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Biomedical subjects

E D London

Publications and source records attributed to E D London.

At least 91 records · Page 5Linked to original sources
PubMed1995

Magnetic resonance imaging reveals no ventriculomegaly in polydrug abusers.

Previous studies of cerebral structure in substance abusers yielded controversial results, largely due to issues of subject selection and/or limitations of experimental techniques. The purpose of the present study was to assess whether the ventricle-to-brain ratio (VBR), determined volumetrically by magnetic resonance imaging (MRI), differed in polysubstance abusers (n = 10), as compared with age-matched controls (n = 10). Subjects were male volunteers 21-39 years of age. The values of VBR in the polydrug abuse group were not larger than those in control group, nor was there any tendency toward relative ventriculomegaly in the substance abusers. Therefore, the present findings provide no evidence that polysubstance abuse produces abnormalities of gross brain structure in relatively young and physically healthy men.

Adult↗
PubMed1995

PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent sigma-receptor ligand, decreases brain injury after transient focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that administration of 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a potent sigma-receptor ligand, during transient focal ischemia would affect early postischemic brain injury. METHODS: Halothane-anesthetized cats underwent left middle cerebral artery occlusion for 90 minutes followed by 4 hours of reperfusion. Control cats received saline (n = 10). Experimental cats (2 groups, n = 10 per group) were treated with PPBP at a rate of 0.1 mumol/kg per hour (PPBP-0.1) or administered 1 mumol/kg per hour (PPBP-1) intravenously from 75 minutes after initiation of ischemia and continuing during the 4 hours of reperfusion. RESULTS: As measured by the microsphere method, blood flow to the ipsilateral caudate nucleus was decreased similarly in all groups during ischemia. Blood flow to the ipsilateral inferior temporal cortex was decreased during ischemia in all groups but was higher in cats subsequently treated with PPBP at the highest dose, even before drug administration. There was no difference in blood flow to the ipsilateral caudate nucleus or inferior temporal cortex (area of greatest cortical injury) during reperfusion. Triphenyltetrazolium-determined injury volume of the ipsilateral cerebral hemisphere (control, 29 +/- 5%; PPBP-0.1, 17 +/- 3%; PPBP-1, 6 +/- 1% of ipsilateral hemisphere; mean +/- SEM) and caudate nucleus (control, 49 +/- 5%; PPBP-0.1, 39 +/- 6%; PPBP-1, 25 +/- 5% of ipsilateral caudate nucleus) was less in cats treated with 1 mumol/kg per hour of PPBP compared with cats treated with saline. Cats treated with 0.1 mumol/kg per hour had a 45% smaller hemispheric injury volume than the control group without differences in intraischemic blood flow. Recovery of somatosensory evoked potential amplitude was greater in cats treated with PPBP-1 compared with control (control, 18 +/- 11%; PPBP-0.1, 30 +/- 14%; PPBP-1, 54 +/- 14% of baseline). CONCLUSIONS: These data indicate that sigma-receptors may play an important role in the mechanism of acute injury in both the cortex and the caudate nucleus after 90 minutes of transient focal ischemia in the cat. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may contribute to the progression of injury in ischemic border regions.

Animals↗
PubMed1995

An improved method to calculate cerebral metabolic rates of glucose using PET.

UNLABELLED: PET methods for single-scan measurement of the cerebral metabolic rate of glucose (CMRglc) generally involve sampling of radioactivity in arterial plasma over the course of the experiment. The purpose of this study was to develop an analytic procedure that would require substantially fewer plasma samples to measure CMRglc using the single-scan method. METHODS: This technique uses a model for the curve describing the time course of radioactivity in plasma. RESULTS: This model obviates the need to draw arterial samples at short time intervals or at all during the first 30 min after radiotracer injection. The new technique uses six samples to provide the same accuracy and precision as the conventional method provides with 30 or more samples. CONCLUSION: The proposed method greatly simplifies quantitative PET studies of glucose metabolism.

Adult↗
PubMed1995

Inhibitors of nitric oxide synthase and the opioid withdrawal syndrome.

