Biomedical subjects

J W Dailey

Publications and source records attributed to J W Dailey.

At least 37 records · Page 2Linked to original sources

PubMed1998

A video data base system for studying animal behavior.

Classification of farm animal behavior is based on oral or written descriptions of the activity in which the animal is engaged. The quantification of animal behavior for research requires that individuals recognize and code the behavior of the animal under study. The classification of these behaviors can be subjective and may differ among observers. Illustrated guides to animal behavior do not convey the motion associated with most behaviors. Video-based guides offer a method of quantifying behaviors with real-time demonstrations of the components that make up a behavior. An animal behavior encyclopedia has been developed to allow searching and viewing of defined (video-recorded) behaviors on the Internet. This video data base is being developed to initiate a system that automatically extracts animal motion information from an input animal activity video clip using a multiobject tracking and reasoning system. Eventually, the extracted information will be analyzed and described using standard animal behavior definitions (the behavior encyclopedia). The intended applications of the behavior encyclopedia and video tracking system are 1) an accessible data base for defining and illustrating behaviors for both research and teaching and 2) to further automate the collection of animal behavior data.

Animals↗

PubMed1997

Enhancement of the anticonvulsant effect of fluoxetine following blockade of 5-HT1A receptors.

Serotonin reuptake inhibitors, such as fluoxetine, have been shown to exert anticonvulsant effects in several animal models of epilepsy. In view of recent studies showing that 5-HT1A receptor antagonists (somatodendritic autoreceptor antagonists) enhance the increase in extracellular 5-hydroxytryptamine (5-HT, serotonin) produced by serotonin reuptake inhibitors, it was of interest to determine if these antagonists also enhance the anticonvulsant effect of fluoxetine in Genetically Epilepsy-Prone Rats (GEPRs). The 5-HT1A receptor antagonists (-)-pindolol and LY 206130 (1-[1-H-indol-4-yloxy]-3-[cyclohexylamino]-2-propanol maleate) were examined in the present study and both enhanced the anticonvulsant action of fluoxetine in severe seizure GEPRs (GEPR-9s). The latter effect of LY 206130 was found to be dose- and 5-HT-dependent. These findings provide further evidence that the increase in extracellular serotonin observed after administering fluoxetine in combination with a 5-HT1A receptor antagonist is physiologically important and that the anticonvulsant effect of fluoxetine in the GEPR is mediated through an increase in extracellular 5-HT.

Acoustic Stimulation↗

PubMed1997

Dizocilpine (MK-801) increases not only dopamine but also serotonin and norepinephrine transmissions in the nucleus accumbens as measured by microdialysis in freely moving rats.

The extracellular concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the nucleus accumbens (NACC) of freely moving rats were monitored simultaneously via intracerebral microdialysis. Local infusion of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) (5-250 microM) produced significant increases in extracellular levels of DA, NE and 5-HT in a concentration-dependent fashion. Perfusion with tetrodotoxin (TTX, 1 microM) blocked the ability of focal MK-801 (50 microM) to increase DA, NE and 5-HT in the dialysate. Systemic administration of MK-801 (0.3 mg/kg, i.p.) also produced small, but statistically significant, increases in extracellular concentrations of DA, NE and 5-HT in the NACC. Our microdialysis results are consistent with the hypothesis that, in addition to dopaminergic, serotonergic and noradrenergic neurotransmissions in the NACC are involved in the mechanism by which MK-801 alters behavior in rats. Also, the present study gives further support to the concept that NMDA receptors within the NACC do not regulate DA release through direct excitatory control.

Animals↗

PubMed1997

Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+.

