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Biomedical subjects

D L Cheney

Publications and source records attributed to D L Cheney.

At least 19 recordsLinked to original sources
PubMed1995

Pregnenolone sulfate antagonizes dizocilpine amnesia: role for allopregnanolone.

Pregnenolone (PREG) is metabolized in brain to progesterone (PROG), 5 alpha-dihydroprogesterone (5 alpha-DHP) and allopregnanolone (ALLO). Infusion of adrenalectomized/castrated rats with PREG sulfate prevented the cognition deficit elicited by the ionotropic glutamate receptor antagonists, dizocilpine and CPPene. Using a new gas chromatographic/mass-spectrometric method, we demonstrated that PREG sulfate infusion markedly increased the PREG, PROG, 5 alpha-DHP and ALLO brain content. The increase in 5 alpha-DHP and ALLO, but not PREG or PROG content and the antagonism of dizocilpine amnesia observed by injecting rats with PREG sulfate was reversed by inhibiting the conversion of PROG to 5 alpha-DHP with the 5 alpha-reductase blocker SKF 105111. We and others have shown that ALLO potently modulate GABAA receptor function whereas 5 alpha-DHP fails to induce rapid changes in neurotransmitter receptor function. Thus it is possible to suggest that the increase in the brain content of ALLO, rather than 5 alpha-DHP, mediates the effect of PREG sulfate on dizocilpine- or CPPene-induced cognition deficit.

Amnesia↗
PubMed1995

The responses of female baboons (Papio cynocephalus ursinus) to anomalous social interactions: evidence for causal reasoning?

Baboons' (Papio cynocephalus ursinus) understanding of cause-effect relations in the context of social interactions was examined through use of a playback experiment. Under natural conditions, dominant female baboons often grunt to more subordinate mothers when interacting with their infants. Mothers occasionally respond to these grunts by uttering submissive fear barks. Subjects were played causally inconsistent call sequences in which a lower ranking female apparently grunted to a higher ranking female, and the higher ranking female apparently responded with fear barks. As a control, subjects heard a sequence made causally consistent by the inclusion of grunts from a 3rd female that was dominant to both of the others. Subjects responded significantly more strongly to the causally inconsistent sequences, suggesting that they recognized the factors that cause 1 individual to give submissive vocalizations to another.

Animals↗
PubMed1995

Gas chromatographic-mass fragmentographic quantitation of 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats.

Coupling high performance liquid chromatography with gas chromatography-mass fragmentography has made it possible to simultaneously measure subpicomolar concentrations of allopregnanolone and its precursors, pregnenolone, progesterone and 5 alpha-dihydroprogesterone (5 alpha-DHP) in various brain areas. Allopregnanolone was measured in the brain of adrenalectomized/castrated (ADX/CX) rats in nanomolar concentrations long after peripheral sources of allopregnanolone were removed. A partial decrease (approximately 30%) in the content of allopregnanolone was found in the brains of ADX/CX rats compared to sham-operated rats. Moreover, the content of allopregnanolone in brains of sham-operated as well as ADX/CX rats was nonuniformly distributed (olfactory bulb > striatum > cortex > hippocampus) and was one to two orders of magnitude higher than in plasma or liver. Infusion of pregnenolone sulfate in ADX/CX rats elicited a fourfold increase in 5 alpha-DHP and progesterone content and a seven- to eightfold increase in the content of allopregnanolone in brain but not in liver or plasma. Furthermore, the content of allopregnanolone in brain increased to the same extent in both sham-operated and ADX/CX rats following pregnenolone sulfate infusion. The 5 alpha-reductase inhibitor, (17 beta)17[[bis(1-methylethyl)amino]carbonyl] androstane-3,5-diene-3-carboxylic acid (SKF 105111), reduced the brain content of allopregnanolone and blocked the increased formation of allopregnanolone in brain following pregnenolone sulfate infusion. The results clearly demonstrate that the synthesis of allopregnanolone from 5 alpha-DHP and progesterone occurs in the brain and that a significant amount of allopregnanolone is synthesized locally in brain from its precursors. These experiments suggest that the brain, like adrenals and gonads, is a steroidogenic organ which produces allopregnanolone as one of its own most important physiologically relevant steroids.

