Search PubMed⌕ Search

Biomedical subjects

D A Bennett

Publications and source records attributed to D A Bennett.

At least 127 records · Page 7Linked to original sources
PubMed1987

A comparison of diazepam stimuli in aged and adult rats.

Young adult rats (5 months) were compared with aged (28 months) rats in their ability to learn and perform in a diazepam drug discrimination. Both groups of rats were drug naive at the onset of the experiment. Adult and aged animals learned to discriminate diazepam. In general, the response rates under both drug and vehicle conditions were significantly lower for the aged group. The diazepam stimuli were dose-dependent in each group. Similar dose-dependent generalization with chlordiazepoxide, pentobarbital, and methocarbamol was also noted in both the aged and adult animals. These data suggest that aged animals, who have experienced anxiolytic compounds over a period of time (in this case, repeated administration of diazepam in the discrimination procedure), respond in a similar fashion to drug treatment as do young adult animals, verifying the reliability and validity of results obtained in aging rats who are repeatedly exposed to drug treatment.

Aging↗
PubMed1987

Pharmacology of the pyrazolo-type compounds: agonist, antagonist and inverse agonist actions.

Five compounds that bind to the benzodiazepine (BZ) receptor, but show different pharmacological characteristics from the classical BZs, are profiled. CGS 8216 is a BZ antagonist/inverse agonist that reverses the effects of diazepam and also acts as a proconvulsant. CGS 9895 is also a potent BZ antagonist. In addition, this compound shows an anxiolytic profile. CGS 9896, CGS 17867A and CGS 20625 are BZ agonists (i.e., anxiolytics and anticonvulsants) which produce varying magnitudes of antagonist effect. All of these compounds are unique from the classical BZs in that each has a reduced propensity to produce the sedative and/or muscle relaxant effects characteristically associated with BZs.

Animals↗
PubMed1987

CPP, a selective N-methyl-D-aspartate (NMDA)-type receptor antagonist: characterization in vitro and in vivo.

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) was synthesized as a rigid analog of 2-amino-7-phosphonoheptanoate, a previously known antagonist at the N-methyl-D-aspartate (NMDA) preferring, or NMDA-type, of excitatory amino acid receptor. CPP was found to be a potent, selective and competitive antagonist of NMDA-type receptors. CPP antagonized with an IC50 of 8 muM [3H]ACh release which was evoked from rat striatal brain slices by NMDA (50 muM). In contrast, the release of [3H]ACh evoked by elevated KCI was not inhibited by CPP even at a concentration of 100 muM. The antagonism by CPP of NMDA-evoked [3H]ACh release was competitive, with a pA2 of 5.66 for CPP, compared with a pA2 value of 5.22 for 2-amino-7-phosphonoheptanoate. CPP affected neither the uptake of L-[3H]glutamate nor the inhibition by aconitine of L-[3H]glutamate uptake, suggesting a lack of membrane-stabilizing or local anesthetic effects, and also suggesting that CPP itself may not be taken up through the L-glutamate membrane transporter. Moreover, [3H] CPP was not accumulated by synaptosomes (P2 fraction) which avidly accumulate L-[3H]glutamate, supporting the concept that this NMDA-type receptor antagonist acts at an NMDA-type receptor on the external surface of the plasma membrane. CPP (10 muM) failed to interact with any of 21 other putative neurotransmitter receptors including alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding (quisqualate-type receptor) and [3H]kainate binding (kainate-type receptor). Audiogenic convulsions in DBA/2 mice were blocked by CPP (ED50 = 1.5 mg/kg i.p.) as were NMDA-induced seizures in CF-1 mice (ED50 = 1.9 mg/kg i.p.). In both strains, CPP impaired the traction reflex at higher doses (ED50 = 6.8 mg/kg and 6.1 mg/kg and 6.1 mg/kg i.p. for DBA/2 and CF-1, respectively). The traction reflex impairment by CPP may be due to muscle relaxant effects of the compound, an explanation supported by the finding that CPP reduced muscle tone as assessed by electromyogram measurement in animals whose muscle tone had been increased by opiate administration. Finally, cerebellar cyclic GMP levels, known to be sensitive to neurotransmission via NMDA-type receptors, were decreased by CPP (ED50 = 4.7 mg/kg i.p.) in mice. In conclusion, based upon the competitive antagonism by CPP of NMDA-evoked [3H] ACh release in vitro and the antagonism of NMDA-induced convulsions in vivo, the data presented are consistent with competitive antagonism of NMDA-type receptors.