Carbamazepine administration causes large increases in extracellular serotonin concentration and dose-related anticonvulsant effects in genetically epilepsy-prone rats (GEPRs). In order to determine the generality of the effect on serotonin, we determined the anticonvulsant ED50 for carbamazepine against maximal electroshock seizures in outbred, non-epileptic Sprague-Dawley rats. We then administered anticonvulsant carbamazepine doses to Sprague-Dawley rats and observed extracellular serotonin concentration in hippocampi by way of microdialysis. We found that administration of carbamazepine, either systemically or through the dialysis probe, resulted in significant and dose-related increases in extracellular serotonin concentration. Basal serotonin release was decreased by tetrodotoxin administration through the dialysis probe. Tetrodotoxin administration through the dialysis probe did not decrease the effect of systemically or focally administered carbamazepine on extracellular serotonin concentration. Similarly, elimination of Ca2+ from the dialysate did not alter the release of serotonin caused by carbamazepine. These findings suggest that the serotonin releasing effect of carbamazepine does not take place by exocytosis and does not require action potentials in the brain area in which the release takes place. Further they suggest that the effect is mediated by an action of carbamazepine directly on serotonergic nerve terminals.

Animals↗

PubMed1997

Anticonvulsant doses of carbamazepine increase hippocampal extracellular serotonin in genetically epilepsy-prone rats: dose response relationships.

The antiepileptic drug carbamazepine produces dose related anticonvulsant effects in genetically epilepsy-prone rats (GEPRs) and most other animal seizure models. Carbamazepine releases serotonin as part of the pharmacodynamic action by which it suppresses convulsions in GEPRs and it releases serotonin in non-epileptic Sprague-Dawley rats. The two strains which make up the GEPR seizure model (moderate seizure GEPR-3s and severe seizure GEPR-9s) experience anticonvulsant effects in response to different doses of carbamazepine (GEPR-3 ED50 = 25 mg/kg; GEPR-9 ED50 = 3 mg/kg). The present study determined that carbamazepine produces a dose related increase in extracellular serotonin in each of the two GEPR strains. The doses of carbamazepine required to increase extracellular serotonin are similar to the doses required for an anticonvulsant effect in each of the strains. This result provides further support for the hypothesis that release of serotonin by carbamazepine is an important part of the pharmacodynamic action by which this drug suppresses seizures.

Analysis of Variance↗

PubMed1996

Antidepressants and seizures: clinical anecdotes overshadow neuroscience.

Pharmacological treatment of depression in persons with epilepsy has been an area of controversy because some drugs commonly are perceived specifically to induce or exacerbate seizures in patients with seizure disorders. This prevailing misconception is unjustified by scientific studies, yet it continues to prevent afflicted persons from receiving appropriate therapy. The scientific literature shows that tricyclic antidepressant drugs cause seizures in overdose in both animals and humans. In lower doses, these drugs have anticonvulsant activity in humans and animals. Thus, the antidepressant drugs are like several antiepileptic drugs that can both prevent and cause seizures. The anticonvulsant activity of antidepressant drugs has been studied extensively in animals and almost certainly stems from their capacity to block norepinephrine and/or serotonin reuptake. The pharmacodynamic action responsible for their convulsant effects has not been well studied but may be due to their local anesthetic, antihistaminic, or antimuscarinic activity. The newer, more selective monoamine uptake blockers have very low convulsant liability, and it is suggested that their anticonvulsant activity, which is well documented in animals, be investigated further in humans. If their effects in humans are analogous to those in animals, these drugs can be used safely in epileptic patients with depression, and it is possible that their anticonvulsant activity can be exploited for use in the treatment of epilepsy.

Animals↗

PubMed1996

Focal ethanol elevates extracellular dopamine and serotonin concentrations in the rat ventral tegmental area.

