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G B Baker

Publications and source records attributed to G B Baker.

At least 73 records · Page 4Linked to original sources
PubMed1996

In vivo biodistribution, pharmacokinetic parameters, and brain uptake of 5-halo-y-methoxy(or ethoxy)-5,6-dihydro-3'-azido-3'-deoxythymidine diastereomers as potential prodrugs of 3'-azido-3'-deoxythymidine.

A new class of 5-halo-6-alkoxy-5,6-dihydro-3'-azido-3'-deoxythymidine diastereomers (5-x-6-OR -5,6-dihydro-AZTs; X = I, Br, Cl; R = Me, Et) were evaluated as potential anti-AIDS prodrugs of 3'-azido-3'-deoxythimidine (AZT). In vivo regeneration of AZT from these 5-X-6-OR-5,6-dihydro-AZTs was examined in Balb/c mice after intravenous tail vein injection. The (5R,6R)- and (5S,6S)-5-bromo(or iodo)-6-methoxy-5,6-dihydro derivatives of AZT (BMAZT, IMAZT) were rapidly converted to AZT, resulting in AZT plasma concentrations after a 144 micromol/kg dose similar to those after an equivalent dose (144 microg/kg, 38.5 mg/kg) of AZT, whereas AZT was not detectable by HPLC after the same dose of the chloro diastereomer (5R,6R)-CMAZT. The interaction of AZT and the 5-X-6-methoxy-5,6dihydro-AZT diastereomers with the 6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine equilibrative-sensitive nucleoside transporter in murine erythrocytes was also studied. The (5R,6R)- and (5S,6S)-5-X-6-OMe-5,6-dihydro-AZT diastereomers demonstrated a high affinity (K(i) = 0.2-0.5 mM) for the transporter relative to AZT (K(i) = 1.3 mM), with the exception of (5S,6R)-5-chloro-6-methoxy-5,6-dihydro-3'-azido-3'-deoxythymidine (CMAZT) which has a K(i) value larger than 1.5 mM. [2-(14)C]-Labeled (5R,6R)- and (5S,6S)-5-bromo-6-methoxy(or ethoxy)- 5,6-dihydro-3'-azido-3'-deoxythymidines were synthesized by the regiospecific addition of methyl hypobromite or ethyl hypobromite to the 5,6-olefinic bond of [2-(14)C]-AZT in high radiochemical yield [(5R,6R)-BMAZT, 48%, and (5S,6S)-BMAZT, 33%; (5R,6R)-BEAZT, 61%, and (5S,6S)-BEAZT, 15%), high radiochemical purity (>98%), and high specific activity (56mCi/mmol)]. The amounts of radioactivity in mouse brain after iv injection of [2-(14))C]-labeled (5R,6R)-BMAZT, (5S,6S)-BMAZT, or (5R,6R)-BEAZT were 2-4 fold higher that that for [2-(14)C]-AZT (P < 0.05). The radioactivity remaining in blood after dosing with these 5-bromo-6-alkoxy-5,6-dihydro-AZTs was up to 20-fold higher than after injection of [2-(14)C]-AZT at longer time intervals after injection. The amounts of radioactivity present in femoral bone following injection of [2(-14)C]-AZT, or these 5-bromo-6-alkoxy-5,6-dihydro-AZTs, were similar. Subcellular and regional distributions of [2-(14)C]-labeled AZT, (5R,6R)-BMAZT, or (5R,6R)-BEAZT in mouse brain after jugular vein injection did not show preferential concentration in any particular subcellular fraction nor a marked preferential regional localization for either AZT or these 5,6-dihydro prodrugs of AZT.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Glutamate receptor agonists decrease extracellular dopamine in the rat nucleus accumbens in vivo.