The NOS inhibitors L-NARG and L-NAME attenuate weight loss and wet dog shakes, two specific signs of opioid withdrawal in rats. NMMA is more potent than L-NAME, consistent with the in vivo actions of these compounds as inhibitors of NOS. In addition, NMMA antagonizes naloxone-induced jumping in morphine-dependent rats. The NOS inhibitors generally increase teeth chattering in precipitated withdrawal. The profile of the diminished withdrawal signs produced by these drugs differs from that produced by clonidine, which stimulates locomotor activity and does not increase teeth chattering in precipitated opioid withdrawal (Kimes et al. 1990). These findings suggest that administration of inhibitors of NOS may be an effective treatment of the opioid withdrawal syndrome alone or in combination with clonidine (U.S. patent #5,225,40).

Animals↗
PubMed1994

Spermidine potentiates dizocilpine-induced impairment of learning performance by rats in a 14-unit T-maze.

The NMDA receptor, a ligand-gated ion channel complex, has been reported to be involved in memory processes. Learning is impaired following administration of dizocilpine, a non-competitive antagonist of the NMDA receptor. Polyamines, such as spermine and spermidine, interact with the NMDA receptor to enhance binding of dizocilpine, which blocks the ion channel. The present study assessed action of polyamines as modulators of learning via NMDA receptor activation. Dizocilpine (0.05 mg/kg) was given i.p. before maze learning, at a dose that produced a slight, nonsignificant impairment of maze learning. Pretreatment with 80 mg/kg but not 15 or 40 mg/kg spermidine (i.p.) before dizocilpine impaired maze learning compared to saline controls. Administration of 80 mg/kg spermidine without dizocilpine did not impair maze learning. The results are consistent with the view that systemic injection of a polyamine can modulate learning processes involving the NMDA receptor.

Analysis of Variance↗
PubMed1994

New pharmacological strategies for cognitive enhancement using a rat model of age-related memory impairment.

We have developed the Stone maze paradigm for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Evidence produced thus far clearly implicates both the cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results have been very inconsistent regarding the cognitive enhancing abilities of cholinomimetics for use in Alzheimer's disease, new classes of cholinesterase inhibitors may offer greater therapeutic efficacy. The use of glycine and polyamine agonists appears to be a viable strategy for positive modulation of the NMDA receptor. In addition, an approach that combines stimulation both of cholinergic and glutamatergic systems may have greater potential than agonism of either separately. Manipulation of signal transduction events might also have potential for cognitive enhancement. The influx of Ca2+ through the NMDA receptor stimulates production of NO via the action of NOS. By using NARG to block NOS activity, we have demonstrated in rats that NO production appears to influence learning in the Stone maze. We are currently exploring the age-related changes in NOS activity in specific brain regions of rats to determine if loss in the NO generating system is related to age-related memory impairment observed in the Stone maze. In addition, we are exploring pharmacological strategies for inducing NO production; however, because of the potential neurotoxicity for NO overstimulation, this strategy will present some obstacles. The identification of NO as a simple molecule serving vital physiological functions but representing potential for neurotoxicity presents an important unifying area for neurobiological investigations searching for mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease.

Aging↗
PubMed1994

Further characterization of [3H]ifenprodil binding in rat brain.