Acetylcholine↗
PubMed1987

Home cage pretreatment with diazepam: effects on subsequent conflict testing and rotorod assessment.

In various anxiolytic tests, benzodiazepines produce a maximal anxiolytic response only upon repeated treatment. The question arises as to whether repeated treatment produces an increase in anxiolytic efficacy or a decrease in another benzodiazepine-mediated effect (i.e., muscle relaxation/sedation) that functions to attenuate the full expression of the anxiolytic response. To address this issue, rats were pretreated in their home cages with either vehicle, diazepam or CGS 9896 (a nonsedating, non-muscle relaxant partial benzodiazepine agonist with anxiolytic efficacy) and challenged, 7 days later, with either diazepam or CGS 9896 in either a conflict (anxiolytic efficacy) or a rotorod (muscle relaxant/sedative effects) procedure. Rats who first experienced diazepam in the test situation (vehicle home cage pretreatment) showed only a moderate anxiolytic response and a compromised motor response. Pretreatment with diazepam in the home cage produced a tolerance to the motor-decreasing effects of diazepam and induced a maximal anxiolytic effect upon first challenge with diazepam in the test situation. CGS 9896, on the other hand, produced a maximal anxiolytic effect regardless of home cage pretreatment. Home cage pretreatment with CGS 9896 did not obviate the muscle relaxant/sedative or submaximal anxiolytic effects of diazepam, suggesting that repeated exposure to an anxiolytic effect is not the underlying basis for the repeated benzodiazepine treatment phenomenon. Rather, the motor-impairing effects of the benzodiazepines cause the submaximal response noted upon first exposure to these drugs in the anxiolytic test situation. This effect tolerates, leaving the expression of the maximal response.

Animals↗
PubMed1986

2-Amino-7-phosphonoheptanoic acid (AP7) produces discriminative stimuli and anticonflict effects similar to diazepam.

The N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, was evaluated in two animal test procedures known to be sensitive to the effects of diazepam. In rats trained to discriminate diazepam from vehicle, AP7 produced dose-dependent generalization to the diazepam interoceptive stimuli. This NMDA antagonist also increased the rates of conflict responding in a chronic test procedure used to identify compounds with potential anxiolytic effects. A comparison of AP7 with diazepam and two muscle relaxants (methocarbamol and baclofen) showed that excitatory amino acid antagonists (of the receptor site stimulated by NMDA) produce a muscle relaxant effect (drug discrimination) and may represent a new class of compounds for the treatment of anxiety-related disorders (conflict test).

2-Amino-5-phosphonovalerate↗
PubMed1985

The non-sedating anxiolytic CGS 9896 produces discriminative stimuli that may be related to an anxioselective effect.

Sprague Dawley albino rats were trained to discriminate an internal stimulus associated with CGS 9896, a non-sedating pyrazoloquinoline that exhibits anxiolytic activity in animals. Classical anxiolytics (diazepam and meprobamate) and proposed anxiolytic drugs having low sedative potential (CL 218,872 and tracazolate) generalized to the CGS 9896 discriminative cue. The CGS 9896 cue appeared to be mediated by a pure anxiolytic action as previous research has shown that this compound does not produce sedation or muscle relaxation. As such, the CGS 9896 stimulus would have both research and clinical application in the investigation of selective anxiomodulation. This is the first report of discriminative stimuli established on one of the newer atypical anxiolytics in which the discriminative cue appeared related to an anxiolytic effect.

Animals↗
PubMed1985

CGS 9896: agonist-antagonist benzodiazepine receptor activity revealed by anxiolytic, anticonvulsant and muscle relaxation assessment in rodents.