Intracerebral microdialysis was used to investigate the effects of local application of L-glutamate, N-methyl-D-aspartate, and the glutamate uptake inhibitor 1-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) in the nucleus accumbens (NAc) on extracellular dopamine (DA) concentrations. The effects of locally applied PDC on extracellular glutamate concentrations were also examined. Glutamate produced a concentration-dependent decrease in extracellular DA that could be blocked by concurrent, local application of the broad spectrum ionotropic glutamate receptor antagonist kynurenic acid (KYN:1 mM). N-Methyl-D-aspartate had a concentration-dependent effect on DA release, with a low concentration (0.1 mM) producing a decrease and a higher concentration (1.0 mM) resulting in an increase. Both effects were blocked by KYN. PDC (1 mM) increased extracellular glutamate concentrations to 102% above baseline. The same concentration of PDC decreased extracellular DA concentrations, and coapplication of KYN attenuated this effect. These results indicate that glutamate receptor agonists can have both facilitatory and inhibitory effects on extracellular DA concentrations. However, the effects of PDC indicate that inhibition of DA release is the more physiologically relevant effect. Furthermore, the results of these and other experiments suggest that glutamate's inhibitory effects on DA release in the NAc are not due to direct actions of this excitatory amino acid on DA terminals. A multisynaptic model that accounts for glutamate's actions on DA release is proposed.

Animals↗
PubMed1996

Inhibition of rat brain monoamine oxidase enzymes by fluoxetine and norfluoxetine.

Fluoxetine and its primary metabolite, norfluoxetine, are inhibitors of neuronal uptake of 5-hydroxytryptamine. While fluoxetine has also been reported to inhibit monoamine oxidase (MAO) in vitro at concentrations much lower than those measured in brain following chronic fluoxetine treatment, neurochemical profiles are not consistent with substantial MAO inhibition in vivo. In an attempt to explain this inconsistency, we have examined the interactions of fluoxetine and norfluoxetine with rat brain MAO-A and -B by a radiochemical assay method. Fluoxetine and norfluoxetine were competitive inhibitors of MAO-A in vitro, with Ki values of 76.3 microM and 90.5 microM, respectively. Both compounds were non-competitive or uncompetitive inhibitors of MAO-B in vitro. Inhibition of MAO-B was time-dependent and was very slowly reversible by dialysis. IC50 values versus metabolism of 50 microM beta-phenylethylamine were 17.8 microM (fluoxetine) and 18.5 microM (norfluoxetine). Analysis of the time-dependence of MAO-B inhibition by fluoxetine revealed that an initial competitive interaction between the enzyme and the inhibitor (Ki 245 microM) was followed by tight-binding enzyme inactivation (K(inact) 0.071 min-1). Following administration of fluoxetine (20 mg kg-1 day-1) for 7 days, the cortical concentration of fluoxetine + norfluoxetine was estimated by gas-liquid chromatography to be 700 microM. Such drug treatment reduced MAO-A activity by 23% in 1:8 (w/v) cortical homogenates, but not in 1:80 homogenates. Inhibition of MAO-B in 1:8 homogenates was modest (12%) and was not significantly reduced by homogenate dilution. The concentration of 5-hydroxyindole-3-acetic acid, measured by high pressure liquid chromatography, was reduced by 47% in cortices from drug-treated rats, while concentrations of 5-hydroxytryptamine, noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were unchanged. These results suggest that, following chronic drug administration leading to relatively high tissue concentrations of fluoxetine and norfluoxetine, inhibition of either form of MAO would be restricted by competition for the enzyme with intraneuronal amine substrates.

Animals↗
PubMed1996

Anti-serotonergic effects of urethane and chloral hydrate may not be mediated by a blockade of 5-HT2 receptors. Short communication.

The general anesthetics urethane and chloral hydrate have profound anti-serotonergic effects both in the rat cortex in vivo and the rat aortic ring in vitro. The suggestion that these effects may be due to an action on 5-HT2 receptors was tested using ex vivo and in vitro [3H]ketanserin binding assays with membrane-enriched fractions from rat brain. Urethane did not alter [3H]ketanserin binding in the ex vivo assay. In the in vitro assay, urethane, chloral hydrate, and its active metabolite 2,2,2-trichloroethanol produced slight reductions (of 16%, 9%, and 18%, respectively) of [3H]ketanserin binding. These studies suggest that anti-serotonergic effects of urethane and chloral hydrate may not be mediated by a blockade of 5-HT2 receptors.

