Biomedical subjects

E D Levin

Publications and source records attributed to E D Levin.

At least 109 records · Page 6Linked to original sources

PubMed1989

Suppressive effects of halothane on reactive synaptogenesis in the dentate gyrus of rats.

Reactive synaptogenesis was studied in the dentate gyrus of rats exposed to 100 parts per million of halothane for 15 days starting on the day after unilateral entorhinal lesioning. Halothane exposure markedly affected the replacement of synapses. Only 17% of the lost synapses were restored by day 15 postlesion in rats exposed to halothane, while 73% of the lost synapses were recovered in rats not exposed to halothane. However, this suppression in initial reactive synaptogenesis did not result in permanent deficits in synaptic population. After halothane exposure was stopped, reactive synaptogenesis resumed, and by day 30 after the lesion, the synaptic population of the experimental group caught up to the control level. This suppressive action of halothane suggests its utility as a research tool for delaying synaptogenesis during selected developmental epochs to study the relationship between synaptic and behavioral recovery.

Animals↗

PubMed1989

Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia.

Glutamate decarboxylase (GAD) activity was measured in the nuclei of the basal ganglia in patients with neuroleptic-induced tardive dyskinesia (TD) and controls matched for age and premortem state. In five TD patients, who all had a sudden death, a significant decrease in GAD activity was found in the subthalamic nucleus (STN). The lowered GAD activity in the STN may represent a biochemical substrate for neuroleptic-induced TD.

Aged↗

PubMed1989

Chronic neuroleptic effects on spatial reversal learning in monkeys.

Cebus apella monkeys were chronically administered the antipsychotic drug fluphenazine decanoate for periods ranging from 3.5 to 5.5 years. In the present study, four of these monkeys and two controls were tested for cognitive abilities on a spatial learning task, which consisted of an original discrimination and four reversals of that discrimination. No effect of fluphenazine administration was seen in the rate of learning the original discrimination, but the carryover of learning across discrimination reversals was significantly reduced by fluphenazine. After overtraining on the original discrimination, the controls showed the normal difficulty in learning the first reversal. The fluphenazine-treated monkeys showed no such disruption. On subsequent reversals, the controls showed continually improving performance, so that on the third and fourth reversals they had near-perfect scores. On the other hand, the fluphenazine-treated monkeys showed no change over the four reversals. Unlike normal monkeys, their learning did not improve with practice. Although simple forms of learning seem to be relatively unaffected by chronic fluphenazine administration, more complex learning is disrupted.

Animals↗

PubMed1989

Radial-arm maze performance in rats is impaired by a combination of nicotinic-cholinergic and D2 dopaminergic antagonist drugs.

Performance on the radial-arm maze depends on the integrity of both cholinergic and dopaminergic systems. We have previously found that administration of either the nicotinic-cholinergic antagonist, mecamylamine, or the muscarinic-cholinergic antagonist, scopolamine, impairs choice accuracy in the radial-arm maze. Co-administration of the dopaminergic antagonist, haloperidol, ameliorated the performance deficit caused by scopolamine but exacerbated the deficit caused by mecamylamine. Furthermore, antagonism of the effect of scopolamine is due specifically to blockade of D1 receptors. In the present experiment behaviorally subthreshold doses of mecamylamine and the D2 antagonist raclopride impaired maze performance when administered together. No interactive effects were observed between mecamylamine and the D1 antagonist SCH 23390. Although several of the drug treatments studied significantly increased choice latency, an index of motor behavior, there was no perfect relationship between choice accuracy and choice latency. These data indicate that nicotinic-cholinergic and muscarinic-cholinergic systems interact selectively and differentially with D1 and D2 dopaminergic systems.

Animals↗

PubMed1989

Mecamylamine increases nicotine preference and attenuates nicotine discrimination.

Eight subjects evaluated various qualities of cigarette smoke after being given a range of doses (0, 2.5, 10 and 20 mg) of the nicotinic receptor blocker mecamylamine. In one test condition, subjects were given either high or low nicotine tobacco smoke to determine the effects of mecamylamine on their subjective responses. In another test condition, subjects were allowed to adjust the nicotine dose level of the smoke to determine the effects of mecamylamine on dose preference. When the subjects evaluated puffs of smoke with high and low nicotine content, mecamylamine caused a dose-related decrease in the self-rated strength and harshness of the high nicotine dose level smoke. In contrast, there was little effect on the low dose smoke. At the highest mecamylamine dose (20 mg) there was no significant difference in the ratings of high and low nicotine cigarettes. Low doses of mecamylamine decreased the reported desire for a cigarette, and also attenuated the reduction in desire for a cigarette caused by smoking. When the subjects were allowed to select their preferred level of nicotine intake using a smoke mixing device, the 10 and 20 mg doses of mecamylamine caused a significant increase in self-administered nicotine dose level. Despite this compensatory increase in nicotine self-administration, the reduction in desire for a cigarette after smoking was still less than after placebo.