CGS 9896, a pyrazoloquinoline that potently binds to benzodiazepine receptors, has been reported to have anticonflict activity in conventional footshock paradigms and to antagonize pentylenetetrazol-induced seizures. In the present experiments, the pentylenetetrazol discriminative cue was blocked by CGS 9896 with a potency comparable to that of diazepam. CGS 9896 also selectively lengthened the latency to terminate self-initiated brain stimulation reward. These procedures extend the anxiolytic activity of CGS 9896 to models that do not rely upon footshock-induced conflict. CGS 9896 did not impair the traction reflex in mice, did not impair rotorod performance in rats, did not reduce unpunished operant responding and decreased motor activity only slightly, indicating no distinguishable sedation or muscle relaxation in rodent models. In fact, diazepam-induced rotorod impairment was blocked by CGS 9896. The anticonvulsant effects of CGS 9896, as indicated by audiogenic seizure and pentylenetetrazol-induced seizure studies, were substantial but were weaker than those of diazepam, possibly because of the muscle relaxant component of diazepam. Ethanol-induced motor impairment was potentiated more markedly by diazepam than by CGS 9896. Mixed agonist-antagonist properties of CGS 9896 therefore emerge when a comprehensive battery of behavioral assessments is utilized. CGS 9896 may have clinical anxiolytic activity without sedation or muscle relaxation.

Acoustic Stimulation↗
PubMed1982

Comparison of the actions of trimethadione and chlordiazepoxide in animal models of anxiety and benzodiazepine receptor binding.

Trimethadione was compared with chlordiazepoxide for anti-anxiety activity in two behavioral tests known to predict the anxiolytic action of drugs. In the drug-discrimination test, male hooded rats were trained to discriminate the anxiogenic action of pentylenetetrazol from saline by responding for food reinforcement on one of two levers after treatment with pentylenetetrazol (1450 mumol/kg) and on the other lever after injection of saline. Pretreatment with either chlordiazepoxide (2.8-33 mumol kg) or trimethadione (559-2236 mumol/kg) prior to the injection of pentylenetetrazol, produced a dose-dependent antagonism of the anxiogenic stimulus. In the other test, male Wistar rats were trained to respond for milk reinforcement in a conflict procedure in which some of the reinforced responses resulted in the delivery of footshock. Treatment of these rats with chlordiazepoxide (17-67 mumol/kg) or trimethadione (1118-2236 mumol/kg) antagonized the footshock-induced suppression of responding. In a receptor binding study, trimethadione failed to inhibit flunitrazepam binding. These data suggest that trimethadione is an effective anxiolytic agent whose action does not directly involve benzodiazepine receptors.

Animals↗
PubMed1982

Discriminative stimulus properties of the vasodilator, hydralazine: differential generalization with alpha 1 and alpha 2 adrenoreceptor drugs.

1. Male albino rats were trained to an operant procedure of lever pressing on an FR-10 schedule of food reinforcement to respond on one lever located on one side of the food cup after an injection of hydralazine (1,25 mg/kg), and to respond on an alternate lever located on the other side of the food cup after an injection of saline. 2. Seven out of ten rats learned the hydralazine-saline discrimination to the rigid criterion of selecting the correct lever for reinforcement on ten consecutive sessions. 3. The elicitation of the discriminative stimulus was dose-dependent (r = 0,98; p less than .001) with 100, 43, and 14% of the subjects selecting the hydralazine lever following hydralazine doses of 1,25; 0,32 and 0,08 mg/kg, respectively (ED50, 0,28 mg/kg). 4. A reduction in response rate and blood pressure was noted only at the 1.25 mg/kg dose. 5. No tolerance to the hypotensive effect of hydralazine was found. 6. In generalization tests, prazosin, an alpha 1 antagonist, was found to produce a dose-dependent generalization to hydralazine (ED50, 1, 25 mg/kg) while clonidine, an alpha 2 agonist, did not generalize. 7. These data indicate that hydralazine produces a discriminable interoceptive stimulus exact site of action of which is not known.

Animals↗
PubMed1982

Discriminative stimuli produced by clonidine: an investigation of the possible relationship to adrenoceptor stimulation and hypotension.

In a leverpressing operant procedure, male rats were trained to respond for food reinforcement on one lever after an injection of clonidine (0.04 mg/kg) and to respond on an alternate lever for food reinforcement after an injection of saline. All 36 rats learned to discriminate the drug reliably from saline, thereby indicating that clonidine produces discriminative interoceptive stimuli. The discriminative stimulus was both dose- and time-dependent, with an ED50 of 0.018 mg/kg and an optimum time of action occurring from 15 to 60 min after injection. Although clonidine produced a reduction in response rate, this was not the basis of the discriminative stimulus as other drugs with similar depressant action did not generalize. The clonidine stimulus was dose-dependently antagonized by the alpha-2 adrenergic antagonist, yohimbine, whereas receptor antagonists of alpha-1 adrenergic, beta adrenergic, dopaminergic, serotonergic, cholinergic or opioid systems were ineffective in blocking the interoceptive stimulus produced by clonidine Lofexidine, guanabenz and methyldopa, all centrally acting hypotensive drugs that act through alpha-2 adrenoceptor mechanisms dose-dependently generalized to the clonidine cue, whereas hydralazine, minoxidil, propranolol and prazosin, hypotensive drugs acting through other mechanisms, did not generalize. These results suggest that clonidine produces interoceptive stimuli that are discriminable by rats and mediated through central alpha-2 adrenoceptor stimulation.

