PubMed Health⌕ Search

Biomedical subjects

James M Cook

Publications and source records attributed to James M Cook.

At least 37 records · Page 2Linked to original sources
PubMed2005

Contribution of alpha 1GABAA and alpha 5GABAA receptor subtypes to the discriminative stimulus effects of ethanol in squirrel monkeys.

Ethanol's ability to enhance GABA neurotransmission via GABA(A) receptors has been implicated as an important mechanism underlying its discriminative stimulus (DS) effects in animals and subjective effects in humans. The present study assessed the contribution of alpha(1)GABA(A) and alpha(5)GABA(A) receptors to the DS effects of ethanol. Squirrel were monkeys trained to discriminate i.v. ethanol from saline under a fixed-ratio schedule of food delivery. Under test conditions, ethanol engendered a dose-dependent increase in drug-lever responding, reaching an average maximum of >80%. In substitution experiments, the alpha(1)GABA(A) agonists zolpidem, zaleplon, and CL 218,872 (3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine), the alpha(5)GABA(A) agonists QH-ii-066 (1-methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzo[e]-1,4-diazepin-2-one) and panadiplon [3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)imidazo(1,5-a)quinoxalin-4(5H)-one], and representative nonselective agonists partially to fully reproduced the ethanol DS. In antagonism studies, the alpha(1)GABA(A) antagonist beta-carboline-t-butyl ester did not attenuate the DS effects of ethanol or the ethanol-like effects of zolpidem and zaleplon. In contrast, pretreatment with the alpha(5)GABA(A) inverse agonist L-655,708 (ethyl[S]-11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxlate) dose-dependently attenuated the DS effects of ethanol and the ethanol-like effects of QH-ii-066. RY-23 (tert-butyl 8-[(trimethylsilyl)ethynyl]-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]-[1,4]benzodiazepine-3-carboxylate), another alpha(5)GABA(A) inverse agonist, similarly attenuated the ethanol-like DS effects of QH-ii-066. Antagonism of both QH-ii-066 and ethanol by the alpha(5)GABA(A) inverse agonists occurred at doses that did not alter the rate of responding suggesting that this blockade was pharmacologically specific and not the result of a nonspecific disruption of operant behavior. These findings suggest a key role for alpha(5)GABA(A), but not alpha(1)GABA(A), receptor mechanisms in the DS effects of ethanol and the ethanol-like DS effects of benzodiazepine agonists.

Animals↗
PubMed2005

Selective antagonism of GABAA receptor subtypes: an in vivo approach to exploring the therapeutic and side effects of benzodiazepine-type drugs.

Benzodiazepines (BZs) are clinically used as anxiolytic, hypnotic, anticonvulsant, and antispasmodic drugs. Research using transgenic mouse models has suggested that the effects of BZs involve multiple subtypes of the gamma-aminobutyric acid type A (GABAA) receptor, identified by specific a subunits (alpha1, alpha2, alpha3, alpha5). This review discusses the experimental uses of b-carboline-3-carboxylate-t-butyl ester (betaCCT), a drug that binds preferentially to the GABAA alpha1 subtype but exerts no action (ie, is a pharmacologic antagonist at the GABAA alpha1 subtype receptor). betaCCT blocks the anxiolytic-like effects of BZs, although studies in primates suggests this antagonism may reflect multiple receptor populations. betaCCT antagonized the ataxic but not muscle relaxant effects of BZs, a finding that implicates the GABAA alpha1 subtype receptor in ataxia but not muscle relaxation. The potential clinical utility of betaCCT is discussed, both in terms of treatment (ie, hepatic encephalopathy) and as a diagnostic imaging agent. Altogether, these results indicate that subtype-selective antagonists represent a useful approach to studying receptor mechanisms underlying the behavioral effects of BZ-type drugs.

Animals↗
PubMed2005

Selective GABAA alpha5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol.