5-alpha-Dihydroprogesterone↗
PubMed1994

Mitochondrial diazepam-binding inhibitor receptor complex agonists antagonize dizocilpine amnesia: putative role for allopregnanolone.

In rats trained to retain a passive avoidance response or to retrieve a learned task in the radial and water maze tests, a pretreatment with 2-hexyl-3-indoleacetamide (FGIN-1-27) (IC50 57 mumol/kg p.o.) or 4' chlorodiazepam (4'CD) (15 mumol/kg i.p.), two steroidogenic ligands at the mitochondria diazepam-binding inhibitor receptor complex (MDRC), antagonized the performance deficit elicited by dizocilpine (0.3 mumol/kg i.p.), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The 1-(2-chlorophenyl)-N-methyl-N-(-1-methyl-propyl)-3-isoquinoline carboxamide (PK-11195), an antagonist at MDRC in vivo, failed to modify the disruptive effect of dizocilpine in the passive avoidance response but reversed the FGIN-1-27- or 4' CD-induced antagonism of dizocilpine behavioral actions. Pretreatment with pregnenolone sulfate (48 mumol/kg i.p.), 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one (THDOC) (15 mumol/kg i.v.) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) (15 mumol/kg i.v.) also reduced the passive avoidance retention deficit elicited by dizocilpine. The (17-beta)-17-[[bis(1-methylethyl)amino[carbonyl]androstane-3,5-diene-3- carboxylic acid (SKF-105111), a 5 alpha-reductase inhibitor, blocked the antagonism of dizocilpine behavioral actions by pregnenolone sulfate or by FGIN-1-27 but not those caused by THDOC or allopregnanolone either in normal or adrenalectomized-castrated rats. Thus, it is inferred that the amnesic effect of dizocilpine is counteracted by FGIN-1-27, 4'CD and pregnenolone sulfate because of their ability to increase brain accumulation of allopregnanolone.

Amnesia↗
PubMed1993

Vocalizations of rhesus (Macaca mulatta) and Japanese (M. fuscata) macaques cross-fostered between species show evidence of only limited modification.

Two rhesus and two Japanese macaque infants were cross-fostered between species in order to study the effects of auditory experience on vocal development. Both the cross-fostered and normally raised control subjects were observed over the first 2 years of life and their vocalizations were tape-recorded. We classified 8053 calls by ear, placed each call in one of six acoustic categories, and calculated the rates at which different call-types were used in different social contexts. Species differences were found in the use of "coo" and "gruff" vocalizations among control subjects. Japanese macaques invariably produced coos almost exclusively. In contrast, rhesus macaques produced a mixture of coos and gruffs and showed considerable interindividual variation in the relative use of one call type or the other. Cross-fostered Japanese macaques adhered to their species-typical behavior, rarely using gruffs. Cross-fostered rhesus subjects also exhibited species-typical behavior in many contexts, but in some situations produced coos and gruffs at rates that were intermediate between those shown by normally raised animals of the two species. This outcome suggests that environmentally mediated modification of vocal behavior may have occurred, but that the resulting changes were quite limited.

Animals↗
PubMed1993

Characterization of the bisphosphonate recognition site on hydroxyapatite using radioligand binding techniques with [14C]citric acid.