Adult↗

PubMed1989

Effects of dopamine D1 and D2 receptor antagonists on oral activity in rats.

Two experiments were performed to investigate the actions of the selective D1 blocker SCH 23390 and the selective D2 blocker sulpiride, on oral movements in rats; these were quantified by a human observer scoring vacuous chewing movements (VCMs), jaw tremor and head movements, as well as a computer analysis system which measured the amplitude and slope of each movement. In the first experiment it was found that both SCH 23390 and sulpiride decreased VCMs and head movements in a dose-dependent manner, with SCH 23390 more effectively decreasing head movements and sulpiride more effectively decreasing VCMs. In a second experiment, the effectiveness of these two drugs in blocking the actions of selective D1 (SKF 38393) and D2 (LY 171555) agonists was studied. The SKF 38393-induced increase in computer-scored movement was attenuated by both sulpiride and SCH 23390, whereas the LY 171555-induced decrease in VCMs was attenuated by sulpiride, while SCH 23390 exacerbated it. These findings, together with our earlier results, suggest a simple relationship of D1 receptors to oral movement, with increased activation resulting in increased oral movement and decreased activation resulting in decreased oral movement. The relationship of D2 receptors to oral movement shows a more complex pattern, with both stimulation and blockade decreasing oral movement. One possibility may be the existence of more than one subpopulation of D2 receptors mediating these effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1989

D1 and D2 dopamine receptor interactions with pilocarpine-induced oral activity in rats.

To investigate the relationship between dopamine (DA) and acetylcholine (ACh) systems in the control of oral movement, we studied the effects of specific D1 and D2 drugs on vacuous chewing movements induced by the muscarinic ACh agonist, pilocarpine. In previous experiments we found that when given alone, the D1 agonist SKF 38393 increased vacuous chewing and the D1 antagonist SCH 23390 decreased it, while both the D2 agonist LY 171555 (quinpirole) and the D2 antagonist sulpiride decreased vacuous chewing. In the present experiment, the effects of the D1 drugs had similar effects in rats concurrently given pilocarpine. In contrast, the effects of both of the D2 drugs were altered by pilocarpine. Surprisingly, the actions of D2 agonist and antagonist were affected in opposite ways. The effect of sulpiride in reducing oral movement activity was eliminated by pilocarpine, while the effect of LY 171555 in reducing oral movement was enhanced by pilocarpine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1989

Reversal of a mecamylamine-induced cognitive deficit with the D2 agonist, LY 171555.

Pharmacological blockade of either nicotinic or muscarinic cholinergic receptors has been found to impair choice accuracy in the radial-arm maze. Simultaneous blockade of both of these receptor types causes an additive impairment. However, despite these common effects, nicotinic and muscarinic receptors have been found to have differential involvement with dopamine receptors. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the D1 antagonist SCH 23390 but is unaffected by the D2 antagonist raclopride. In contrast, the cognitive impairment caused by the nicotinic antagonist mecamylamine is unaffected by SCH 23390 but is potentiated by raclopride. In the current study, the D2 agonist LY 171555 was found to be effective in reversing the radial-arm maze choice accuracy impairment caused by mecamylamine. In contrast, the D1 agonist SKF 38393 was not found to be effective. Thus, we have found selective dopaminergic D1 and D2 treatments which counteract the adverse cognitive effects of either nicotinic or muscarinic blockade. A combination of these treatments may be useful in treating the cognitive effects of generalized cholinergic underactivation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1989

Nicotinic-dopaminergic relationships and radial-arm maze performance in rats.

Accurate performance on the radial-arm maze is dependent upon the integrity of nicotinic-cholinergic, muscarinic-cholinergic, and dopaminergic systems. Pharmacological blockade of these systems with mecamylamine, scopolamine, or haloperidol impairs choice accuracy in the maze. We have previously demonstrated that the performance deficit caused by muscarinic blockade is enhanced by coadministration of the nicotinic antagonist, mecamylamine, and is diminished by coadministration of the dopamine antagonist, haloperidol. In the present study, it was found that the choice accuracy deficit produced by nicotinic blockade is enhanced, not antagonized, by coadministration of haloperidol. Thus, although both nicotinic and muscarinic cholinergic systems are involved in radial-arm maze performance and antagonists of these receptors are additive in the deficits they cause, nicotinic and muscarinic interactions with dopaminergic systems are opposite in nature.

Animals↗

PubMed1989

Effects of combined muscarinic and nicotinic blockade on choice accuracy in the radial-arm maze.

