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D W Gallager

Publications and source records attributed to D W Gallager.

At least 19 recordsLinked to original sources
PubMed1992

Effect of amygdala kindling on the in vivo release of GABA and 5-HT in the dorsal raphe nucleus in freely moving rats.

Our laboratory has previously reported a significant subsensitivity to iontophoretically applied GABA (gamma-aminobutyric acid) in dorsal raphe neurons of amygdala-kindled rats. This subsensitivity was selective for GABA and persisted at least 3 months after the last kindled seizure. In the present series of experiments, we explored mechanisms by which kindling could result in persistent GABA sensitivity changes, using in vivo microdialysis to quantitate neurotransmitter [including GABA and 5-hydroxytryptamine (5-HT)] release in the dorsal raphe nucleus of awake, unrestrained amygdala-kindled rats. Depolarization-induced release of GABA is markedly increased in the dorsal raphe nucleus in amygdala-kindled animals. This change in depolarization-induced GABA release appeared to be graded, dependent upon the stage to which the animal is kindled. Thus GABA release is increased in animals kindled to Stage 2 and even greater in animals kindled to Stage 5 seizures. The change in GABA release is also selective, since no consistent change in the release of other putative amino acid neurotransmitters or 5-HT was observed in these same animals. We hypothesize that this increase in depolarization-induced release of GABA in the amygdala-kindled animal underlies the development of subsensitivity to GABA in dorsal raphe neurons.

Amino Acids↗
PubMed1992

Development of long-term subsensitivity to GABA in dorsal raphe neurons of amygdala-kindled rats.

Previously we reported a long-term change in neuronal sensitivity to GABA following amygdala kindling. Dorsal raphe neurons of amygdala-kindled rats exhibited significant subsensitivity to GABA 4 weeks after the last fully generalized (Stage 5) seizure. We hypothesized that this alteration in GABA sensitivity might reflect neuronal changes corresponding to kindled seizure susceptibility and subsequent experiments have investigated this hypothesis. The progression towards neuronal subsensitivity to GABA during amygdala kindling can be correlated with the Stage to which an animal has been kindled. That is, when measured 4 weeks after the last kindled seizure, dorsal raphe neurons are supersensitive to GABA following a Stage 2 seizure, not different from controls following a Stage 3 seizure and subsensitive to GABA following a Stage 5 seizure. In addition, subsensitivity to GABA appears to be permanent in that it is still measurable 3 months after the last Stage 5 seizure. Thus, amygdala kindling produces long-term, perhaps permanent, changes in neuronal sensitivity to GABA and these changes reflect the Stage to which an animal has been kindled.

Amygdala↗
PubMed1992

GABAA receptor subunit mRNA levels are differentially influenced by chronic FG 7142 and diazepam exposure.

Levels of mRNA for the alpha 1, gamma 2 and beta 1 subunits of the GABAA receptor complex were examined in rats maintained on a chronic, continuous schedule of exposure to the benzodiazepine inverse agonist FG 7142. The effect of chronic exposure to the benzodiazepine agonist diazepam was also examined on levels of gamma 2 subunit mRNA. FG 7142 (2 mg/ml of 100% dimethyl sulfoxide (DMSO) or vehicle (100% DMSO) was administered continuously for 8 days in the right ventricle via an osmotic minipump. At the end of the eighth day of exposure, the brain was removed and cerebral cortex, cerebellum and hippocampus were dissected and mRNA prepared from each region. Levels of GABAA alpha 1 and gamma 2 subunit mRNA were examined by Northern blot analysis with cDNA probes specific for these subunits. A significant increase in alpha 1 mRNA was measured in both cortex and hippocampus, but not in cerebellum, of rats chronically exposed to FG 7142 relative to vehicle-treated rats. A significant increase in gamma 2 subunit mRNA in cortex was also evident in drug-treated rats; however, no change in gamma 2 subunit mRNA was observed in either the hippocampus or cerebellum. Examination of GABAA beta 1 subunit mRNA by solution hybridization using a beta 1 riboprobe revealed no effect of chronic FG 7142 treatment on this subunit in either cortex, hippocampus or cerebellum. In rats chronically exposed to diazepam (21 days via silastic implants), levels of gamma 2 subunit mRNA were significantly decreased in cortex, but not changed in either hippocampus or cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Isomerases↗
PubMed1992

Developmental profile of polyadenylated and non-polyadenylated GABAA receptor subunit mRNAs.