The present study was undertaken to characterize [3H]ifenprodil binding in rat brain. [3H]Ifenprodil showed saturable, high-affinity binding at 4 degrees C. Specific binding, defined with 10 microM ifenprodil as a competitor, was inhibited biphasically by the s receptor ligands, GBR 12909, 1,3-di-o-tolylguanidine (DTG), and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP). At 4 degrees C, 3 microM GBR 12909, which inhibited about 50% of specific binding of [3H]ifenprodil was used to mask sigma receptors. Under these conditions, specific binding of [3H]ifenprodil was inhibited potently by ifenprodil, SL 82.0715, poly(L-arginine), poly(L-lysine), neomycin, ruthenium red, spermine, arcaine and spermidine. In the presence of 3 microM GBR 12909, Zn2+ and Mg2+ partially inhibited specific binding of [3H]ifenprodil at 4 degrees C. In contrast, in the absence of GBR 12909, at 37 degrees C specific binding of [3H]ifenprodil was partially inhibited by Zn2+, but not by Mg2+. The anatomical distribution of [3H]ifenprodil binding at 4 degrees C (GBR 12909 included) in rat brain closely paralleled that of [3H]MK-801 (dizocilpine) binding (r = 0.971, P < 0.005). Without GBR 12909, specific [3H]ifenprodil binding at 37 degrees C was inhibited potently by sigma ligands. In the presence of 3 microM GBR 12909, [3H]ifenprodil binding at 4 degrees C was highest in synaptosomal and myelin fractions; however, without GBR 12909, [3H]ifenprodil binding at 37 degrees C was highest in microsomal and myelin fractions, consistent with the subcellular distribution of sigma receptors. The results suggest that, in the presence of 3 microM GBR 12909, at 4 degrees C, [3H]ifenprodil binds to sites that are sensitive to polyamines and related compounds; and that without GBR 12909, at 37 degrees C, [3H]ifenprodil interacts with sigma receptors in rat brain.

Adrenergic alpha-Antagonists↗
PubMed1994

Spermine interacts with cocaine binding sites on dopamine transporters.

These studies were designed to assess the potential interaction of the polyamine spermine with cocaine binding to dopamine and serotonin transporters. The results of the experiments presented here indicate that spermine inhibits binding of the cocaine congener [3H] CFT to striatal synaptosomal membranes. Further, although [3H] CFT is known to interact with both dopamine and serotonin transporters, our results indicate that the observed inhibition of [3H] CFT binding is likely to reflect a specific inhibition of binding to dopamine transporters. Spermine significantly inhibited the binding of both [3H] CFT and [3H] mazindol to dopamine transporters, while it had no apparent effects on the binding of the potent serotonin uptake inhibitor [3H] paroxetine. Finally, saturation experiments show that the inhibition of ligand binding to the cocaine binding site on dopamine transporters appears not to be due to a modification of ligand affinity for the transporter, but to a decrease in the apparent density of ligand binding sites. The results of these experiments indicate that endogenously produced polyamines can alter cocaine binding to the dopamine transporter. The results are discussed in terms of possible impact on novel approaches for pharmacologically manipulating cocaine reinforcement and craving in clinical treatments for cocaine addiction, as well as for emergency treatment of cocaine overdose.

Animals↗
PubMed1994

Rodent models of memory dysfunction in Alzheimer's disease and normal aging: moving beyond the cholinergic hypothesis.

The Stone maze paradigm has been developed for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Results from several studies have demonstrated the involvement of both cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results of clinical studies on the cognitive enhancing abilities of cholinomimetics for treatment of memory impairment in Alzheimer's disease have been inconsistent, new classes of cholinesterase inhibitors offer greater potential for therapeutic efficacy. The physostigimine derivative, phenserine, appears to have marked efficacy for improving learning performance of aged rats or of young rats treated with scopolamine in the Stone maze. Declines in markers of glutamatergic neurotransmission in Alzheimer's disease and in normal aging suggest that pharmacological manipulation of this system might also prove beneficial for cognitive enhancement. Treatment with glycine and/or polyamine agonists is suggested as a strategy for activating the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In addition, the use of combined pharmacological activation of cholinergic and glutamatergic systems is suggested. Manipulation of signal transduction events should also be considered as a strategy for cognitive enhancement. The influx of Ca2+ through the channel formed by the NMDA receptor stimulates the production of the oxyradical, nitric oxide (NO*), via the action of nitric oxide synthase (NOS). Compounds that inhibit NOS activity impair acquisition in the Stone maze, suggesting an involvement of NO*. Thus, strategies for inducing NO* production to enhance cognitive performance may be beneficial. Because of the potential neurotoxicity for NO*, this strategy is not straightforward. Although many new directions beyond the cholinergic hypothesis can be suggested, each has its potential benefits which must be weighed against its risks. Nonetheless, an important unifying area for neurobiological research examining mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease, might emerge from the identification of NO* as a simple molecule serving vital physiological functions but representing potential for neurotoxicity.

