Biomedical subjects

J F McElroy

Publications and source records attributed to J F McElroy.

At least 19 recordsLinked to original sources

PubMed1994

Piperidinyltetralin sigma ligands.

Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whether restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses and the structure-activity relationships of these compounds are reported herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po).

Aggression↗

PubMed1994

Discriminative stimulus properties of 7-OH-DPAT, a dopamine D3-selective receptor ligand.

7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) is a high affinity and selective ligand at dopamine D3 receptors. Rats were trained to discriminate 7-OH-DPAT (0.05 mg/kg) from drug vehicle using a food-reinforced (FR 10) two-lever operant procedure. Six out of nine rats learned to discriminate 7-OH-DPAT, requiring a mean of 29 training sessions. After the training dose was increased to 0.10 mg/kg the remaining three rats reached discrimination performance criterion. The 7-OH-DPAT stimulus was dose-dependent. Doses of 0.01, 0.03, 0.056, and 0.1 mg/kg 7-OH-DPAT produced 0, 11, 78, and 100% drug-correct lever selection, respectively, with the ED50 value calculated to be 0.038 mg/kg. These results demonstrate that the D3-selective ligand 7-OH-DPAT can control differential operant responding in rats on the basis of its discriminative stimulus properties.

Animals↗

PubMed1992

Novel piperidine sigma receptor ligands as potential antipsychotic drugs.

sigma receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine sigma ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for sigma sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these sigma ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.

Animals↗

PubMed1991

Effects of ovariectomy on thermogenesis in brown adipose tissue and liver in Syrian hamsters.

Weight gain in ovariectomized Syrian hamsters occurs without increased food intake, which suggests that metabolic efficiency may be enhanced through a reduction in energy expenditure. We examined the effect of ovariectomy on metabolic activity in brown adipose tissue and liver. Four groups of hamsters (n = 13, each) were killed 0, 2, 4, or 16 weeks following ovariectomy. Ovariectomized hamsters rapidly gained weight without overeating. Body weights stabilized after 8 weeks and remained 12-17% above sham-operated control weights for the duration of the experiment. Weight gain in the hamsters ovariectomized for 16 weeks was characterized by significant increases in retroperitoneal white adipose tissue weight and carcass lipid content. Similar trends were seen in 2-week and 4-week ovariectomized animals. There were no differences in interscapular brown adipose tissue weight, protein content, DNA content, or norepinephrine (NE) content among sham-operated and 2-, 4-, or 16-week ovariectomized hamsters, indicating that ovariectomy had no effect on brown adipose tissue growth. Similarly, there was no difference in either sympathetic nervous system activity (estimated by the rate of NE turnover) or mitochondrial GDP binding among the four groups of hamsters. In contrast, hepatic cytochrome P-450 activity was significantly reduced 2, 4, and 16 weeks after ovariectomy. These results suggest that reduced thermogenic activity in liver, but not in brown adipose tissue, could contribute to the weight gain in Syrian hamsters after ovariectomy.

Adipose Tissue, Brown↗

PubMed1989

Effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance behavior in rats.

The acute effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance responding in rats were examined. Clenbuterol (0.01-3.0 mg/kg), salbutamol (0.01-30 mg/kg), and prenalterol (30-300 mg/kg) suppressed avoidance responding in a dose-dependent manner at doses that did not produce escape failures. For comparative purposes, the effects of the tricyclic antidepressant desipramine (1.0-30 mg/kg) and the antipsychotic haloperidol (0.03-0.3 mg/kg) were similarly assessed. Both compounds suppressed avoidance responding in a dose-dependent manner. Only haloperidol (0.3 mg/kg) produced escape failures. Administered alone, the beta adrenergic antagonist propranolol (1.0 and 10 mg/kg) did not affect avoidance behavior. When administered prior to clenbuterol (0.1 mg/kg), salbutamol (1.0 mg/kg), or prenalterol (100 mg/kg), propranolol antagonized the beta adrenergic agonist-induced suppression of avoidance responding. The suppressive effect of desipramine (3.0 mg/kg) on avoidance performance only tended to be attenuated by propranolol. Propranolol had no effect on the ability of haloperidol (0.1 mg/kg) to reduce avoidance responding. These results suggest that the effects of the beta adrenergic agonists clenbuterol, salbutamol, and prenalterol on discrete trial avoidance behavior are mediated, in part, through agonist interactions with beta adrenergic receptors.

Adrenergic beta-Agonists↗

PubMed1988

Discriminative stimulus properties of clenbuterol: evidence for beta adrenergic involvement.