The present studies characterize the binding of [14C]citric acid to synthetic hydroxyapatite (HA) crystals. [14C]Citric acid specifically bound to HA and was dependent upon the concentration of HA in the assay. The binding of [14C] citric acid to HA reached equilibrium within 20 min and remained stable for at least 90 min. Dissociation of bound [14C]citric acid was biphasic in nature since both rapid and more slowly reversible binding components were detected. Saturation experiments also indicated that [14C]citric acid labeled two recognition sites with different affinity (KdH = 42 nM and KdL = 24,000 nM) and density (BmaxH = 161 fmol/micrograms HA and BmaxL = 8.8 pmol/micrograms HA). Ligand competition experiments revealed that compounds that are known to readily bind bone (e.g., sodium pyrophosphate, methylene diphosphonic acid, etidronate) potently inhibited the binding of [14C]citric acid to HA, whereas compounds known to have poorer affinity for bone (e.g., oxalic acid and GABA) did not. Computer analysis of these inhibition curves revealed specific ligand interactions at two different affinity recognition sites. The present results indicate that [14C]citric acid binds discrete sites on synthetic HA in a fashion consistent with a specific labeling of the bisphosphonate recognition site. Analysis of the binding of [14C]citric acid to HA provides a useful method to further explore the structure activity relationships of novel compounds that have binding affinity for bone.

Binding Sites↗
PubMed1990

The representation of social relations by monkeys.

Monkeys recognize the social relations that exist among others in their group. They know who associates with whom, for example, and other animals' relative dominance ranks. In addition, monkeys appear to compare types of social relations and make same/different judgments about them. In captivity, longtailed macaques (Macaca fascicularis) trained to recognize the relation between one adult female and her offspring can identify the same relation among other mother-offspring pairs, and distinguish this relation from bonds between individuals who are related in a different way. In the wild, if a vervet monkey (Cercopithecus aethiops) has seen a fight between a member of its own family and a member of Family X, this increases the likelihood that it will act aggressively toward another member of Family X. Vervets act as if they recognize some similarity between their own close associates and the close associates of others. To make such comparisons the monkeys must have some way of representing the properties of social relationships. We discuss the adaptive value of such representations, the information they contain, their structure, and their limitations.

Animals↗
PubMed1988

Constant infusion of [13C6]glucose: simultaneous measurement of turnover of GABA and glutamate in defined regions of the brain of individual animals.

A new method has been developed to measure simultaneously the turnover rates of glutamate and GABA in individual areas of the brain of the rat. Rats received a constant infusion of [13C6]glucose, such that the flux of this stable isotope label through the pools of glucose, glutamate and GABA in the central nervous system (CNS) could be monitored by gas chromatography-mass fragmentography. The ratios of glucose/GABA and glucose/glutamate labelling were then used to calculate the fractional rate constants for GABA and glutamate, respectively. Using this approach, baclofen (20 mg/kg) decreased the turnover rates of both glutamate and GABA in the cerebellum, prefrontal cortex, striatum and hippocampus of the rat. In contrast, only the turnover of GABA was decreased in the septum and superior colliculus. Muscimol decreased the turnover rates of both amino acids in all regions of the brain examined. These data, therefore, provide in vivo support for the results of previous in vitro studies which indicated that cortical glutamatergic nerve endings and/or cell bodies possess inhibitory GABAB receptors. The present data further suggest that not all glutamatergic projections possess these receptors.

Amino Acids↗
PubMed1987

Antagonism of N-methyl-D-aspartate (NMDA) evoked increases in cerebellar cGMP and striatal ACh release by phencyclidine (PCP) receptor agonists: evidence for possible allosteric coupling of NMDA and PCP receptors.

A comparison was made of the actions of phencyclidine receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists in two well-defined neurochemical test systems. These included (i) [3H]acetylcholine release from striatal cholinergic interneurons in vitro, a system known to be positively modulated by corticostriatal excitatory amino acid inputs in vivo; and (ii) cerebellar cGMP levels in vivo, an indicator of cerebellar Purkinje cell activity, which is also modulated by excitatory amino acid inputs. Using these neuronal systems, we report that phencyclidine receptor agonists demonstrated a noncompetitive antagonism of NMDA receptor agonist actions.

Acetylcholine↗
PubMed1984

On the neurotoxicity of chlordecone: a role for gamma-aminobutyric acid and serotonin.