Acetylcholine (ACh) systems have been found to be crucial for the maintenance of accurate cognitive performance. A great variety of studies have shown that the muscarinic ACh receptor blocker scopolamine impairs choice accuracy in the radial-arm maze. Recently, it has been found that the nicotinic ACh receptor blocker mecamylamine also impairs radial-arm maze choice accuracy. In the present study, we investigated the effects of combined administration of these two ACh blockers. Scopolamine (0.15 mg/kg) and mecamylamine (10 mg/kg) each moderately impaired choice accuracy. Combined treatment with scopolamine and mecamylamine significantly decreased choice accuracy relative to either drug alone. This combination treatment lowered choice accuracy to chance levels. These data show that nicotinic and muscarinic blockade have at least additive effects in producing an anterograde memory deficit. Concurrent blockade of these two components of ACh systems may provide a better animal model of cognitive impairments due to the loss of cholinergic neurons, such as Alzheimer's disease.

Animals↗

PubMed1988

Behavioral effects of developmental lead exposure in rhesus monkeys.

Postnatal lead exposure has been found to cause long-term learning and memory deficits in monkeys. Pulse-chronic exposure, consisting of acute high-level exposure followed by chronic lower-level exposure, has been particularly effective in causing these impairments. We investigated possible antecedents of lead-induced cognitive dysfunction by evaluating the behavioral effects of pulse-chronic lead exposure in rhesus monkeys during the first 6 months of postnatal life. Blood lead concentrations in the monkeys reached a peak of 55.8 +/- 7.8 ug/dl during week 5 after birth and then averaged between 33.1 and 42.9 ug/dl during the rest of the first 6 months after birth. Zinc protoporphyrin levels were increased by lead exposure, but hematocrits were unaffected. Significant lead-related effects were detected on a visual exploration test and a neonatal behavioral assessment battery. Lead-treated monkeys exhibited decreased looking behavior on the visual exploration test and decreased muscle tonus and increased arousal or agitation on the behavioral assessment battery. No effects were seen on a Piagetian object permanence task and no toxic effects on health or growth were detected. In addition to providing indices of behavioral dysfunction during postnatal lead exposure, performance on these early behavioral tests may predict later lead-induced cognitive dysfunction.

Animals↗

PubMed1988

Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration.

Rats were chronically administered either haloperidol (HAL) or fluphenazine (FLU) via depot injections for 8 months, given these same drugs in their drinking water for the next 2 months, and then withdrawn from the drugs. Throughout the experiment the animals were tested repeatedly in an enclosed tube using a computerized device which measured computer-scored movelets (CSMs) and, in the latter half of the experiment, were also scored by a human observer in the tube, as well as in an open cage, for observed oral movements (OMs). In the tube, the animals in both neuroleptic-treated groups showed initial decreases in the number of CSMs and made sluggish CSMs; these effects were generally larger in the FLU animals. After 6 months of chronic neuroleptics, the HAL-treated animals showed increased oral movements, both as reported by the human observer and in CSMs of all amplitudes, and this effect increased upon drug withdrawal. FLU-treated animals showed a more persistent depression of both OMs and CSMs of large amplitudes. However, the behavior most characteristic of both neuroleptic-treated groups was the gradual development of increases in CSMs of the smallest amplitudes measurable. A different pattern was observed in the open cage test, where both neuroleptic groups showed significant increases in vacuous OMs during drug administration which rapidly became attenuated upon drug withdrawal. These results indicate a complex syndrome of oral activity in the drugged animals which changed over time. The measure of oral activity which most clearly showed the time-course for late-onset changes in oral activity was CSMs of the smallest amplitudes.

Animals↗

PubMed1988

Delayed spatial alternation deficits resulting from perinatal PCB exposure in monkeys.

Monkeys exposed to low, chronic levels of polychlorinated biphenyls (PCBs) in utero and during nursing until 4 months after birth were tested at 4-6 years of age on delayed spatial alternation (DSA), a spatial learning and memory task. Deficits in performance accuracy were detected in two cohorts of monkeys whose mothers had been fed 2.5 ppm of the PCB mixture, Aroclor 1248, in their diet for an 18-month period ending at least 12 months prior to pregnancy. The deficit was most apparent at the shorter delays, suggesting that it was not due to memory impairment, but may have been due to impairments in associational or attentional processes. There may also have been a deficit in a group of monkeys whose mothers were fed 1.0 ppm of the PCB mixture, Aroclor 1016. However, the deficit in this group was less pronounced than in the other groups. The appearance of a PCB-induced cognitive deficit more than 3 years after the end of exposure indicated the existence of very long-term adverse consequences of low-level perinatal PCB exposure.

Animals↗

PubMed1988

Behavioral effects of acute hexamethonium in rats chronically intoxicated with nicotine.