BACKGROUND: Previous research has implicated the alpha5-containing GABAA receptors of the hippocampus in the reinforcing properties of alcohol. In the present study, a selective GABAA alpha5 benzodiazepine inverse agonist (e.g., RY 023) was used in a series of in vivo and in vitro studies to determine the significance of the alpha5-receptor in the neurobehavioral actions of alcohol. METHODS: In experiment one, systemic injections of RY 023 (1 to 10 mg/kg IP) dose-dependently reduced ethanol-maintained responding by 52% to 86% of controls, whereas bilateral hippocampal infusions (0.3 to 20 microg) reduced responding by 66% to 84% of controls. Saccharin responding was reduced only with the highest intraperitoneal (e.g., 10 mg) and microinjected (e.g., 20 microg) doses. In experiment two, RY 023 (3.0 to 15 mg/kg IP) reversed the motor-impairing effects of a moderate dose of alcohol (0.75 g/kg) on an oscillating bar task in the absence of intrinsic effects. In the open field, RY 023 (3.0 to 7.5 mg/kg) produced intrinsic effects alone but attenuated the suppression of the 1.25 g/kg ethanol dose. Because the diazepam-insensitive receptors (e.g., alpha4 and alpha6) have been suggested to play a role in alcohol motor impairing and sedative actions, experiment three compared the efficacy of RY 023 with Ro 15-4513 and two prototypical benzodiazepine antagonists (e.g., flumazenil and ZK 93426) across the alpha4beta3gamma2-, alpha5beta3gamma2-, and alpha6beta3gamma2-receptor subtypes in Xenopus oocytes. RESULTS: RY 023 produced classic inverse agonism at all receptor subtypes, whereas Ro15-4513 and the two antagonists displayed a neutral or agonistic profile at the diazepam-insensitive receptors. CONCLUSIONS: Overall, the results extend our previous findings by demonstrating that an alpha5-subtype ligand is capable of attenuating not only the rewarding action of alcohol but also its motor impairing and sedative effects. We propose that these actions are mediated in part by the alpha5-receptors of the hippocampus. The hippocampal alpha5-receptors could represent novel targets in understanding the neuromechanisms regulating the neurobehavioral actions of alcohol in humans.

Alcohol Deterrents↗
PubMed2004

Oviposition strategies, host coercion and the stable exploitation of figs by wasps.

A classic example of a mutualism is the one between fig plants (Ficus) and their specialized and obligate pollinating wasps. The wasps deposit eggs in fig ovules, which the larvae then consume. Because the wasps derive their fitness only from consumed seeds, this mutualism can persist only if the wasps are prevented from laying eggs in all ovules. The search for mechanisms that can limit oviposition and stabilize the wasp-seed conflict has spanned more than three decades. We use a simple foraging model, parameterized with data from two Ficus species, to show how fig morphology reduces oviposition rates and helps to resolve the wasp-seed conflict. We also propose additional mechanisms, based on known aspects of fig biology, which can prevent even large numbers of wasps from ovipositing in all ovules. It has been suggested that in mutualistic symbioses, the partner that controls the physical resources, in this case Ficus, ultimately controls the rate at which hosts are converted to visitors, regardless of relative evolutionary rates. Our approach provides a mechanistic implementation of this idea, with potential applications to other mutualisms and to theories of virulence.

Animals↗
PubMed2004

Determination of the stable conformation of GABA(A)-benzodiazepine receptor bivalent ligands by low temperature NMR and X-ray analysis.

The stable conformations of GABA(A)-benzodiazepine receptor bivalent ligands 2 and 3 were determined by low temperature NMR spectroscopy and confirmed by single crystal X-ray analysis. The linear conformation was important for these dimers to access the binding site and exhibit potent in vitro affinity as illustrated for alpha5 subtype selective ligand 2 (15 nM). Bivalent ligand 3 with the 5 atom linker folded back upon itself both in solution and in the solid state, moreover, it did not bind to Bz receptors.

Crystallography, X-Ray↗
PubMed2004

Stereocontrolled total synthesis of (-)-vincamajinine and (-)-11-methoxy-17-epivincamajine.