Thirty rats were trained to discriminate the centrally acting beta adrenergic agonist clenbuterol (0.1 mg/kg) from saline using a water-reinforced (fixed-ratio 10 schedule) two-lever operant task. Discrimination acquisition required a mean +/- S.E.M. of 42 +/- 7 training sessions (median of 26 training sessions). The clenbuterol stimulus was dose-dependent (ED50 = 0.03 mg/kg) and stereoselective, and had a rapid onset (5 min) and a duration of approximately 1 hr. The beta adrenergic antagonist propranolol fully antagonized the clenbuterol discriminative stimulus (IC50 = 0.18 mg/kg). Other beta adrenergic agonists such as SOM 1122 (ED50 = 0.01 mg/kg), zinterol (ED50 = 0.03 mg/kg), salbutamol (ED50 = 0.23 mg/kg) and prenalterol (ED50 = 1.91 mg/kg) substituted for clenbuterol. The monoamine uptake inhibitor despiramine (ED50 = 2.25 mg/kg), the psychomotor stimulants amphetamine (ED50 = 0.33 mg/kg) and pentylenetetrazol (ED50 = 0.31 mg/kg), and the dopamine receptor antagonists haloperidol (ED50 = 0.08 mg/kg) and chlorpromazine (ED50 = 2.32 mg/kg) similarly substituted for clenbuterol. However, chlordiazepoxide, pentobarbital, fentanyl, cocaine and fenfluramine produced little or no clenbuterol lever selection up to doses that decreased response rate markedly. The ability of SOM 1122, zinterol, salbutamol, despiramine, amphetamine, pentylenetetrazol and haloperiol to substitute for the clenbuterol stimulus was antagonized by prior treatment with propranolol. Taken together, these results suggest that the discriminative stimulus properties of clenbuterol are mediated, at least in part, through an interaction with beta adrenergic receptors. The same drugs also were assayed for in vitro inhibition of [125I]iodopindolol binding to beta adrenergic receptor preparations of rat cerebral cortex and cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗

PubMed1987

Comparison of the effects of chlordiazepoxide and CL 218,872 on serum corticosterone concentrations in rats.

Fifteen minute exposure to a novel environment plus 120 dB sound stimulation produced a three-fold increase in serum corticosterone concentrations in rats. A low dose of intraperitoneally (IP) administered chlordiazepoxide (CDP) (5 mg/kg) attenuated this response, whereas a higher dose (20 mg/kg) elevated corticosterone concentrations in rats not subjected to sound stress. Parallel results were obtained after intracerebroventricular (ICV) drug administration, with a low dose of CDP (5 micrograms) reducing the sound stress response and higher doses (25 and 50 micrograms) increasing corticosterone concentrations in unstressed animals. Thus, despite the presence of benzodiazepine (BDZ) receptors at every level of the hypothalamic-pituitary-adrenocortical axis, it appears that BDZs alter the activity of this system via an interaction with BDZ receptors in brain. CL 218,872 (2.5-20 mg/kg), a novel non-BDZ anxiolytic compound, did not attenuate the corticosterone elevation produced by sound stimulation, and also failed to alter baseline corticosterone concentrations in unstressed animals. The fact that CL 218,872 is a selective agonist for brain Type I BDZ receptors suggests that BDZs are not influencing corticosterone secretion through an interaction with this BDZ receptor subtype. Furthermore, these results indicate that stress (as measured by pituitary-adrenocortical activation) can be dissociated from anxiety (as measured by conflict paradigms), thus challenging the validity of the corticosteroid stress test as a screening procedure for anxiolytic activity.

Animals↗

PubMed1987

Short- and long-term effects of ovariectomy on food intake, body weight, carcass composition, and brown adipose tissue in rats.

This experiment examined both the short-term and the long-term effects of ovariectomy on brown adipose tissue growth and function in rats to determine if reduced brown adipose tissue thermogenesis might contribute to the weight gain and adiposity. Brown adipose tissue function was assessed by measuring sympathetic nervous system activity (estimated by the rate of norepinephrine turnover) and mitochondrial proton conductance (estimated by specific GDP binding) in interscapular brown adipose tissue. Rats (n = 12 per group) were killed 0 (sham), 1, 2, 4, and 12 weeks after ovariectomy. During the first five weeks after ovariectomy rats overrate and rapidly gained weight. The weight gain was due to increases in all carcass components. Five weeks after ovariectomy food intake returned to control levels, and body weights stabilized 12-16% above sham-operated control weights for the duration of the experiment. Between week 4 and week 12 after surgery there was a redistribution of carcass composition, with decreases in carcass water and fat-free dry weights offset by a further increase in total carcass lipid. Brown adipose tissue pads were heavier in the 1-, 2-, and 4-week ovariectomy groups, but only in the 4-week group was the increase statistically significant. Brown adipose tissue protein, DNA, and norepinephrine content was unchanged 1-, 2-, 4-, or 12-weeks after ovariectomy. There was no difference in either the rate of norepinephrine turnover or specific mitochondrial GDP binding between sham-operated and 1-, 2-, 4-, or 12-week ovariectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗

PubMed1986

A comparison between chlordiazepoxide and CL 218,872, a synthetic non-benzodiazepine ligand for benzodiazepine receptors, on serotonin and catecholamine turnover in brain.

Serotonin (5-HT) and catecholamine (CA) turnover rates in midbrain-hindbrain were investigated in rats treated with the benzodiazepine chlordiazepoxide (CDP) or with the anxiolytic triazolopyridazine CL 218,872. A single injection of CDP (2.5-20 mg/kg) decreased 5-HT but not CA turnover rates. Seven daily CDP injections decreased the turnover rates of both 5-HT and CA. In contrast, neither acute nor chronic administration of CL 218,872 (2.5-20 mg/kg) altered baseline turnover rates of 5-HT or CA. Since CL 218,872 has a selective affinity for Type I benzodiazepine receptors, these results suggest that stimulation of Type I receptors is not sufficient to decrease 5-HT or CA turnover rates in midbrain-hindbrain. More importantly, these results question the long-held belief that benzodiazepines exert their anxiolytic and depressant effects through reductions in 5-HT and CA turnover respectively.

5-Hydroxytryptophan↗

PubMed1986

Short photoperiod stimulates brown adipose tissue growth and thermogenesis but not norepinephrine turnover in Syrian hamsters.

This experiment examined the effect of short photoperiod on food intake, body weight, carcass composition, and brown adipose tissue (BAT) activity in female Syrian hamsters (Mesocricetus auratus). BAT function was assessed by measuring sympathetic nervous system (SNS) activity in BAT (estimated by the rate of norepinephrine (NE) turnover), BAT mitochondrial content (estimated by cytochrome c oxidase activity), and BAT mitochondrial proton conductance (estimated by guanosine-5'-diphosphate (GDP) binding to isolated BAT mitochondria). Food intake and body weight were both increased in short photoperiod-housed hamsters (8-hr light, 16-hr dark; LD 8:16) when compared to those of the long photoperiod-housed controls (LD 16:8). The weight gain was entirely due to an increase in carcass lipid. Interscapular BAT (IBAT) pads from short photoperiod-housed hamsters were 53% heavier and contained comparably more protein and DNA. Short photoperiod produced a 118% increase in BAT cytochrome c oxidase activity and a 41% increase in specific mitochondrial GDP binding. Whether expressed per mg wet tissue or per pad, neither the endogenous concentration of NE nor its rate of turnover were changed by short photoperiod exposure. These results demonstrate a dissociation of BAT thermogenesis from SNS activity in BAT from short photoperiod-housed Syrian hamsters.

Acclimatization↗

PubMed1986

Effects of diet and photoperiod on NE turnover and GDP binding in Siberian hamster brown adipose tissue.

This experiment examined the effects of diet and photoperiod on food intake, body weight, and brown adipose tissue (BAT) activity in female Siberian hamsters (Phodopus sungorus sungorus). BAT function was assessed by measuring both the sympathetic nervous system activity of BAT [estimated by the rate of norepinephrine (NE) turnover] and BAT thermogenic activity (estimated by GDP binding to BAT mitochondria). Nineteen weeks of high-fat feeding in long photoperiod [16:8 light-dark cycle (LD)] caused a 20% increase in food intake but did not affect body weight. Both NE turnover rate and GDP binding in interscapular BAT (IBAT) were increased four- to eightfold relative to that from chow-fed controls. Thus it appears that in Siberian hamsters BAT can serve the same energy-dissipating function during diet-induced overeating previously established in rats and mice. Nineteen-week exposure to a short photoperiod (LD 8:16) produced a reduction in body weight but did not affect food intake. Both NE turnover rate and GDP binding in IBAT were increased two- to fourfold relative to that from long-photoperiod controls. Thus it appears that in Siberian hamsters the photoperiod-induced improvements in thermogenic capacity are mediated via the same mechanisms as are cold- or diet-induced thermogenesis.