Anesthetics, Intravenous↗
PubMed1996

The antidepressant drug phenelzine produces antianxiety effects in the plus-maze and increases in rat brain GABA.

Research on the effects of antidepressant/ antipanic drugs in animal models of anxiety has yielded equivocal results, even after chronic drug regimens. In contrast, we found that the antidepressant/antipanic drug phenelzine, given acutely, produced a clear anxiolytic effect in the elevated plus-maze, a widely-used animal model of "anxiety" that is primarily sensitive to benzodiazepine-type anxiolytics (e.g., diazepam). Furthermore, the effective dose of phenelzine (15 mg/kg) administered to rats was associated with more than a 2- fold increase in whole brain levels of gamma-aminobutyric acid (GABA), whereas an ineffective dose of phenelzine (5.1 mg/kg) did not significantly change GABA levels. The N-acetylated metabolite of phenelzine, N2-acetylphenelzine, produced neither an anxiolytic effect in the elevated plus-maze nor a significant change in whole-brain levels of GABA. However, both phenelzine and N2-acetylphenelzine potently inhibited monoamine oxidase, a mechanism commonly thought to be involved in the therapeutic effects of monoamine oxidase inhibitors such as phenelzine in the treatment of depression in humans. These results suggest that the mechanism whereby phenelzine produces anxiolytic effects in the plus-maze model is unique to a facilitatory action on brain levels of GABA, in contrast to classical benzodiazepines, which produce anxiolytic effects by enhancing the affinity of the GABAA-receptor for GABA.

Animals↗
PubMed1996

The role of brain noradrenaline in cortical activation and behavior: a study of lesions of the locus coeruleus, medial thalamus and hippocampus-neocortex and of muscarinic blockade in the rat.

Local injection of 6-hydroxydopamine in the locus coeruleus resulted in a 90% depletion of noradrenaline (NA) in the cerebral cortex as assessed by high-pressure liquid chromatography. This NA depletion had no effect on scopolamine-resistant hippocampal rhythmical slow activity and only an occasional effect on scopolamine-resistant neocortical low voltage fast activity. However, NE depletion resulted in a slight deficit in a behavioral swim-to-platform test and increased the deficit produced on the test by systemic treatment with scopolamine. Large surgical lesions of the medial thalamus or hippocampal formation plus posterior neocortex greatly increased the behavioral deficit produced by scopolamine. It is concluded that ascending noradrenergic projections play only a modest and possibly indirect role in the control of electrocortical activation and that a number of different brain lesions increase the behavioral impairment produced by central muscarinic blockade.

Animals↗
PubMed1996

The future of antidepressants.

A common action of many antidepressants is the inhibition of the reuptake of the biogenic amines norepinephrine, serotonin (5-HT) and/or dopamine into nerve terminals. Another postulated mechanism of action for many antidepressants is the downregulation of beta-adrenergic receptors postsynaptically after chronic administration. Many antidepressants have been reported to produce changes in the regulation of 5-HT1 and 5-HT2 receptors chronically. None of these mechanisms is completely satisfactory as a common antidepressant mechanism of action. Is it possible to unify these hypotheses of antidepressant action? A number of receptor changes have been recognized in depression. Usually, these implicated receptors are linked to a G protein. Thus, it could be hypothesized that depression may be the result of a disorder of the large family of receptor-linked G proteins. Depression, a disorder in which there seems to be an important genetic component, could be expressed in either the receptor or in the G proteins, leading to a defective linkage between the receptor and the G protein, resulting in abnormal transduction mechanisms. The concept of antidepressants is changing rapidly as these agents appear with new therapeutic indications other than depression, such as panic disorder, obsessive compulsive disorder, etc. It can be expected that the presently available antidepressants might eventually be considered anxiolytics or that benzodiazepines and 5-HT1A agonists could come to be viewed as disinhibiting substances.

