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Biomedical subjects

D W Gallager

Publications and source records attributed to D W Gallager.

At least 73 records · Page 4Linked to original sources
PubMed1981

Strychnine: brainstem and spinal mediation of excitatory effects on acoustic startle.

The present study investigated the effects of the glycine antagonist strychnine on the acoustic startle response in rats. Strychnine (0.25, 0.50, 1.0, 1.25, 1.5 and 2.0 mg/kg) administered intraperitoneally (i.p.) was found to produce a dose-dependent increase in startle amplitude that reached its greatest magnitude within 10-15 min after injection. These doses did not produce convulsions or behavioral activation. In order to localize the site of action of this excitatory strychnine effect, rats were implanted with catheters in the lumbar region of the spinal cord (intrathecal implantation), in the cisterna magna, or in the lateral ventricle and later tested for startle after microinjections of strychnine. Dose-dependent excitatory effects on acoustic startle were found when strychnine was injected onto the spinal cord (3.12-12.5 microgram) or into the cisterna magna (6.25-25.0 microgram), whereas infusion into the lateral ventricle produced inhibition (6.25-25.0 microgram). The peak increases in startle following intrathecal (164%) and intracisternal (144%) strychnine were similar to the increase seen following systemic strychnine (160%). Thus, the excitatory effect of systemic strychnine appears to be mediated in the spinal cord and/or brainstem, consistent with data showing that glycine receptors are primarily localized in the caudal regions of the central nervous system. Furthermore, these results suggest that glycine exerts a tonic inhibitory influence on acoustic startle. The possible relation of such a system to phenomena that involve reduction in startle amplitude (e.g., habituation, pre-pulse inhibition) is discussed.

Acoustic Stimulation↗
PubMed1981

Effects of phenytoin on [3H]diazepam binding in dissociated primary cortical cell culture.

The effects of chronic exposure of primary dissociated cerebral cortical cells in culture to the anticonvulsant drug phenytoin have been investigated using benzodiazepine binding techniques. By separating benzodiazepine binding into pharmacologically distinct subtypes, the data indicate that clonazepam-displaceable benzodiazepine binding (associated primarily with neuronal membranes) is significantly decreased by exposure to therapeutic and toxic doses of phenytoin while R05-4864-displaceable benzodiazepine binding (associated principally with non-neuronal elements) is enhanced. The ratio of clonazepam-displaceable to R05-4864-displaceable benzodiazepine binding appears to be the most sensitive indicator for these changes.

Animals↗
PubMed1981

[3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization.

Two types of benzodiazepine binding sites for [3H]diazepam in mammalian central nervous tissue were identified using selective in vitro tissue culture and in situ kainic acid lesion techniques. These two binding sites were pharmacologically distinguished by differential displacement of the [3H]diazepam radioligand using the centrally active benzodiazepine, clonazepam, and the centrally inactive benzodiazepine, RO5-4864. Clonazepam-displaceable binding sites were found to be located principally on neuronal membranes, while RO5-4864-displaceable binding sites were found to be located on non-neuronal elements. These pharmacological distinctions can be used to characterize the predominant cell types which bind benzodiazepines in nervous tissue. It is suggested that one quantitative measure of different cell populations is the ratio of clonazepam- to RO5-4864-displaceable [3H]diazepam binding within a single neuronal tissue simple.

Animals↗
PubMed1980

Interaction of diphenylhydantoin and benzodiazepines in the CNS.

Using extracellular unit recording and microiontophoretic techniques, the anticonvulsant diphenylhydantoin (DPH) was found to increase the physiological efficacy of the benzodiazepines. This increased biological effect could be correlated with an enhanced specific binding of benzodiazepines measured in vivo following pretreatment of rats with DPH. The increased binding of benzodiazepines is due to an increase in the total number of benzodiazepine binding sites without an alteration in the affinity of these sites for [3H]diazepam. The data show that the effects of DPH on benzodiazepine binding are qualitatively different and independent from the effects of gamma-amino-butyric acid. Based on the dose-responsive relationship between benzodiazepine binding effects and the anticonvulsant activity of DPH and reports of other convulsant, anticonvulsant compounds which alter benzodiazepine binding, it is suggested that the benzodiazepine binding site may be relevant to convulsant-anticonvulsant activity.

Animals↗
PubMed1980

Diphenylhydantoin: pre- and postnatal administration alters diazepam binding in developing rat cerebral cortex.

Close correlations between the development of the anticonvulsant effects of diphenylhydantoin and increases in tritiated diazepam binding were observed in rats from fetal day 16 to maturation. In contrast, significant decreases in tritiated diazepam binding were observed in 2- and 3-week-old rats that were exposed in utero to diphenylhydantoin. These changes can be correlated with reported increases in seizure susceptibility after prenatal exposure to diphenylhydantoin.

Animals↗
PubMed1980

Receptors for the age of anxiety: pharmacology of the benzodiazepines.

Investigation of the actions of the benzodiazepines has provided insights into the neurochemical mechanisms underlying anxiety, seizures, muscle relaxation, and sedation. Behavioral, electrophysical, pharmacological, and biochemical evidence indicates that the benzodiazepines exert their therapeutic effects by interacting with a high-affinity binding site (receptor) in the brain. The benzodiazepine receptor interacts with a receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter, and enhances its inhibitory effects. The benzodiazepine receptor may also interact with endogenous substances and several naturally occurring compounds, including the purines and nicotinamide, are candidates for this role. Both the purines and nicotinamide possess some benzodiazepine-like properties in vivo, although further work will be required to confirm their possible roles as endogenous benzodiazepines.

Animals↗
PubMed1980

GABA-benzodiazepine interactions: physiological, pharmacological and developmental aspects.

Many of the pharmacological actions of the benzodiazepines can be attributed to their actions on gamma-aminobutyric acid (GABA) systms in the brain. Electrophysiological studies on dorsal raphe neurons indicate that the benzodiazepines act postsynaptically to potentiate GABAergic inhibition in this midbrain nucleus. Direct binding studies have shown that both in vitro and in vivo binding of [3H]diazepam to a specific high affinity benzodiazepine binding site in cerebral cortical tissue are enhanced by the direct in vitro addition of GABA and GABA agonists or by pretreatment of animals with GABA analogs and agents that elevate GABA levels in brain. Ontogenic development of [3H]diazepam binding in brain parallels the development of the sodium-independent [3H]GABA binding. The ability of GABA to enhance benzodiazepine binding is present throughout development and inversely related to age. These data suggest that there is a functionally significant interaction between the benzodiazepines and GABA throughout development and at maturity. A model is proposed to relate these interactions to conformational changes in a benzodiazepine/GABA/Cl- ionophore complex.

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↗