Adipose Tissue, Brown↗

PubMed1986

Dissociation of sympathetic and thermogenic activity in brown fat of Syrian hamsters.

Syrian hamsters (Mesocricetus auratus) were fed a high-fat (HF) diet for up to 16 wk. Sympathetic and thermogenic activities in their brown adipose tissue (BAT) were assessed by measuring norepinephrine content and turnover and mitochondrial GDP binding and cytochrome c oxidase activity. Chronic ingestion of the HF diet resulted in significant increases in carcass lipid and interscapular BAT wet weight by the end of the second week. HF-fed hamsters were slightly hyperphagic during the first 2 wk of HF feeding only. Significant weight gains persisted beyond the period of hyperphagia. Hypertrophy of interscapular BAT after 16 wk on the HF diet was accompanied by increases in protein and DNA content, indicating growth of functional tissue. Norepinephrine turnover and content in BAT were decreased throughout the entire period of HF feeding, regardless of changes in caloric intake or body weight. Mitochondrial cytochrome c oxidase activity and GDP binding were increased after 16 wk on the HF diet, a time when the HF-fed animals were obese but not hyperphagic. These results demonstrate a dissociation of BAT thermogenesis from sympathetic activity in the tissue. It appears that sympathetic nervous system activity in BAT was suppressed by the HF diet, whereas thermogenic activity of the tissue was activated when the hamsters became obese.

Adipose Tissue, Brown↗

PubMed1986

Some catecholamine inhibitors do not cause accumulation of nuclear estrogen receptors in rat hypothalamus and anterior pituitary gland.

We have recently shown that the dopamine-beta-hydroxylase inhibitor, U-14,624, decreases the concentration of cytosol estrogen receptors in the mediobasal hypothalamus (MBH) and anterior pituitary gland (AP) in ovariectomized rats, but that it also causes cell nuclear accumulation of estrogen receptors. We tried to determine if this is the mechanism by which other catecholaminergic inhibitors decrease the concentration of cytosol estrogen receptors in either the MBH or AP. The previously reported decrease in the concentration of cytosol estrogen receptors in AP by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine was confirmed. Also, the decrease in the concentration of cytosol estrogen receptors in MBH after treatment with the dopamine-beta-hydroxylase inhibitors, diethyldithiocarbamate and FLA 63 was demonstrated. In no case was an increase in the concentration of nuclear estrogen receptor accumulation detected after treatment with the drugs. Results of assays of norepinephrine and dopamine levels in MBH after the various treatments suggest that, at the dosage used, U-14,624 has a greater effect on norepinephrine and dopamine levels that the other dopamine-beta-hydroxylase inhibitors. The results of these experiments suggest that inhibitors of dopamine-beta-hydroxylase and tyrosine hydroxylase cause decreases in the concentration of cytosol estrogen receptors in either the MBH or AP that are not referable to increased cell nuclear accumulation of estrogen receptors.

Animals↗

PubMed1985

A comparison between chlordiazepoxide and CL 218,872--a synthetic nonbenzodiazepine ligand for benzodiazepine receptors on spontaneous locomotor activity in rats.

Spontaneous locomotor activity was investigated in rats treated with chlordiazepoxide (CDP) or CL 218,872, a synthetic nonbenzodiazepine ligand for benzodiazepine receptors. Acute administration of CDP (2.5 mg/kg) increased activity, whereas a higher dose (10 mg/kg) decreased activity. Acute injection of CL 218,872 (2.5-10 mg/kg) produced a significant dose-dependent suppression of locomotor activity, a finding at variance with a previous report that anxiolytic doses of CL 218,872 are devoid of depressant side effects. Chronic pretreatment with CDP or CL 218,872 (10 mg/kg daily for 6 days) produced a tolerance to the sedative effect of CDP (10 mg/kg), but not to the activity suppressant action of CL 218,872 (10 mg/kg).

Animals↗

PubMed1984

Serotonergic stimulation of pituitary-adrenocortical activity in rats: evidence for multiple sites of action.

5-Hydroxytryptophan (5-HTP) elevated serum corticosterone concentrations when administered either intraperitoneally (i.p.) or intraventricularly. Inhibition of aromatic L-amino acid decarboxylase outside of the blood-brain barrier antagonized the corticosterone response, but only when the 5-HTP was given i.p. Stimulation of the pituitary-adrenocortical system by fenfluramine was not affected by 5,7-dihydroxytryptamine pretreatment, whereas the stimulation produced by quipazine administration was blocked by lesions of the basomedial hypothalamus. These results suggest that serotonergic drugs can act at multiple sites (i.e., both central and peripheral) to evoke a pituitary-adrenocortical response.