The first total syntheses of (-)-vincamajinine (5) (from Na-methyl-d-tryptophan methyl ester) and (-)-11-methoxy-17-epivincamajine (6) (from Na-methyl-6-methoxy-d-tryptophan ethyl ester) are described. The syntheses have been completed in a highly stereocontrolled manner (>98% ee). Key steps included the asymmetric Pictet-Spengler reaction, enolate-mediated palladium cross-coupling reaction, and acid-catalyzed formation of the C(7)-C(17) bond. In addition, the triethylsilane/TFA-mediated incorporation of the 2alpha-H (11 to 12) and the borohydride generation of the C(17) hydroxyl function (R) were also stereospecific. The unique highly conjested carbon skeletons of the two alkaloids were completed in a concise manner and in regiospecific fashion.

Alstonia↗
PubMed2004

Regiospecific, enantiospecific total synthesis of the 12-alkoxy-substituted indole alkaloids, (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline.

[reaction: see text] The enantiospecific synthesis of 7-methoxy-d-tryptophan was completed by combination of the Larock heteroannulation process with a Schöllkopf-based chiral auxiliary in good yield. This ester was then employed in the first total synthesis of (+)-12-methoxy-Na-methylvellosimine, (+)-12-methoxyaffinisine, and (-)-fuchsiaefoline in regiospecific, stereospecific fashion in excellent overall yield. The asymmetric Pictet-Spengler reaction and enolate-driven palladium-catalyzed cross coupling processes served as key steps.

Journal Article↗
PubMed2004

Bidirectional effects of benzodiazepine binding site ligands in the elevated plus-maze: differential antagonism by flumazenil and beta-CCt.

Recent research using genetically modified mice has pointed to the specific contribution of individual receptor subtypes to the various effects of benzodiazepines. The aim of this study was to examine the relative significance of alpha(1)-containing GABA(A) receptors in the effects of modulators at the benzodiazepine site in the elevated plus-maze (EPM) under dim red light in rats. We tested the effects of the non-selective antagonist flumazenil (0-20.0 mg/kg), the preferential alpha(1)-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt, 0-30.0 mg/kg), the non-selective agonist midazolam (0-2.0 mg/kg), the preferential alpha(1)-subunit selective agonist zolpidem (0-2.0 mg/kg) and the non-selective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM, 0-2.0 mg/kg). The influence of flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg) on the effects of both kinds of agonists were also examined. The standard spatio-temporal parameters reflecting anxiety (percentage of open arm entries and time) and locomotion (closed and total arm entries) were analyzed. beta-CCt did not affect behavior, while flumazenil at the highest dose (20.0 mg/kg) decreased indices of open arm activity and total arm entries. Midazolam at the dose of 1.0 mg/kg significantly increased the percentage of open arm time, whereas at 2.0 mg/kg both anxiety-related parameters were increased. In contrast to the open arm entries, the open arm time was independent of the decreased closed arm entries, observed at 2.0 mg/kg. Flumazenil abolished these effects, whereas beta-CCt partially potentiated the anxiolytic actions of midazolam. Zolpidem significantly increased both open-arm indices at 1.0 mg/kg, but the effect was dependent on the decreased closed arm entries. The selectivity of the anxiolytic-like effects of zolpidem was further checked under brighter white illumination. In these settings, the influence on anxiety-related, but not activity-related parameters, was absent. All of the activity-related effects of midazolam and zolpidem were mainly counteracted by both antagonists. DMCM produced significant anxiogenic effects at 1.0 mg/kg (open arm time) and 2.0 mg/kg (both parameters). beta-CCt (30.0 mg/kg) and flumazenil at higher dose (20.0 mg/kg) antagonized the effects of DMCM. The results indicate the anxiolytic effects of a non-selective benzodiazepine site agonist involve a predominant role of subunits other than alpha(1), whereas the behavioral indices of the anxiolytic-like properties of an alpha(1)-selective ligand, if observed, depend on the experimental settings and the changes in locomotor activity, and hence were behaviorally non-specific. The present results generally correspond well to the behavioral findings with the genetically modified mice. On the other hand, the relative significance of the alpha(1)-subunit in the anxiogenic effects of DMCM could not be clearly deduced.