The present study describes the effects of local perfusion with ethanol on extracellular dopamine and serotonin (5-hydroxytryptamine, 5-HT) concentrations in the ventral tegmental area. Various concentrations of ethanol in artificial cerebrospinal fluid (ACSF) (0.1-10%, v/v) were administered through a microdialysis probe into the ventral tegmental area of freely moving Sprague-Dawley rats. A significant and concentration-dependent increment in dialysate output of both dopamine and serotonin was observed after local infusion of ethanol. Perfusion with Ca(2+)-free medium or tetrodotoxin (1 microM in ACSF) produced a significant reduction in basal extracellular dopamine and serotonin concentration but failed to block dopamine or serotonin release produced by infusion of 10% ethanol. Perfusion with 100 mM K+ before and after infusion of 10% ethanol revealed that the second perfusion with high K+ solution still produced an increase in dopamine and serotonin concentration, similar in magnitude to the first response, indicating that perfusion with 10% ethanol did not cause irreversible damage to either dopamine cell bodies or serotonin terminals in the ventral tegmental area. These results suggest that dopamine and serotonin release from the ventral tegmental area produced by focal application of 10% ethanol is mediated, at least in part, by a non-exocytotic mechanism. Direct stimulation of the ventral tegmental area dopamine neurons by ethanol might be involved in the reinforcing properties of the drug.

Animals↗

PubMed1996

Neurochemical correlates of antiepileptic drugs in the genetically epilepsy-prone rat (GEPR).

The GEPR model is composed of two independently derived strains of rats each characterized by a broad-based seizure predisposition. Moderate seizure GEPRs (GEPR-3s) exhibit generalized clonus with loss of righting reflex in response to a standardized sound stimulus. The same stimulus in severe seizure GEPRs (GEPR-9s) produces a tonic-clonic convulsion much like that produced by supramaximal electroshock. The numeric descriptors (3 and 9) derive from the ordinal rating scale developed by Jobe and coworkers for evaluation of convulsion intensity. GEPRs experience an anticonvulsant effect in response to all established and many experimental antiepileptic drugs and distinctions between the classes of drugs can be made. Since serotonin plays an anticonvulsant role in nearly all animal seizure models, we examined the effects of antiepileptic drugs on serotonin using microdialysis. Among clinically effective anticonvulsants, carbamazepine, antiepilepsirine (used in China) and loreclezole produced dose-related anticonvulsant effects and increases in extracellular serotonin in GEPRs. Similarly, drugs known to block serotonin reuptake and increase extracellular serotonin (fluoxetine and sertraline) produce dose related anticonvulsant effects in GEPRs and other animal models. Accentuation of serotonin release by treating GEPRs with fluoxetine and 5-hydroxytryptophan enhances the anticonvulsant effect produced by fluoxetine. Depletion of serotonin greatly decreased the anticonvulsant effect produced by carbamazepine, antiepilepsirine and fluoxetine. Phenytoin produced a dose related anticonvulsant effect in GEPRs but did not increase extracellular serotonin. Depletion of serotonin did not diminish the anticonvulsant effect produced by phenytoin. Thus, serotonin appears to play a role in the anticonvulsant effect of several but not all anticonvulsant drugs.

Animals↗

PubMed1996

Effect of 5,7-dihydroxytryptamine on audiogenic seizures in genetically epilepsy-prone rats.

To further assess the role of 5-HT in the modulation of audiogenic seizures (AGS) in the Genetically Epilepsy-Prone Rat (GEPR), changes in AGS severity after widespread chronic depletion of brain 5-HT by intracerebroventricular administration of 5,7-dihydroxytryptamine (5,7-DHT) were examined in moderate seizure GEPRs (GEPR-3s). Following treatment with 5,7-DHT (150 micrograms/30 microliters), a significant increase in seizure severity was observed at 2, 3 and 4 weeks as compared to vehicle-injected controls. The increase in seizure severity was evidenced by a significant increase in the incidence of tonic convulsions in 5,7-DHT treated animals (53% in treated animals compared to 0% in vehicle treated controls) over the testing period. Interestingly, the latency to wild running was increased in 5,7-DHT treated GEPRs, suggesting that depletion of brain 5-HT may slow initiation of AGS. Neurochemical analysis revealed marked depletion of 5-HT in the cortex (-96%), hippocampus (-94%), thalamus (-80%), hypothalamus (-62%), midbrain (-51%) and pons-medulla (-52%) in animals that received 5,7-DHT. However, no significant reductions in brain norepinephrine content were observed in any of the regions assayed due to the pretreatment of all animals with protriptyline. The present findings lend further support for an inhibitory action of brain 5-HT on audiogenic seizures in GEPRs.