5-Hydroxytryptophan↗

PubMed1984

Discriminative stimulus properties of fenfluramine: evidence for serotonergic involvement.

Rats were trained to discriminate 3 mg/kg fenfluramine (FEN) from saline using a milk-reinforced (FR 10 schedule) two-lever operant task. To assess the involvement of the serotonin (5-HT) system in elicitation of the FEN cue, 5-HT compounds were tested for their ability to substitute for or to antagonize the the discriminative stimulus produced by FEN. Following acquisition, the FEN cue was dose-dependent, had a rapid onset (10 min) and a long duration (12 h), and was stereospecific. The putative 5-HT receptor antagonists methysergide and cinanserin antagonized the FEN discriminative stimulus, while chlordiazepoxide, an indirect inhibitor of 5-HT turnover, did not. The FEN cue was also antagonized by the selective 5-HT reuptake inhibitor fluoxetine. Norfenfluramine, p-fluoro-amphetamine, and p-chloroamphetamine, compounds structurally and pharmacologically similar to FEN, substituted for FEN, whereas fluoxetine, cinanserin, methysergide, and chlordiazepoxide did not. The 5-HT precursor 5-hydroxytryptophan partially generalized to the FEN cue. It was further shown that the discriminative stimulus properties of FEN are not based on its anorectic action. These results suggest that the cue properties of FEN might be partially mediated through an interaction with the 5-HT system.

Amphetamine↗

PubMed1984

Fenfluramine, p-chloroamphetamine and p-fluoroamphetamine stimulation of pituitary-adrenocortical activity in rat: evidence for differences in site and mechanism of action.

Serum corticosterone concentrations were measured in rats after injection of fenfluramine (FEN), p-chloroamphetamine (PCA) and p-fluoroamphetamine (PFA), halogenated amphetamine derivatives believed to exert their behavioral and physiological effects through the release and/or depletion of brain serotonin (5-HT). Animals were pretreated with various serotonergic drugs before FEN, PCA or PFA in order to ascertain the role of 5-HT in mediating the pituitary-adrenocortical response to each compound. Systemic administration of FEN, PCA or PFA caused a dose-dependent corticosterone elevation, with a potency rank ordering of PCA greater than FEN greater than PFA. Chronic depletion of brain 5-HT by pretreatment with p-chlorophenylalanine or 5,7-dihydroxytryptamine antagonized the PCA-induced elevation, but not that produced by FEN or PFA. When injected i.c.v., PCA and PFA elevated corticosterone levels whereas FEN did not. The central PCA-induced elevation was prevented by pretreatment with either the 5-HT reuptake inhibitor fluoxetine or the 5-HT receptor blocker methysergide. Fluoxetine or methysergide also antagonized the corticosterone elevation produced by systemically injected PCA or FEN, but not that produced by PFA. In the final experiment, pretreatment with dexamethasone, an inhibitor of pituitary adrenocorticotropic hormone secretion, prevented the corticosterone elevation produced by all three drugs. Thus, despite their structural and pharmacological similarities, FEN, PCA and PFA each act differently to stimulate corticosterone secretion. As expected, PCA elevates corticosterone levels through a central serotonergic mechanism that requires the continued synthesis and storage of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1982

The effects of fenfluramine and fluoxetine on the acquisition of the conditioned avoidance response in rats.

This study tested a behavior-suppressing punishment system and how its activity may be altered by agents known to interrupt or enhance serotonergic (5-HT) transmission. Holtzman male albino rats were tested for shuttle box avoidance acquisition and intertrial responding either 1 or 8 h following daily injection of fenfluramine (FEN) or fluoxetine (FXT). When the drug-test interval was 1 h, a time when both drugs are presumably potentiating 5-HT activity, avoidance acquisition and intertrial responding were impaired. When testing occurred 8 h after drug treatment, a time when 5-HT level are unaltered by FXT and are maximally reduced by FEN, these drugs had no effect on avoidance acquisition, but FEN produced an increase in intertrial responses whereas FXT did not. These results support the proposal of an inhibitory 5-HT system. Furthermore, these data demonstrate that FEN is capable of exerting a biphasic action on intertrial responding and suggest that the time interval between drug administration and behavioral testing is a crucial variable when investigating FEN.

Analysis of Variance↗