Animals↗
PubMed2004

GABA(A) and opioid receptors of the central nucleus of the amygdala selectively regulate ethanol-maintained behaviors.

The present study tested the hypothesis that GABA(A) and opioid receptors within the central nucleus of the amygdala (CeA) regulate ethanol (EtOH), but not sucrose-maintained responding. To accomplish this, betaCCt, a mixed benzodiazepine (BDZ) agonist-antagonist with binding selectivity at the alpha1 subunit-containing GABA(A) receptor, and the nonselective opioid antagonist, naltrexone, were bilaterally infused directly into the CeA of alcohol-preferring rats. The results demonstrated that in HAD-1 and P rat lines, betaCCt (5-60 microg) reduced EtOH-maintained responding by 56-89% of control levels. On day 2, betaCCt (10-40 microg) continued to suppress EtOH maintained responding in HAD-1 rats by as much as 60-85% of control levels. Similarly, naltrexone (0.5-30 microg) reduced EtOH-maintained responding by 56-75% of control levels in P rats. betaCCt and naltrexone exhibited neuroanatomical and reinforcer specificity within the CeA. Specifically, no effects on EtOH-maintained responding were observed following infusion into the caudate putamen (CPu), a locus several millimeters dorsal to the CeA. Additionally, responding maintained by sucrose, when presented concurrently with ethanol (EtOH) or presented alone, was not altered by betaCCt. Naltrexone reduced sucrose-maintained responding only under the 5 microg dose condition when sucrose was presented alone, however, it did not alter sucrose responding when given concurrently with EtOH. These results support the hypothesis that GABA(A) and opioid receptors within the CeA can selectively regulate EtOH-maintained responding. The CeA may represent a novel target site in the development of prototypical GABA(A) and opioidergic receptor ligands, which selectively reduce alcohol abuse in humans.

Alcoholism↗
PubMed2003

Synthesis, in vitro affinity, and efficacy of a bis 8-ethynyl-4H-imidazo[1,5a]- [1,4]benzodiazepine analogue, the first bivalent alpha5 subtype selective BzR/GABA(A) antagonist.

The synthesis and in vitro affinity of the alpha5beta3gamma2 (alpha5) subtype selective BzR/GABA(A) antagonist 7 is described. This ligand is selective for alpha5 subtypes in vitro and is a potent antagonist of the effects of diazepam only at alpha5beta3gamma2 subtypes (oocytes). Ligands such as 7 will be important in the determination of which physiological function(s) are subserved by this GABA(A) alpha5 subtype.

Animals↗
PubMed2003

A high affinity ligand for GABAA-receptor containing alpha5 subunit antagonizes ethanol's neurobehavioral effects in Long-Evans rats.

RATIONALE: Previously, we reported that the GABA(A)receptor containing alpha(5)subunit played a significant role in the reinforcing actions of EtOH in rats selectively bred to consume alcohol. However, the role of the alpha(5) receptor in regulating the neurobehavioral effects of EtOH in outbred rats is not known. OBJECTIVE: In the present study, RY024, a novel benzodiazepine (BDZ) inverse agonist with high affinity (K(d) approximately 0.40 nM) and selectivity (approximately 67.3-fold) for the alpha(5)receptor, was investigated for its capacity to antagonize EtOH's reinforcing, motor impairing, and sedative effects in Long-Evans rats. METHODS: Rats were trained to lever press for EtOH under a fixed-ratio 1 schedule of reinforcement. Subsequent studies evaluated EtOH's motor-impairing effects in an oscillating bar task, while EtOH's sedative effects were measured in the open field. RESULTS: RY024 (0.125-3.5 mg/kg; IP) markedly reduced EtOH-maintained responding with no effects on water responding, except for the highest dose. RY024 (3.0-15 mg/kg; IP) also reversed the motor impairing effects of a moderate (0.75 g/kg), and intoxicating EtOH dose (1.25 g/kg) in the absence of intrinsic effects. Finally, RY024 (7.5 mg/kg) attenuated the sedation produced by the 1.25 g/kg EtOH dose; however, it failed to attenuate the sedation induced by the 0.75 g/kg EtOH dose. Given alone, RY024 exhibited intrinsic effects in the open field. CONCLUSION: The results suggest the GABA(A)receptor containing alpha(5)subtype plays an important role in regulating the reinforcing, motor-impairing, and sedative effects of alcohol in outbred rats.