Antidepressive Agents↗
PubMed1996

Differential effects of clonidine, lithium and quinine in the forced swimming test in mice for antidepressants: possible roles of serotoninergic systems.

The forced swimming test (FST) is a behavioral test used to predict the efficacy of antidepressant (AD) treatments. In the present study, it was found that, when combined with clonidine, lithium or quinine, subactive doses of several types of ADs (tricyclics, 5-HT uptake inhibitors and atypical ADs) produced anti-immobility effects in mice. Clonidine (0.06 mg/kg) was found to potentiate the AD-like effects of all the drugs tested in the FST. More interesting is the additivity of gepirone with lithium (1 mEq/l), and ondansetron with quinine (0.5 mg/kg). The results of the present study are in favour of the potentiation of AD activity by clonidine via 5-HT2 receptors, lithium through 5-HT1A receptors, and quinine through 5-HT3 receptors. Further studies to examine in detail which of these three 5-HT receptors or their subtypes is the most important in the actions of individual ADs are warranted.

Animals↗
PubMed1996

Chronic administration of antipanic drugs alters rat brainstem GABAA receptor subunit mRNA levels.

Mental illness, such as panic disorder and depression, display comorbidity as well as common therapeutic treatments. These features point toward a common etiology and/or therapeutic pathway. There is evidence to suggest that some antipanic agents may mediate their effects by altering gamma-aminobutyric acid (GABA) levels or by modulating the activity of the GABAA receptor. Chronic stimulation of GABAA receptors by agonists or modulators results in changes in the pharmacological properties of the receptor concomitant with alterations in the expression of specific GABAA receptor subunits. Therefore, we investigated the hypothesis that long-term exposure to three antidepressant/antipanic drugs (imipramine, phenelzine and alprazolam) would produce changes in the steady-state levels of those subunit mRNAs that are believed to encode the major GABAA receptor subtype. Further, these changes in gene expression would be different to those produced by the non-antipanic anxiolytic (buspirone). We report here that, following a 21 day treatment, imipramine, phenelzine, alprazolam and buspirone differentially altered rat brainstem levels of GABAA receptor alpha 1-, beta 2- and gamma 2-subunit RNAs. These results demonstrate novel actions of antidepressant/antipanic drugs on GABAergic neurotransmission.

Animals↗
PubMed1996

A schematic representation of the psychopharmacological profile of antidepressants.

1. Using simple animal tests, "behavioural" and "biochemical" aspects of depression, anxiolysis, disinhibition, psychostimulation and sedation were investigated in mice using a variety of antidepressant drugs. 2. Dothiepin and mianserin (16 and 32 mg/kg), fluoxetine (32 and 64 mg/kg), maprotiline and imipramine (16, 32 and 64 mg/kg) and viloxazine (16 mg/kg) significantly potentiated mortality following acute administration with yohimbine. 3. Dothiepin and imipramine (32 mg/kg), fluoxetine (16 and 32 mg/kg), viloxazine (8 and 16 mg/kg), maprotiline (32 mg/kg) and mianserin (32 mg/kg) reduced immobility time in the forced swimming test. 4. In the black and white box, dothiepin (32 mg/kg) significantly increased the time spent in the bright compartment: Fluoxetine (8 and 16 mg/kg) significantly increased the number of crossings between compartments, an effect indicative of desinhibition. 5. It can be concluded that dothiepin possesses both antidepressant and anxiolytic properties in these animal models. The present procedure is useful not only for the screening of compounds that may possess antidepressant properties, but is also of value in determining other properties that may contribute to the overall clinical efficacy of the drugs.