Rats receiving the chlorinated insecticide, chlordecone (80 mg/kg i.p.), exhibit hyperexcitability, exaggerated startle response and tremors within a few hours after the injection. Since the chlordecone-elicited tremors are relieved by injections of muscarinic receptor blockers, acetylcholine has been implicated indirectly in the mechanism of chlordecone toxicity. Our studies on acetylcholine steady-state levels and turnover in several brain structures failed to detect evidence for an involvement of cholinergic presynaptic mechanisms in the chlordecone toxicity. We then investigated whether GABA is involved by measuring the rate of its accumulation following intraventricular injection of gabaculine. Chlordecone reduced the rate of GABA accumulation in striatum, but not in cerebellum, brainstem or hippocampus. Such inhibition appeared 4 h after drug injection thereby preceding the onset of tremors. Since tremors elicited by chlordecone are attenuated by the administration of serotonin receptor blockers and since chlordecone increases serotonin (5-HT) turnover, we studied whether 5-HT recognition sites are modified following chlordecone administration. We have found a reduction of the Bmax of 5-HT1 receptors in striatum and hippocampus without any modification in the kinetic characteristics of 5-HT2 receptors. We have also shown that the temporal relationship between down regulation of 5-HT1 recognition sites, reduction of striatal GABA turnover and tremors caused by chlordecone allows one to consider these 3 phenomena as reciprocally dependent. In conclusion our results favor the possibility that tremors may result from a decrease in the striatal GABergic tone which probably is elicited by an increase of serotonergic activity caused by chlordecone by a yet unknown mechanism.

Acetylcholine↗
PubMed1984

An immunohistochemical study on the location of GABAergic neurons in rat septum.

Antisera against L-glutamate decarboxylase (GAD), the synthesizing enzyme of gamma-aminobutyric acid (GABA) were used to locate GABAergic neurons and nerve terminals in the septal complex of the rat by using the peroxidase-antiperoxidase method. Varying densities of immunoreactive terminals were observed in saline-treated rats but nerve cell bodies were only demonstrated after interventricular or intraseptal injections of colchicine. Small and medium-sized GAD-positive neurons were found in lateral septal nuclei, the largest number of these cells being in the pars dorsalis, and in the bed nucleus of the stria terminalis. Several GAD-immunoreactive neurons were located in the medial septal nucleus and the nucleus of the diagonal band of Broca (DB), where the cells were larger in the ventral than dorsal parts of the region. In the medial septal nucleus and in DB the GAD-positive cell bodies were distributed similarly to cholinergic neurons. Large GAD-positive neurons were also found in the septofimbrial nucleus. Intense immunoreactivity in nerve terminals was observed in the lateral septal nucleus, around the island of Calleja magna, between the DB and nucleus accumbens, and in the septofimbrial and triangular septal nuclei. In contrast, the medial septal nucleus, the DB, and the bed nucleus of the stria terminalis only showed weak to moderate immunoreactivity. These results provide direct morphological evidence for the presence of neurons capable of synthesizing GABA in septal nuclei. We suggest that there are two different GABAergic neuronal systems operating in the septum: a population of small cells in the lateral septal nucleus and a group of large cells in the medial septum and DB.

Animals↗
PubMed1984

In vitro characterization of agonist, antagonist, inverse agonist and agonist/antagonist benzodiazepines.

The efficacy of coupling between the benzodiazepine receptor and chloride channel as well as the coupling to the GABA receptor is differentially affected by different benzodiazepine ligands. In general, the order of efficacy with regard to allosteric effects of benzodiazepine ligands on the chloride channel ([35S]TBPS) and GABA receptor ([3H]muscimol), is: agonist greater than agonist/antagonist greater than partial agonist greater than antagonist; with inverse agonists acting in a manner opposite to the classical benzodiazepine agonists. The chloride ionophore is allosterically modulated both by benzodiazepine and GABA receptors.

Animals↗
PubMed1984

The acoustic features of vervet monkey grunts.

