of the FSL rats, but increased in the FRL. These findings suggest an involvement of the Y1, but not the Y2, receptor subtype in depressive disorder. Overall, the results appear to sustain the importance of the FSL rats as an animal model of depression in view of the impairment of NPY genes and the ability of fluoxetine treatment to normalize NPY-related gene expression selectively in this strain.

Animals↗

PubMed1998

Brain 5-HT1A receptor autoradiography and hypothermic responses in rats bred for differences in 8-OH-DPAT sensitivity.

Three rat lines were selectively bred for high (HDS), random (RDS), or low (LDS) hypothermic responses to the specific 5-HT1A receptor agonist 8-OH-DPAT. Forty-five minutes after 8-OH-DPAT administration (0.5 mg/kg), body temperatures dropped 3-5 degrees C in HDS rats, yet this dose produced only about 1.2 degrees C and 0.7 degree C drops in RDS and LDS rats, respectively. To investigate the relationship of body temperature of 5-HT1A receptor binding sites, autoradiographic analyses of [3H]8-OH-DPAT binding to 5-HT1A receptors in brains of these rats were conducted. Significant differences in binding were found in specific limbic cortical projection sites, with the HDS line having the greatest density of sites. Body temperature responses correlated significantly with [3H]8-OH-DPAT receptor binding in only a few areas of frontal cortex. Binding in many other brain regions, including the anterior and posterior hypothalami (regions long associated with body temperature regulation) and the raphe showed no significant differences among the lines. [3H]Ketanserin binding to cortical 5-HT2 receptors did not differ among the lines, except in the cingulate and superficial frontal cortices where HDS exhibited higher binding. These data suggest that differences in 5-HT1A receptor number may contribute to the exaggerated hypothermic response to 8-OH-DPAT in HDS rats. These studies also suggest that genetic regulation of receptor density may be brain region specific which should encourage future studies of the mechanisms of 5-HT1A receptor activity in brain and the action of drugs affecting this receptor.

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

PubMed1998

Effects of melatonin receptor ligands on swim test immobility.

The Flinders Sensitive Line (FSL) rats have been proposed as a genetic animal model of depression because their innately high immobility in the forced swim test is counteracted by antidepressants. This model was used to test the acute and chronic effects of two novel compounds which have either an agonist or antagonist-like effect at melatonin receptors. In the acute study FSL and control Flinders Resistant Line (FRL) rats were unaffected by either the agonist S 20304 (1 or 20 mg/kg) or the antagonist S 20928 (1 or 10 mg/kg) given 1 h prior to a single 5 min swim test. In the chronic study a reduction in immobility in the FSL rats at the highest dose of the agonist was the only significant drug effect. These findings suggest that the melatonin receptor agonist S 20304 may have antidepressant potential.

Animals↗

PubMed1998

Genetically transmitted cholinergic hyperresponsiveness predisposes to experimental asthma.

The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.

Airway Obstruction↗

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↗