Aging↗
PubMed1994

In vivo labeling of nicotinic cholinergic receptors in brain with [3H]cytisine.

[3H]Cytisine was evaluated as an in vivo ligand for the nicotinic cholinergic receptor (nAchR) in mouse brain. The tracer was injected intravenously, and radioactivity in brain regions was analyzed. Radioactivity peaked in the brain at 30 minutes. It was highest in the thalamus, intermediate in the superior colliculi, prefrontal cortex and hippocampus, and low in the cerebellum. Pretreatment with unlabeled cytisine inhibited binding in the thalamus, but not in the cerebellum. Binding was displaced by l-nicotine, but not by d-nicotine or dexetimide. The results suggest that cytisine, appropriately labeled with a positron emitting radionuclide, may be useful for study of nicotinic cholinergic receptors in humans by emission computed tomography.

Alkaloids↗
PubMed1994

Morphine effects on the spontaneous electroencephalogram in polydrug abusers: correlations with subjective self-reports.

The spontaneous electroencephalogram (EEG) was recorded after the intramuscular (IM) injection of morphine sulfate (15, 30 mg) or saline (0.9% NaCl). Correlations between changes in EEG spectral power and subjective self-reports, as measured on subscales of the Addiction Research Center Inventory (ARCI), were evaluated. Morphine increased alpha 1 and alpha 2 power and theta power, and attenuated the increase in delta power observed after placebo. Positive correlations were found between the change in alpha 1, alpha 2, beta 1, and beta 2 power in response to 30 mg of morphine and scores on Morphine-Benzedrine Group (MBG) subscale of the ARCI. Negative relationships were observed between changes in alpha 1, and beta 2 and scores on the Pentobarbital Chlorpromazine Alcohol Group (PCAG) subscale. The findings indicate that positive subjective effects of opioids, as measured by the MBG subscale, are related to increases in alpha and beta activity and are associated with reduction of opioid-induced sedation, as measured by the PCAG subscale.

Adult↗
PubMed1994

Cocaine-induced increases in EEG alpha and beta activity: evidence for reduced cortical processing.

To understand the effects of cocaine on the cerebral cortex, 14 male polydrug abusers were enrolled in a study on the effects of cocaine on the electroencephalogram (EEG). The experimental treatments were placebo, 20 mg cocaine or 40 mg cocaine i.v. administered in a double-blind, pseudorandom design. The EEG was recorded from 13 electrode positions over the left hemisphere during a 3-minute baseline recording and for 30 minutes after initiation of the i.v. injection. The spectral power for delta, theta, alpha and beta EEG bands was calculated from data collected in each 3-minute interval. Cocaine significantly increased beta in frontal and central areas and enhanced alpha in frontal and temporal regions. Cocaine-induced increases in EEG beta power had a cortical distribution similar to those produced by barbiturates and benzodiazepines. As all of these drugs reduce cortical glucose metabolism, the increases in beta power may reflect a reduction in cortical neural activity.

Adult↗
PubMed1994

Cerebral responses to single and multiple cocaine injections in newborn sheep.

Newborn infants exposed to cocaine near birth display a wide range of neurologic abnormalities, but the mechanism or mechanisms for these injuries remain unknown. We studied the cerebral effects of a single acute dose (4 mg/kg; n = 7) and multiple binge doses (4 mg/kg hourly for 5 h; n = 7) of i.v. cocaine in unanesthetized newborn (5 +/- 1 d old) sheep. We measured cerebral blood flow, mean arterial blood pressure, arterial blood gases, and cerebral O2 metabolism. Measurements were made at baseline; 30 s; and 5, 15, and 60 min after a single injection of cocaine in the acute group and at the same time intervals after the 5th dose of cocaine in the binge group. CBF increased by 98 +/- 68% (mean +/- SD) at 30 s after a single acute dose and by 97 +/- 94% at 30 s after the 5th of five hourly binge doses. Although it returned to baseline by 5 min in the acute group, cerebral blood flow remained elevated 5, 15, and 60 min after the 5th cocaine dose in the binge group. At 30 s, mean arterial blood pressure increased by 57 +/- 21% in the acute group and 46 +/- 15% in the binge group. In both groups, mean arterial blood pressure remained elevated at 5 min. Although no change occurred in cerebral O2 metabolism in the acute group, an increase in cerebral O2 consumption (7.4 +/- 1.3 mL/100 g/min versus 5.5 +/- 1.1 at baseline) was observed at 5 min in the binge group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Further characterization of [3H]ifenprodil binding to sigma receptors in rat brain.