Adrenergic alpha-Antagonists↗
PubMed1995

GABA-elevating effects of the antidepressant/antipanic drug phenelzine in brain: effects of pretreatment with tranylcypromine, (-)-deprenyl and clorgyline.

The antidepressant/antipanic drug phenelzine (PLZ) is both an inhibitor of, and a substrate for, monoamine oxidase (MAO). PLZ also causes an elevation of brain levels of the amino acid neurotransmitter gamma-aminobutyric acid (GABA); this action can be reversed by pretreatment with the MAO inhibitor tranylcypromine (TCP), suggesting that the GABA-elevating effect is largely the result of a metabolite of PLZ formed by MAO. In the present report, rats were pretreated with the nonselective MAO inhibitor TCP, the MAO-A inhibitor clorgyline and the MAO-B inhibitor (-)-deprenyl: at the doses used, clorgyline and (-)-deprenyl caused selective inhibition of MAO-A and MAO-B, respectively. Both TCP and (-)-deprenyl caused a greater reduction in the GABA-elevating action of PLZ than did clorgyline, suggesting that MAO-B is more important than MAO-A in the formation of the active metabolite of PLZ. The results also suggest that an effect other than, or in addition to, inhibition of GABA transaminase by the metabolite may be important in the GABA-elevating action.

4-Aminobutyrate Transaminase↗
PubMed1995

Chronic administration of the antidepressants phenelzine, desipramine, clomipramine, or maprotiline decreases binding to 5-hydroxytryptamine2A receptors without affecting benzodiazepine binding sites in rat brain.

1. The effects of chronic administration of five antidepressant drugs on the benzodiazepine and 5-HT2A binding sites in the same rat brain were assessed. 2. Clomipramine, desipramine, maprotiline, fluoxetine, and phenelzine (all 10 mg/kg/day) were administered s.c. for 21 days by Alzet osmotic minipumps. 3. Results showed that none of the drugs changed the density or affinity of benzodiazepine binding sites, yet at the same dose all the drugs with the exception of fluoxetine decreased binding to 5-HT2A receptors in the same animals.

Animals↗
PubMed1995

Comparative behavioural and neurochemical studies with a psychomotor stimulant, an hallucinogen and 3,4-methylenedioxy analogues of amphetamine.

Spontaneous behaviours were assessed in freely moving rats after treatment with equimolar doses of drugs that share a basic amphetamine structure. The drugs used included a psychomotor stimulant [(+)-amphetamine (AMPH)], an hallucinogen [para-methoxyamphetamine (PMA)] and the entactogens 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxy-N-ethylamphetamine (MDE). A detailed analysis of the frequency and duration of 30 different behaviours and the temporal organization of the behaviours was conducted in addition to measuring motor activity with an automated device. Levels of the biogenic amines and their acid metabolites in discrete brain regions and brain drug levels were also obtained. The automated motor activity measures discriminated among entactogens, the stimulant and the hallucinogen, but failed to distinguish between the hallucinogen and vehicle. Principal components analysis and cluster analysis of the frequencies and durations of the behaviours did not improve the classification of the drugs over the automated motor activity measures. Only the cluster analysis of the transitions between individual behaviours succeeded in differentiating the drug classes from each other and from vehicle treatment. All the behavioural measures classified one entactogen (MDE) as an hallucinogen. Cortical 5-hydroxytryptamine (5-HT) measures grouped MDE with the other entactogens but did not distinguish AMPH from vehicle. However, striatal dopamine measures differentiated AMPH from vehicle treatment. Variations in the durations of behavioural effects across drugs were associated with large differences in drug levels 3 h after injection. Although the neurochemical data provided a classification system that most closely parallels human subjective effects of these drugs, both the neurochemical and the behavioural measures supported the existence of an entactogen class distinct from a psychomotor stimulant and an hallucinogen.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

p-chlorophenylalanine-induced serotonin depletion: reduction in exploratory locomotion but no obvious sensory-motor deficits.