5,7-Dihydroxytryptamine↗

PubMed1996

Abnormalities in 5-HT1A and 5-HT1B receptor binding in severe-seizure genetically epilepsy-prone rats (GEPR-9s).

The present study was designed to determine whether abnormalities in serotonin receptor binding co-exist with the presynaptic serotonergic deficits that have previously been identified in the genetically epilepsy-prone rat (GEPR) brain. In vitro binding of [3H]8-OH-DPAT (0.16-10.3 nM) to 5-HT1A receptor sites was found to be decreased in the hippocampus of severe seizure GEPRs (GEPR-9s) when compared to nonepileptic control rats, while no difference in [3H]8-OH-DPAT binding was observed in the GEPR-9 corpora quadrigemina or midbrain tegmentum. The decreased binding of [3H]8-OH-DPAT to hippocampal membranes was due to a decrease in Bmax (P < 0.001), rather than to a change in the Kd. Conversely, in vitro binding of [125I]cyanopindolol (2-400 pM) to 5-HT1B receptor sites was increased in the GEPR-9 hippocampus, corpora quadrigemina and midbrain tegmentum when compared to nonepileptic control rats. The increased binding of [125I]cyanopindolol in all three regions resulted from an increase in the Bmax (P < 0.05), rather than a change in the Kd. These finding suggest that in addition to the innate reduction in 5-HT presynaptic markers, GEPR-9s also exhibit abnormalities in the density of 5-HT1A and 5-HT1B receptors in some regions of the brain. Inasmuch as serotonin acts to attenuate audiogenic seizures in GEPRs, these abnormalities in 5-HT receptor binding may contribute to the seizure susceptibility exhibited by these animals.

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

PubMed1996

Abnormalities in brain serotonin concentration, high-affinity uptake, and tryptophan hydroxylase activity in severe-seizure genetically epilepsy-prone rats.

We characterized the nature of the deficit in brain serotonin (5-HT) exhibited by genetically epilepsy-prone rats (GEPR-9s) by regionally assessing three markers for 5-HT terminals/neurons (5-HT content, 5-HT uptake into the P2-synaptosomal fraction, and tryptophan hydroxylase activity) in GEPR-9s and nonepileptic control rats. As compared with controls, GEPR-9s had reduced brain 5-HT concentration, synaptosomal 5-HT uptake, and tryptophan hydroxylase activity (measured in vivo and in vitro) in most regions of the forebrain and in selected regions of brainstem. Analysis of kinetic constants for synaptosomal [(3)H]5-HT uptake and in vitro tryptophan hydroxylase activity showed that the decrements in these parameters exhibited by GEPR-9s resulted from reductions in V(max) rather than changes in K(m). In general, the reduction in each of the presynaptic markers for 5-HT terminals/neurons was similar in both magnitude and in their regional distribution in the GEPR-9 brain. An exception to this was noted in the midbrain tegmentum of GEPR-9s, which displayed a significant reduction in tryptophan hydroxylase activity without showing alterations in 5-HT concentration or in high-affinity 5-HT uptake. The present findings support the hypothesis that there is a widespread reduction in the number of serotonergic/neurons in GEPR-9 brain.

Acoustic Stimulation↗

PubMed1995

Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response.