The ratio of mRNA not selected for polyadenylation (non-poly(A)+ selected) to mRNA selected for polyadenylation (poly(A)+) for the beta 1, alpha 1 and gamma 2 subunits of the GABAA receptor complex was examined in rats as a function of age. RNA was extracted from whole brain of rats that were either 0, 1, 3, 5 or over 60 days of postnatal age. Poly(A)+ mRNA was purified by oligo(dT)-cellulose chromatography. Non-poly(A)+ selected mRNA and poly(A)+ mRNA for the GABAA receptor beta 1, alpha 1 and gamma 2 subunits were examined by Northern blot analysis using cDNA probes specific for these subunits. Levels of GABAA receptor beta 1 subunit mRNA were also examined by solution hybridization analysis with a beta 1 riboprobe. Analysis of Northern blots revealed that levels of poly(A)+ beta 1 subunit mRNA were highest at 0 days of age, but decreased and reached adult levels by 5 days of postnatal age. However, levels of the beta 1 subunit message extracted from non-poly(A)+ selected mRNA were not significantly different at any of the ages examined, suggesting the existence of a population of beta 1 subunit mRNA that is not polyadenylated. The age-related discrepancy between beta 1 subunit levels measured in non-poly(A)+ selected mRNA and poly(A)+ mRNA was also observed using solution hybridization analysis. In contrast, levels of both non-poly(A)+ selected mRNA and poly(A)+ mRNA for the alpha 1 subunit of the GABAA complex increased from 0 days of age to adulthood. Similarly, levels of both non-poly(A)+ selected mRNA and poly(A)+ mRNA for the GABAA receptor gamma 2 subunit increased with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Chronic administration of beta-carboline-3-carboxylic acid methylamide by continuous intraventricular infusion increases GABAergic function.

The repeated, intraperitoneal administration of the benzodiazepine receptor inverse agonist, FG 7142 (beta-carboline-3-carboxylic acid methylamide), leads to pharmacological kindling and an associated decrease in GABA-stimulated influx of 36Cl- into cortical membrane preparations. The chronic administration of benzodiazepine agonists results in the development of tolerance and also results in a decrease in GABA-stimulated uptake of 36Cl-. The present study was designed to evaluate further the paradoxical reports that both chronic treatment with benzodiazepine receptor agonists and inverse agonists results in a decreased ability of GABA to stimulate uptake of 36Cl- into cortical membrane preparations. The effects of continuous administration of FG 7142 on GABA-stimulated uptake of 36Cl-, the threshold for bicuculline-induced seizures and the proconvulsant actions of acute administration FG 7142 were evaluated. The continuous administration of FG 7142 resulted in an increased capacity of GABA to stimulate the uptake of 36Cl- into cortical membrane preparations and a significant increase in the seizure threshold for bicuculline following the acute administration of FG 7142. These data, therefore, indicate that changes in GABAergic function following chronic administration of GF 7142 are dependent on the regimen of administration of drug. The results also suggest that the GABA receptor homeostatically responds to continuous occupation by inverse agonists by an upregulation of its functional response to GABA.

Animals↗
PubMed1990

Effects of continuous diazepam administration on GABAA subunit mRNA in rat brain.

Rats treated chronically with diazepam develop tolerance to diazepam effects and show changes in sensitivity of GABAergic systems. In order to investigate possible molecular mechanisms associated with these changes, we have evaluated the effects of acute and chronic diazepam treatment on levels of mRNA for the alpha 1 and beta 1 subunits of the GABAA receptor. Northern blots were hybridized with 32P-labeled GABA alpha 1 and beta 1 cDNA probes, and resulting bands were quantified by autoradiography and densitometry. Levels of alpha 1 mRNA were significantly decreased in cerebral cortex but not in cerebellum or hippocampus of chronic diazepam-treated rats. Acute diazepam treatment did not change levels of alpha 1 mRNA in any of the brain regions. Levels of beta 1 mRNA were examined by Northern blot analysis and also by solution hybridization analysis using a 32P-labeled riboprobe. Both methods showed that beta 1 mRNA was not significantly changed by chronic diazepam treatment. These results demonstrate a specific change in alpha 1 subunit that is associated with a state of altered GABA sensitivity and provide further support for the regional heterogeneity of chronic diazepam effects.

Animals↗
PubMed1979

Failure of chronic lithium treatment to block tricyclic antidepressant-induced 5-HT supersensitivity.

The ability of chronic lithium administration to modify tricylic antidepressant-induced supersensitivity development in cells receiving 5-hydroxytryptamine (5-HT) input was investigated using microiontophoretic techniques. In these experiments, chronic chlorimipramine (or imipramine) administration for a period of 14 days resulted in a 5-fold increase in the sensitivity of hippocampal pyramidal cells to iontophoretically applied 5-HT. This supersensitivity was not blocked by the concurrent administration of lithium. The data suggests that blockade of supersensitivity development by lithium as previously demonstrated in the dopamine system may not be generalized to all central amine systems.

Animals↗
PubMed1979

Modulation of benzodiazepine binding site sensitivity.

Recent studies on agents which alter benzodiazepine binding site sensitivity in brain are described. GABAergic agonists enhance and antagonists inhibit binding to the brain specific benzodiazepine binding site, and the binding can be correlated with effects on neuronal cell firing in the dorsal raphe nucleus. Anions such as chloride, iodide and nitrite also enhance (3H)diazepam binding and this enhancement is consistent with their role in postsynaptic inhibition. Pretreatment of animals with the anticonvulsant, diphenylhydantoin, enhances both diazepam binding and the electrophysiological response to diazepam suggesting one possible locus for the anticonvulsant action of diphenylhydantoin in brain. Taken together, these results suggest the existence of a GABA/Cl- ionophore/BZ binding complex in brain. Preliminary results on the purification of the BZ component of this complex and fluorescent probes for its study are described.