To investigate the effects of chronic nicotine administration on feeding behavior, hexamethonium, a nicotinic blocker with mainly peripheral actions, was acutely given to rats during and after chronic nicotine administration. Nicotine decreased both the time spent investigating the food and the amount of food consumed. It also decreased the time spent rearing and grooming and increased the time spent resting. These behaviors returned to control levels after nicotine withdrawal. During nicotine administration, 10 mg/kg of hexamethonium increased the amount of time the nicotine-treated rats spent investigating the food but did not change the amount of food actually eaten. These data show that predominantly peripheral nicotinic blockade can partially alleviate the effects of chronic nicotine administration of feeding behavior, suggesting that at least some of the effects of nicotine on feeding are peripheral. The finding that the investigational and consummatory aspects of feeding behavior can be pharmacologically differentiated implies that some aspects of their neural control may be distinct.

Animals↗

PubMed1988

Psychopharmacological effects in the radial-arm maze.

The radial-arm maze (RAM) has become a very widely used method for assessing spatial memory in rodents. It has proven to be quite useful in the investigation of the effects of a variety of pharmacological manipulations on spatial memory. The cholinergic system has been found to be crucial for accurate RAM performance. Blockade of either muscarinic or nicotinic receptors impairs performance. Other transmitter systems such as dopamine and the opiates have also been found to be involved with the maintenance of accurate RAM performance. This test has been found to be sensitive to the effects of a variety of toxicants given either in adulthood or during development. These findings provide a background for the assessment of the effects of novel substances on RAM performance as well as the basis for the further understanding of the neural substrates of memory.

Animals↗

PubMed1988

Cholinergic-dopaminergic interactions in radial-arm maze performance.

Although acetylcholine and dopamine are believed to play complementary roles in motor function, a comparable neurochemical interaction has not been established for cognitive function. The muscarinic receptor blocker scopolamine and the dopaminergic antagonist haloperidol have been found to impair choice accuracy of rats in the radial-arm maze. In the present study, low doses of these two drugs were administered intraperitoneally either alone or in combination to rats trained on a working memory task (food reward) in an eight-arm radial maze. Scopolamine, 0.125 mg/kg, produced a significant decrease in choice accuracy (i.e., arm entries until an error). Haloperidol, 0.0625 mg/kg, did not cause a significant decrease in accuracy, but there was a trend in that direction. The combination of haloperidol with scopolamine attenuated significantly the amnestic effect of scopolamine. These results suggest that, like motor behavior, cognitive function may be influenced by the balance between acetylcholine and dopamine.

Acetylcholine↗

PubMed1988

Scopolamine interactions with D1 and D2 antagonists on radial-arm maze performance in rats.

Recent evidence indicates that acetylcholine and dopamine play complementary roles in cognitive as well as motor functions. In our previous study, the dopamine receptor blocker, haloperidol, was found to attenuate the radial-arm maze choice accuracy deficit caused by the muscarinic acetylcholine receptor blocker, scopolamine. Haloperidol has activity in blocking both D1 and D2 dopamine receptor subtypes. The current study was conducted to determine whether this dopamine-acetylcholine interaction specifically involved D1 or D2 dopamine receptors. The D1 antagonist, SCH 23390, and the D2 antagonist, raclopride, were administered with a dose of scopolamine which caused choice accuracy deficits in the radial-arm maze. The scopolamine-induced deficit was reversed by SCH 23390, the D1 antagonist, indicating that D1 blockade alone is sufficient to reverse the amnestic effects of muscarinic blockade. There was no indication in this study that the D2 blocker, raclopride, had a similar effect. However, this does not mean that such an effect may not be present at other doses of raclopride or with other D2 antagonists. The present finding that D1 blockade counteracts scopolamine-induced cognitive dysfunction not only furthers the understanding of dopamine-acetylcholine relationships in cognitive function, it also suggests a promising direction for the development of treatments for cognitive dysfunction due to cholinergic loss.

Animals↗

PubMed1988

Neurobiochemical changes in tardive dyskinesia.

There is evidence for the view that both up- and downregulation of nigral GABA may give rise to dyskinetic movements. Intranigral infusion of GABA agonists causes stereotyped licking and gnawing in rats, while intranigral GABA antagonists produce vacuous chewing movements. It is hypothesized that during long-term neuroleptic treatment there may be a succession of changes within striatonigral GABA neurons: down-regulation caused by neuroleptic drugs may increase receptor sensitivity, and this may lead to overcompensation and withdrawal dyskinesia during periods of cessation of drug treatment. Reduced nigral GAD activity may be a marker of irreversible brain damage and has not been observed in all chronic experiments, but only in individuals with long-standing or irreversible dyskinesia. Changes within the GABA system seem to be accompanied by changes in the striatal and nigral levels of substance P.

Animals↗