Para-chlorophenylalanine (PCPA) depletes central serotonin (5-hydroxytryptamine, 5-HT) by inhibiting tryptophan hydroxylase, an enzyme necessary for the synthesis of 5-HT. The effects of a wide range of PCPA doses (150-1000 mg/kg) on spontaneous exploratory locomotor activity in a novel environment, activity in running wheels and a number of sensory-motor capacities were examined. Administration of 1000 mg/kg PCPA reduced whole brain levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid to 9.4 and 8.2% of control levels, respectively. Treatment with PCPA produced a dose-dependent decrease in exploratory locomotion in an unfamiliar automated open field relative to vehicle-treated animals. Further, all measures of general, horizontal and vertical activity were suppressed by PCPA treatment. In contrast to previous work, hyperactivity of rats chronically housed in cages with running wheel access was not observed. In their home cages, some PCPA-treated rats exhibited hyper-reactivity to cutaneous stimulation. No other sensory-motor deficits were apparent. Previous theories of 5-HT function state that its action may be to inhibit motor activity or promote sleep. The present results challenge this view and suggest that 5-HT, at least in certain environments, may stimulate locomotor activity without directly controlling various sensory-motor capacities in rats.

Animals↗
PubMed1995

Analysis of the enantiomers of 3,4-methylenedioxy-N-ethylamphetamine (MDE, "Eve") and its metabolite 3,4-methylenedioxyamphetamine (MDA) in rat brain.

The methylenedioxy analogues of amphetamine are used recreationally despite concerns raised regarding potential neurotoxicity of the parent compounds and a number of metabolites. Much has been written regarding 3,4-methylenedioxymethamphetamine (MDMA; 3,4-methylenedioxy-N-ethylamphetamine (MDE; "Eve"), despite recent reports indicating the abuse of this drug and its potentially serious side effects. An assay procedure was developed for the simultaneous quantitation of both enantiomers of MDE and its metabolite MDA; the method involves derivatization with an optically pure reagent and analysis on a gas chromatograph equipped with a capillary column and a nitrogen-phosphorus detector. Brain levels of the enantiomers of MDE and MDA were examined in the rat at different time periods after acute i.p. injections of racemic MDE and the results were compared with levels of MDMA and MDA obtained after i.p. injection of MDMA in a previous study from our laboratories. The levels of the enantiomers of MDE and MDA achieved at 1, 4, and 8 hr were lower than in the case of MDMA. Stereoselective differences in brain levels of enantiomers of the parent drug and metabolite were much less marked with MDE than with MDMA, but where these small differences did exist in the case of MDE, the (R)-(-) vs (S)-(+) relationship was opposite to that reported for MDMA.

3,4-Methylenedioxyamphetamine↗
PubMed1995

Simultaneous quantification of fluoxetine, norfluoxetine, and desipramine using gas chromatography with nitrogen-phosphorus detection.

The combination of fluoxetine (FLU) and desipramine (DMI) has been reported to be useful for the treatment of depression, and these drugs are also known to undergo a metabolic drug-drug interaction because of their effects on cytochrome P-450 2D6. A procedure that separates these two drugs and norfluoxetine (NFLU), the N-demethylated metabolite of FLU, and that allows simultaneous quantification of their levels would be of value and has been developed in our laboratories. The procedure involves an initial extraction into ethyl acetate after basification of the homogenate. The organic phase is retained and taken to dryness; the residue is reconstituted in water and acetylated with acetic anhydride under slightly basic conditions. Ethyl acetate is then used to extract the acetylated compounds from the aqueous medium. The organic layer is taken to dryness and the residue reconstituted in toluene. An aliquot of the solution in toluene is injected directly into a gas chromatograph equipped with a nitrogen-phosphorus detector, a fused silica capillary column, and an integrator/printer. Maprotiline is added to the initial homogenate and carried through the procedure as the internal standard. The assay is rapid and sensitive and has been applied successfully to liver and brain tissue taken from rats treated with FLU, DMI, or the combination.

Animals↗