Animals↗
PubMed2003

GABAA/alpha1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice.

RATIONALE: The positive modulation of gamma-aminobutyric acid type-A (GABAA) receptors is a putative mechanism via which alcohol escalates aggressive behavior. Broad-spectrum benzodiazepine antagonists block alcohol-heightened aggression in rats and monkeys. However, the degree to which GABAA subunit composition plays a role in heightened aggressive behavior induced by self-administration of a moderate alcohol dose remains unresolved. OBJECTIVE: Beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) and zolpidem act preferentially at GABAA receptors containing the alpha1 subunit as antagonist and agonist, respectively, and serve as useful tools to evaluate the role of GABAA receptor subtypes in self-administered alcohol on aggression. METHODS: Male resident mice, housed in breeding pairs, were conditioned to nose-poke in a removable panel in their home cage, with each fifth poke being reinforced by the delivery of 0.05 ml of 6% ethanol (EtOH). After consuming EtOH, the resident mice were given the antagonists beta-CCt and flumazenil or agonists zolpidem and triazolam, and then confronted an intruder male in their home cage for a 5-min period. RESULTS: Following self-administration of EtOH (1.0 g/kg, 1.7 g/kg), 14 of 37 resident mice displayed unusually large increases in the frequency of attack bites and sideways threats. Flumazenil or beta-CCt decreased alcohol-heightened and non-heightened aggression in a dose-dependent manner. Administration of 3 mg/kg beta-CCt lowered the aggression-heightening effects of 1 g/kg and 1.7 g/kg EtOH, but did not antagonize the sedative effects of 3.0 g/kg EtOH. Triazolam and zolpidem decreased alcohol-heightened and non-heightened aggressive behavior, and these antiaggressive effects were accompanied by reduced motor activity, indicating sedation. CONCLUSIONS: Benzodiazepine antagonists, particularly those acting preferentially at GABAA/alpha1 subunit-containing receptors, decrease alcohol-heightened and species-typical aggressive behavior, but are ineffective in attenuating the sedative effects of alcohol.

Aggression↗
PubMed2003

General approach for the synthesis of sarpagine indole alkaloids. Enantiospecific total synthesis of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, (+)-Na-methylvellosimine, and (+)-Na-methyl-16-epipericyclivine.

The first total synthesis of (+)-Na-methyl-16-epipericyclivine (9) was completed [from d-(+)-tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation [[alpha]D +22.8 (c 0.50, CHCl3)] obtained on this material confirmed that the reported optical rotation [[alpha]D 0 (c 0.50, CHCl3)]47 was biogenetically unreasonable. The total syntheses of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, and (+)-Na-methylvellosimine are also described. Moreover, a mixed sample (1:1) of synthetic (-)-panarine and natural (-)-panarine yielded only one set of signals in the 13C NMR; this indicated that the two compounds are identical and further confirmed the correct configuration of (+)-vellosimine, (+)-normacusine B, and (-)-alkaloid Q3. In this approach, the key templates, (-)-Na-H,Nb-benzyltetracyclic ketone 15a and (-)-Na-methyl,Nb-benzyltetracyclic ketone 43 were synthesized on multihundred gram scale by the asymmetric Pictet-Spengler reaction and a stereocontrolled Dieckmann cyclization via improved sequences. An intramolecular palladium (enolate-mediated) coupling reaction was employed to introduce the C(19)-C(20) E-ethylidene function in the sarpagine alkaloids for the first time in stereospecific fashion.