D-20443 is an experimental antiepileptic drug. Its mechanism of antiepileptic action is unknown. We evaluated the anticonvulsant effectiveness of D-20443 against sound-induced seizures in genetically epilepsy-prone rats (GEPRs). This compound produced anticonvulsant effects against sound-induced seizures in moderate seizure GEPRs (GEPR-3s) at significantly lower doses than in severe seizure GEPRs (GEPR-9s). Based on these data and on the responses of GEPRs to other antiepileptic drugs, we predict that D-20443 will be a broad spectrum antiepileptic agent in humans. That is, we predict that D-20443 will suppress both tonic/clonic and absence seizures in humans.

Animals↗

PubMed1995

Further evidence of anticonvulsant role for 5-hydroxytryptamine in genetically epilepsy-prone rats.

1. This study was designed to evaluate further the role of 5-hydroxytryptamine (5-HT) in regulating susceptibility and/or intensity of audiogenic seizures in genetically epilepsy-prone rats. 2. The effects of sertraline, a highly selective and potent inhibitor of 5-HT uptake, on both the intensity of the audiogenic seizures and the extracellular concentrations of 5-HT in the thalamus were evaluated in severe seizure genetically epilepsy-prone rats. 3. Sertraline (7.5, 15 and 30 mg kg-1, i.p.) produced a dose-dependent reduction in the intensity of the audiogenic seizures. 4. Brain microdialysis studies showed that the same doses of sertraline also caused dose-dependent increases in the extracellular 5-HT concentration in the thalamus of the freely moving rats. 5. The peak anticonvulsant effect correlated temporally with the peak increases in the extracellular 5-HT concentration for this drug. 6. It is concluded that enhancement of 5-hydroxytryptaminergic transmission may contribute to the anticonvulsant effect of sertraline in severe seizure genetically epilepsy-prone rats. 7. The present results coupled with earlier investigations support the hypothesis that 5-HT plays an anticonvulsant role in genetically epilepsy-prone rats.

1-Naphthylamine↗

PubMed1995

Alteration in levels of expression of brain calbindin D-28k and calretinin mRNA in genetically epilepsy-prone rats.

Variations in the concentration of free calcium in neurons is believed to play a major role in regulating neuronal excitability. Because calcium-binding proteins such as calbindin D-28k and calretinin help to regulate intracellular calcium, we investigated the possibility that the expression of these proteins may be affected in genetically epilepsy-prone rats (GEPRs). The mRNA levels of both proteins were compared across several brain regions using in situ hybridization histochemistry and Northern blot analysis with semiquantitation by optical density measures in autoradiograms from two GEPR strains that differ in the severity of audiogenic seizures (GEPR9 and GEPR3) and from Sprague-Dawley rats. Results revealed a lower level of expression in calbindin D-28k mRNA in the in the caudate putamen-accumbens nuclei in GEPR3 (-30%) and GEPR9 (-60%) relative to controls. The calbindin D-28k mRNA level was also lower in the reuniens nucleus of the thalamus (-41% in GEPR3; -34% in GEPR9). The calretinin mRNA level was lower in the substantia nigra compacta of both GEPR rat strains (-31% in GEPR3 and -34% in GEPR9 relative to controls). No changes in mRNA were detected in other brain regions expressing calbindin D-28k or calretinin mRNA. These results indicate that the expression of these related calcium-binding proteins is altered in the GEPRs before the induction of seizures. This initial defect could alter either the calcium-buffering capacity or regulation of calcium-mediated processes by these proteins and thus play a role in the molecular cascade of events inducing the genetic susceptibility to, and the generalization of, seizures in these rat strains.

Animals↗

PubMed1994

The anticonvulsant effect of the broad spectrum anticonvulsant loreclezole may be mediated in part by serotonin in rats: a microdialysis study.

Loreclezole is an experimental anticonvulsant drug. We found previously that several established anticonvulsants increase extracellular serotonin as measured by microdialysis. We have concluded that the increase in extracellular serotonin and the anticonvulsant effect produced by these anticonvulsant drugs are related in a cause and effect manner. To determine if anticonvulsant doses of loreclezole increase extracellular serotonin, we determined anticonvulsant dose-response relationships in genetically epilepsy-prone rats (GEPRs). Then, we administered ED99 doses of loreclezole to GEPRs and determined the effect on extracellular serotonin as measured by microdialysis in the striatum. We conclude that loreclezole produces a dose-related anticonvulsant effect in GEPRs and that anticonvulsant doses of loreclezole increase extracellular serotonin in these animals.