This study was undertaken to examine further the pharmacology of [3H]ifenprodil binding in rat brain at 37 degrees C. [3H]Ifenprodil bound specifically to membranes (Kd = 5.09 +/- 0.30 nM; Bmax = 2.36 +/- 0.19 pmol/mg protein). [3H]Ifenprodil binding was potently inhibited by sigma ligands and inhibitors of cytochrome P-450. The levorotatory enantiomers of pentazocine and SKF 10,047 were more potent inhibitors than corresponding dextrorotatory enantiomers. Furthermore, the pharmacological profile of [3H]ifenprodil binding was highly correlated with that of sigma 2 sites, not sigma 1 sites. The results suggest that [3H]ifenprodil labels sigma 2 sites in rat brain at 37 degrees C, and that [3H]ifenprodil would be useful for studying sigma receptor subtypes.

Animals↗
PubMed1993

Dose-dependent effects of D-N-allylnormetazocine on regional cerebral metabolic rates for glucose.

Cerebral metabolic patterns produced by different doses of the benzomorphan opioid drug, D-N-allylnormetazocine (D-NANM), were studied using the 2-deoxy-D-[1-14C]glucose method in rats. The lowest dose of D-NANM (0.5 mg/kg) decreased regional cerebral metabolic rates for glucose (rCMRglc) in areas, such as cranial nerve nuclei, that contain high densities of sigma (sigma) receptors. However, higher doses of the drug (2.7 and 5 mg/kg) increased rCMRglc in components of the extrapyramidal motor and limbic systems. Some of these latter areas (e.g. molecular layer of the dentate gyrus, accumbens nucleus, globus pallidus, ventral posterior nucleus of the thalamus) are not enriched in sigma receptors. Reductions in rCMRglc produced by the lowest dose of D-NANM probably reflect direct interactions of the drug with sigma receptors, whereas increases in rCMRglc observed with the highest doses more likely result from effects of D-NANM on PCP receptors.

Animals↗
PubMed1993

Attenuation of some signs of opioid withdrawal by inhibitors of nitric oxide synthase.

Effects of nitric oxide synthase (NOS) inhibitors (L-NG-nitroarginine, L-NG-nitroarginine methyl ester) on precipitated opioid withdrawal were studied in morphine-dependent rats given naloxone, in order to assess the involvement of nitric oxide (NO) in opioid dependence. L-NG-Nitroarginine (7.5 mg/kg, IP, 1 h before naloxone or b.i.d. on days 4-7 of an 8-day morphine treatment) reduced wet dog shakes and weight loss; when given by osmotic pumps (15 mg/kg per day), the drug reduced wet dog shakes but not weight loss. L-NG-Nitroarginine methyl ester (60 mg/kg, 1 h before naloxone) also reduced wet dog shakes and weight loss. The results indicate that NOS inhibitors warrant further study as potential treatments of the opioid withdrawal syndrome.

Amino Acid Oxidoreductases↗
PubMed1993

Higher levels of nicotine in arterial than in venous blood after cigarette smoking.

We examined differences between arterial and venous concentrations of nicotine in human subjects. Shortly after smoking a cigarette, levels of nicotine in arterial plasma were more than double those in venous plasma. The time course of the rise in arterial nicotine levels and the magnitude of the arteriovenous difference varied considerably among subjects. For some subjects, arterial nicotine concentrations after one cigarette were similar to venous concentrations typically observed after 20 cigarettes and were nearly 10 times greater than venous concentrations. Our findings have implications for understanding the high degree of addictiveness and cardiovascular toxicity of smoked forms of drugs.

Adult↗