Alkaloids↗
PubMed2003

The enantiospecific, stereospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-majvinine, (+)-10-methoxyaffinisine, and (+)-N(a)-methylsarpagine, as well as the total synthesis of the alstonia bisindole alkaloid macralstonidine.

The first stereospecific, enantiospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-N(a)-methylsarpagine (8), (+)-majvinine (14), and (+)-10-methoxyaffinisine (49), as well as the first total synthesis of the Alstonia bisindole alkaloid macralstonidine (9), has been accomplished. This approach employed the Schöllkopf chiral auxiliary for the stereospecific construction of the desired d-(+)-tryptophan unit required for the asymmetric Pictet-Spengler reaction. In addition, the strategy was doubly convergent for the enolate-mediated Pd(0) coupling process and the asymmetric Pictet-Spengler reaction can be employed to synthesize both macroline (2) and N(a)-methylsarpagine (8), the coupling of which provides macralstonidine (9). This approach to ring-A substituted alkoxyindole alkaloids should find wide application for the synthesis of other alkaloids for it is stereospecific and either enantiomer can be prepared with ease.

Alstonia↗
PubMed2003

Enantiospecific total synthesis of (-)-(E)16-epiaffinisine, (+)-(E)16-epinormacusine B, and (+)-dehydro-16-epiaffinisine as well as the stereocontrolled total synthesis of alkaloid G.

An efficient strategy is described for the total synthesis of the sarpagine-related indole alkaloids (-)-(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2), and (+)-dehydro-16-epiaffinisine (4). A key step employed the chemospecific and regiospecific hydroboration/oxidation at C(16)-C(17); this method has also resulted in the synthesis of (+)-dehydro-16-epinormacusine B (5). The oxy-anion Cope rearrangement followed by protonation of the enolate that resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (7) in a highly stereocontrolled fashion (>43:1). Conditions that favor control of the sarpagine stereochemistry at C(16) vs the epimeric ajmaline configuration at the same stereocenter have been determined. The formation of the required cyclic ether in 4, 5, and 7 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF or DDQ/aq THF in excellent yields.

Ajmaline↗
PubMed2003

Lifecycle closure, lineage sorting, and hybridization revealed in a phylogenetic analysis of European oak gallwasps (Hymenoptera: Cynipidae: Cynipini) using mitochondrial sequence data.

Oak gallwasps are cyclically parthenogenetic insects that induce a wide diversity of highly complex species- and generation-specific galls on oaks and other Fagaceae. Phylogenetic relationships within oak gallwasps remain to be established, while sexual and parthenogenetic generations of many species remain unpaired. Previous work on oak gallwasps has revealed substantial intra-specific variation, particularly between regions known to represent discrete Pleistocene glacial refuges. Here we use statistical phylogenetic inference methods on sequence data for a fragment of the mitochondrial cytochrome b gene to reconstruct the relationships among 62 oak gallwasp species. For 16 of these we also include 23 additional cytochrome b haplotype sequences from different Pleistocene refuge areas to test the effect of intra-specific variation on inter-specific phylogeny reconstruction. The reconstructed phylogenies show good intra-generic resolution and identify several conserved clades, but fail to reconstruct either very recent or very ancient divergences. Nine of the 16 species represented by multiple haplotypes are not monophyletic. The apparent discordance between the recovered gene tree and the current taxonomic classification can be explained through: (a) collapsing of some species currently known only from either a sexual or a parthenogenetic generation into a single cyclically parthenogenetic entity; (b) sorting of ancestral polymorphism in diverging lineages, and (c) horizontal transfer of haplotypes, perhaps due to hybridization within glacial refuges. Our conclusions emphasise the need for careful intra-specific sampling when reconstructing phylogenies for radiations of closely related species and imply that for certain taxonomic groups full phylogenetic resolution (using molecular markers) may not be attainable.

Animals↗