Acoustic Stimulation↗

PubMed1994

Evidence that a serotonergic mechanism is involved in the anticonvulsant effect of fluoxetine in genetically epilepsy-prone rats.

Fluoxetine (15 mg/kg i.p.) decreased the audiogenic seizure intensity in 33% of severe seizure genetically epilepsy-prone rats (GEPR-9s). 5-Hydroxytryptophan (5-HTP, 12.5 mg/kg i.p.) produced no anticonvulsant effect in GEPR-9s. When GEPR-9s were treated with a combination of these two drugs, the combination treatment decreased the audiogenic seizure intensity in 83% of the animals tested. Brain microdialysis studies showed that the same combination of 5-HTP and fluoxetine also produced a marked potentiation of the increase in the extracellular serotonin concentration in the thalamus of freely-moving GEPR-9s when compared with administration of either drug alone. A negative correlation between audiogenic seizure intensity and extracellular serotonin concentration existed after either fluoxetine alone or the combination treatment. No significant changes in extracellular norepinephrine concentrations were observed after the combination treatment. These results coupled with our earlier reports strongly suggest that a serotonergic mechanism is involved in the anticonvulsant effects of fluoxetine in GEPRs.

5-Hydroxytryptophan↗

PubMed1994

Role of serotonin in the anticonvulsant effect of fluoxetine in genetically epilepsy-prone rats.

This study was designed to demonstrate a role of serotonin in the anticonvulsant effect of fluoxetine, a serotonin reuptake inhibitor, in genetically epilepsy-prone rats. When varied doses of 5-hydroxytryptophan (12.5, 25, 50 mg/kg) were administered i.p. along with a fixed dose of fluoxetine (15 mg/kg) to severe seizure genetically epilepsy-prone rats, the severity of audiogenic seizures was decreased dose-dependently, and the combination treatment also produced a marked potentiation of the anticonvulsant effect when compared with administration of either drug alone. Pretreatment of severe seizure genetically epilepsy-prone rats with p-chlorophenylalanine depleted brain serotonin and reduced the anticonvulsant effectiveness of fluoxetine. By using intracerebral microdialysis, the depletion of serotonin after p-chlorophenylalanine treatment was confirmed by measuring thalamic extracellular serotonin and 5-hydroxyindoleacetic acid concentrations during basal release and in response to a challenge dose of fluoxetine. We concluded that serotonergic transmission may be involved in the anticonvulsant effect of fluoxetine in severe seizure genetically epilepsy-prone rats.

5-Hydroxytryptophan↗

PubMed1994

Noradrenergic abnormalities in the genetically epilepsy-prone rat.

The genetically epilepsy-prone rat (GEPR) has central nervous system noradrenergic deficits as compared to normal rats. It is possible that these deficits contribute to seizure predisposition because they are exhibited by seizure-naive as well as by seizure-experienced GEPRs. On the basis of pharmacological studies, it is hypothesized that there is an inverse relation between seizure predisposition and levels of noradrenergic activity in brain. Neurochemical studies indicate that deficits exist in areas innervated by both the locus ceruleus and the lateral tegmental noradrenergic systems. These deficits exist in GEPRs without seizure experience and are more pronounced in the severe seizure strain as compared to the moderate seizure strain. We review eight experimental steps undertaken to identify more precisely the anatomical location of noradrenergic determinants of seizure predisposition. These steps illustrate the theoretical bases for the studies and describe the specific experiments completed. Evidence supports the hypothesis that noradrenergic deficits in the superior colliculus and/or ventrally adjacent regions are determinants of seizure predisposition.

Animals↗