Animals↗
PubMedDate not supplied

Effectiveness of nantradol in blocking narcotic withdrawal signs through nonnarcotic mechanisms.

Male rats were made narcotic dependent through continuous intravenous infusion of morphine. During withdrawal, nantradol, clonidine, and morphine were found to block withdrawal signs in a dose-dependent manner. Almost complete alleviation of withdrawal occurred with nantradol or clonidine at 0.16 mg/kg and with morphine at 40 mg/kg. The effectiveness of morphine, but not of nantradol or clonidine, was reversed by naloxone. Likewise, in naive rats given castor oil, naloxone did not block the antidiarrheal effect of nantradol or clonidine. In order to compare possible subjective effects of nantradol with other antiwithdrawal drugs, naive rats were trained to discriminate either morphine, cyclazocine, or clonidine from vehicle by selecting different levers for reinforcement. Nantradol failed to produce any generalization to morphine, cycloazocine, or clonidine, suggesting that this drug does not produce central subjective effects like those of the training drugs. In additional testing in behavioral experiments, nantradol failed to produce any sign of anxiogenic activity.

Animals↗
PubMedDate not supplied

Pathological changes in frontal cortex from biopsy to autopsy in Alzheimer's disease.

We evaluated the change in density of total senile plaques, plaque subtypes, and neurofibrillary tangles, from biopsy to autopsy in left frontal cortical sections from four patients with clinically typical Alzheimer's disease (AD). Comparisons were made on sections stained with modified Bielschowsky and Thioflavin S. In two cases, comparisons were also made on tissue stained with a monoclonal Alz-50 antibody and an antiserum to A beta (beta-amyloid protein). Despite a marked decline in mental status over several years of follow-up clinical evaluations, there was no consistent significant change in numerical density of plaques or tangles among the four cases. However, we did find fewer primitive plaques in the autopsy specimens. These results from longitudinally evaluated persons with typical AD suggest that although plaques and tangles may serve as adequate markers of the presence of AD, their numerical density within a single neocortical region may not reflect dementia severity. This conclusion supports the results of recent cross-sectional studies on the progression of pathology among persons with AD.

Alzheimer Disease↗
PubMedDate not supplied

MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12-77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

Aged↗
PubMedDate not supplied

Alzheimer's disease: in vivo detection of differential vulnerability of brain regions.

The severe cognitive impairment during the later stages of Alzheimer's disease is usually preceded by a selective disturbance in the ability to remember new experiences. With quantitative, high-resolution magnetic resonance imaging techniques, it is now possible to determine, in vivo, differences in the pattern of anatomical changes that might reflect behavioral symptomatology during different stages of the disease. In the present investigation, magnetic resonance imaging examinations were carried out in aged controls and in clinically diagnosed Alzheimer's disease patients who were divided into three groups based upon dementia severity. Atrophy of the hippocampal formation, a region important for memory function, was observed even in Alzheimer's disease patients with the mildest dementia. With more prominent dementia, atrophy extended to the parahippocampal gyrus and the temporal neocortex.

Adult↗
PubMedDate not supplied

Mitochondrial DNA rearrangements in aging human brain and in situ PCR of mtDNA.

Deletions of the mitochondrial DNA (mtDNA) have been shown to accumulate with age in a variety of species regardless of mean or maximal life span. This implies that such mutations are either a molecular biomarker of senescence or that they are more causally linked to senescence itself. One assay that can be used to detect these mtDNA mutations is the long-extension polymerase chain reaction assay. This assay amplifies approximately 16 kb of the mtDNA in mammalian mitochondria and preferentially amplifies mtDNAs that are either deleted or duplicated. We have applied this assay to the aging human brain and found a heterogeneous array of rearranged mtDNAs. In addition, we have developed in situ polymerase chain reaction to detect mtDNA within individual cells of both the mouse and the human brain as a first step in identifying and enumerating cells containing mutant mtDNAs in situ.

Aged↗