East African vervet monkeys give short (125 ms), harsh-sounding grunts to each other in a variety of social situations: when approaching a dominant or subordinate member of their group, when moving into a new area of their range, or upon seeing another group. Although all these vocalizations sound similar to humans, field playback experiments have shown that the monkeys distinguish at least four different calls. Acoustic analysis reveals that grunts have an aperiodic F0, at roughly 240 Hz. Most grunts exhibit a spectral peak close to this irregular F0. Grunts may also contain a second, rising or falling frequency peak, between 550 and 900 Hz. The location and changes in these two frequency peaks are the cues most likely to be used by vervets when distinguishing different grunt types.

Acoustics↗
PubMed1984

In vitro characterization of benzodiazepine receptor agonists, antagonists, inverse agonists and agonist/antagonists.

Using an extensively washed membrane preparation and standardized incubation conditions, the actions of benzodiazepine (BZ) receptor ligands were evaluated on [3H]flunitrazepam [+/- 10 microM gamma-aminobutyric acid (GABA)], [3H]muscimol (+/- 2.5 microM etazolate) and [35S]butyl bicyclophosphorothionate (TBPS) binding. Classical BZ receptor agonists stimulated [35S]TBPS binding and [3H]muscimol binding in the presence of etazolate. These agents also possessed ratios for [3H]flunitrazepam binding in the absence and presence of GABA (GABA ratio) of 2 to 5. BZ antagonists and inverse agonists had GABA ratios less than 1 and did not alter, or reduced, both [35S]TBPS and [3H]muscimol (+etazolate) binding. The nonsedating BZ agonist/antagonist agents CGS 9896, CL 218872, PK 8165 and PK 9084 all possessed GABA ratios between 1.1 and 1.4 and only stimulated [35S]TBPS and [3H]muscimol (+etazolate) binding to approximately 50% of the level of classical BZ agonists. The BZ partial agonists CGS 9895 and RU 39419 both were unique in that they possessed GABA ratios of 1 or less, stimulated [35S]TBPS binding and had no effect on [3H]muscimol binding (+etazolate). Therefore, by monitoring the major components of the BZ receptor complex (BZ receptor, GABA receptor and chloride channel), we were able to distinguish between different BZ drugs and to support suggestions that these drugs act via unique BZ receptor populations which possess differential couplings to the GABA receptor and chloride channel.

Animals↗
PubMed1983

A comparison of the analgesic activities of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and 6-chloro-2[1-piperazinyl]pyrazine (MK 212).

Both the gamma-aminobutyric acid (GABA) mimetic, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and the serotonergic agonist, MK 212 (6-chloro-2[ 1-piperazinyl ]pyrazine) are effective analgesic agents in the mouse hot plate assay. Naltrexone, however, fails to reverse the analgesia elicited by either compound. Acute injection of THIP potentiates the morphine analgesia and chronic administration of THIP produces a functional tolerance to its analgesic effects. MK 212 antagonizes the analgesia induced by either morphine or THIP. These results support the postulate that GABAergic and serotonergic synapses represent two synaptic mechanisms which participate in the modulation of pain threshold in a manner that is independent from opioid receptors. Moreover, GABA and serotonin appear to be able to modulate opioid-mediated analgesia in an opposing manner with GABAergic mechanisms facilitating and serotonergic mechanisms inhibiting morphine-induced antinociception.

Analgesics↗
PubMed1983

The transsynaptic regulation of the septal-hippocampal cholinergic neurons.

There is not yet a complete understanding of the functional interactions among various septal nuclei which regulate hippocampal function. Nevertheless, much has been learned histologically and biochemically about the major connections of the distinct areas of the septal complex and the chemical character of some of these pathways. The cholinergic septal-hippocampal pathway serves as a well defined link between these two important structures of the limbic system. Acetylcholine turnover rates in the hippocampus have been shown to increase or decrease proportionally to the activity of the cholinergic neurons originating in the septum. Moreover, these turnover rates have been shown to be modulated by intraseptal injections of agonists or antagonists of various neurotransmitters or neuromodulators which are stored in various cell groups located in the septum. By coupling this biochemical approach with techniques to study the receptor organization, greater detail concerning the transmitter and cotransmitter interactions among the various neuromodulators can be obtained.

Acetylcholine↗