Aminooxyacetic Acid↗
PubMed1978

Benzodiazepines: potentiation of a GABA inhibitory response in the dorsal raphe nucleus.

Based on evidence that the dorsal raphe nucleus (DR) has specific and independent receptors for 5HT, GABA and glycine (Gallager and Aghajanian, 1976; Wang and Aghajanian, 1977), alterations in the firing rate of DR neurons following the administration of benzodiazepines (BZ) were evaluated to determine whether they were the result of a direct interaction with 5HT receptors or due to interactions of these drugs with GABA and/or glycine. The effects of BZs after both direct and systemic application were tested in rats using microiotophoretic and single-cell recording techniques. Although the BZs did not alter the spontaneous firing rate of the DR, both the systemic and iontophoretic administration of these drugs were found to potentiate the inhibitory response produced by GABA. The data suggest that this potentiation is mediated postsynaptically. Since the effects of BZs on the spontaneous activity of the DR are only apparent following pretreatments with AOAA, it is speculated that these drugs may only have pronounced effects when GABAergic input is prominent.

Aminobutyrates↗
PubMed1978

Afferents to brain stem nuclei (brain stem raphe, nucleus reticularis pontis caudalis and nucleus gigantocellularis) in the rat as demonstrated by microiontophoretically applied horseradish peroxidase.

Using a retrograde tracer technique with microiontophoretically applied horseradish peroxidase (HRP), afferent projections to the brain stem raphe nuclei (BR, raphe magnus, pallidus and obscurus) and to two adjacent reticular nuclei, nucleus reticularis pontis caudalis (nRPC) and nucleus gigantocellularis (nGC) were identified. The most striking difference between the afferent projections to the BR and the adjacent nuclei as determined by this method is that afferents to the BR originate primarily from structures rostral to the pons, especially the mesencephalic central gray and the dorsal and ventral tegmentum. In contrast, the two reticular nuclei studied (nGC and nRPC) received afferent projections within or caudal to the pons-medulla. For example, the nGC receives prominent afferent projections from the gray matter of the spinal cord. In addition, evidence for interconnections between all of the adjacent nuclei (BR, nGC and nRPC) was found. Such afferent projections are compatible with the notion that the brain stem raphe nuclei may serve as connections within the brain stem for a descending system, while the nGC may be a relay in a feedback loop between the spinal cord and the reticular formation.

Animals↗
PubMed1976

Effect of antipsychotic drugs on the firing of dorsal raphe cells. I. Role of adrenergic system.

The activity of serotonergic (5HT) neurons in the dorsal raphe nucleus was inhibited by the i.v. administration of certain antipsychotic drugs (methiothepin, clozapine and thioridazine). However, other antipsychotic agents (chlorpromazine, haloperidol and pimozide) did not inhibit raphe cell firing. The inhibitory potency of these drugs on raphe activity correlates with reported central noradrenergic blocking efficacy. An alpha-adrenergic blocking agent, piperoxane, but not the beta-blocking agents, propranolol and MJ 1999, inhibited raphe activity when administered systemically. All of these drugs appear to act indirectly since they (and NE) have relatively weak or variable effects when applied microiontophoretically to raphe neurons. The depressant effects of certain antipsychotic drugs and piperoxane on 5HT neurons appears to be mediated by a cnetral adrenergic system since (1) the depression could be reversed by the catecholamine releasing agents 1- and d-amphetamine; (2) the depression could be abolished by destruction of adrenergic pathways in the CNS by chemical, mechanical, or electrothermic lesions. While a precise localization has not yet been obtained, the data suggest that these drug effects may be mediated by an adrenergic pathway ascending from the lower brainstem.

Animals↗
PubMed1976

Effect of antipsychotic drugs on the firing of dorsal raphe cells. II. Reversal by picrotoxin.

As reported in the preceding study, the ability of certain antipsychotic and adrenolytic agents to inhibit the spontaneous firing of serotonergic 5HT neurons in the dorsal raphe nucleus appeared to be related to adrenergic blocking efficacy. However, the interaction between adrenergic and serotonergic systems was apparently indirect. In this phase of the study we investigated the hypothesis that another transmitter system could mediate this interaction. We examined the effects of two inhibitory amino acid transmitters (GABA and glycine) for possible effects on dorsal raphe cell firing using single cell recording and microiontophoretic techniques. In addition, the ability of the GABA antagonist, picrotoxin and the glycine antagonist, strychnine to reverse the effects of the antipsychotic and alpha-blocking drugs on dorsal raphe firing was tested. Both GABA and glycine were found to inhibit raphe cell firing selectively, allowing for a possible neurotransmitter function for these amino acids within the dorsal raphe nucleus. However, picrotoxin but not strychnine was found to reverse the effects of the antipsychotic and alpha-blocking drugs on raphe firing. Based on these results, we propose that the adrenergic input may influence 5HT neurons indirectly via a GABAergic interneuron or interposed GABA neuron.

Animals↗