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Biomedical subjects

E D Levin

Publications and source records attributed to E D Levin.

At least 19 recordsLinked to original sources
PubMed1992

Fetal nicotine exposure ablates the ability of postnatal nicotine challenge to release norepinephrine from rat brain regions.

Exposure of the fetus to nicotine is known to affect the function of noradrenergic pathways in the central nervous system. In the current study, synaptic mechanisms underlying the functional defects were evaluated in the offspring of pregnant rats given nicotine infusions of 2 mg/kg/day throughout gestation, administered by osmotic minipumps. At 30 days postpartum, norepinephrine levels in brain regions of the offspring were significantly reduced. More importantly, acute challenge with either 0.1 mg/kg or 0.3 mg/kg of nicotine evoked significant norepinephrine release from brain regions of control animals, but failed to do so in the fetal nicotine cohort. These results suggest that prenatal exposure to nicotine produces a deficit in subsequent noradrenergic responsiveness, deficits which may participate in behavioral and neuroendocrine abnormalities.

Animals↗
PubMed1992

The effect of halothane on cultured fibroblasts and neuroblastoma cells.

Halothane exposure over the cultured cells (100 and 1,000 ppm) caused a disruption of the pattern of actin distribution in both fibroblasts and neuroblastoma cells. Neuroblastoma cells exposed to halothane also lost microspikes; however, neurite elongation was not affected by halothane. The present study suggests that halothane induces the functional disruption of actin, resulting in an interference of normal neural development in vivo.

Actins↗
PubMed1992

Nicotinic systems and cognitive function.

Nicotinic acetylcholine receptors have been found to be important for maintaining optimal performance on a variety of cognitive tasks. In humans, nicotine-induced improvement of rapid information processing is particularly well documented. In experimental animals nicotine has been found to improve learning and memory on a variety of tasks, while the nicotinic antagonist mecamylamine has been found to impair memory performance. Nicotine has been found to be effective in attenuating memory deficits resulting from lesions of the septohippocampal pathway or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with Alzheimer's disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimer's disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.

Animals↗
PubMed1992

Concurrent agonist-antagonist administration for the analysis and treatment of drug dependence.

Two key strategies for the treatment of drug dependence involve the use of agonists to substitute for the abused drug and the use of antagonists to block the reinforcing actions maintaining drug self-administration. A different strategy for the treatment of drug dependence is outlined, comprising the concurrent administration of an agonist and an antagonist. Concurrent administration of an agonist with an antagonist, in the proper ratio, should produce maximal occupancy of receptors and attenuation of the reinforcing actions of the abused drug. The addict would be relatively "insulated" from the reinforcing effects of the abused drug; at the same time the balance of agonist and antagonist effects is predicted to prevent withdrawal symptoms or intoxication resulting from an under- or over-stimulation of drug receptors. Advantages over the use of agonists alone and antagonists alone, and over mixed agonist-antagonist molecules, are discussed. Application of concurrent agonist-antagonist administration to the analysis of mechanisms underlying nondrug reinforcement and to the treatment of disorders involving receptor disregulation is also described.

Animals↗
PubMed1992

Persistence of chronic nicotine-induced cognitive facilitation.

Nicotine has been found in a variety of species and behavioral paradigms to improve memory performance. The beneficial effect of nicotine has been seen after both acute and chronic administration. Interestingly, improved performance has been seen 24 h after acute injection and for at least 2 weeks after chronic administration. However, it is not clear from previous studies whether the persistence of the improved performance represents a true carryover of the drug effect or is due to the behavioral experience while under nicotine's effect. The current study was conducted to determine whether the facilitating effect of nicotine on learning and memory performance could be seen after withdrawal even if there was no behavioral training during the period of chronic nicotine administration. Rats were administered nicotine chronically for 3 weeks but were not tested during that time. Starting 1 week after withdrawal they were trained on a working memory paradigm in an eight-arm radial maze. The nicotine-treated rats started out at control-like levels of performance, but showed significantly faster learning as detected by three different measures of choice accuracy. By the final phase of testing the control subjects had caught up with the nicotine-treated rats. After the acquisition phase, acute challenges with the nicotinic and muscarinic antagonists, mecamylamine and scopolamine, did not elicit any differential effects in the nicotine-treated and control groups. The current study demonstrated that nicotine-induced cognitive facilitation persists for at least 4 weeks after withdrawal and does not depend upon behavioral test experience under the influence of the drug. The mechanism for this persisting effect is not currently understood.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

Dopaminergic drugs reverse the impairment of radial-arm maze performance caused by lesions involving the cholinergic medial pathway.

Pharmacological studies have shown that both cholinergic and dopaminergic transmitter systems are crucial for optimal choice accuracy in the radial-arm maze and that these systems interact in a complex fashion. Lesion studies have provided evidence that the basal nuclear complex of the forebrain, the origin of cholinergic projections to the cerebral mantle, may be critical for the cholinergic modulation of learning and memory. We have shown that knife-cut lesions of the medial cholinergic pathway significantly impair radial-arm maze choice accuracy performance. The current study examined the effectiveness of D1 and D2 ligands in counteracting this lesion-induced deficit. The adverse effects of medial cholinergic pathway lesions were diminished or reversed by daily treatment with a D1 agonist (SKF 38393), a D2 agonist (LY 171555) or a D1 antagonist (SCH 23390), but were not affected by treatment with a D2 antagonist (raclopride). The three beneficial treatments have previously been found to attenuate the adverse effects of nictonic or muscarinic blockade on choice accuracy performance in the radial-arm maze. The finding that these dopaminergic drugs ameliorate the memory deficit caused by lesions involving the cholinergic medial pathway suggests the importance of interactions between cholinergic and dopaminergic systems in radial-arm maze performance. These results may provide leads for the development of novel therapeutic approaches for treating human disorders thought to result from cholinergic hypofunction.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

The effects of smoking-related sensory cues on psychological stress.

Previous studies have shown that the sensory cues of cigarette smoking are important for smoking satisfaction and craving reduction. Sensory cues in the absence of pharmacological doses of nicotine have been found to be moderately satisfying and to reduce craving. The current study was conducted to determine if administration of the sensory cues of cigarette smoking with minimal nicotine would also provide relief from mild anxiety associated with anticipation of a difficult anagram test. This test has previously been shown to be sensitive to the anxiety relieving effects of cigarette smoking. Compared to the placebo control condition, the sensory condition caused a significant alleviation of the stress as measured by components of the Spielberger scale for anxiety. The addition of cigarette smoke containing 0.5 mg of nicotine to the sensory cues caused a slight though nonsignificant enhancement of the stress alleviation. These results demonstrate that sensory cues of smoking can provide similar effects as nicotine containing cigarettes with regard to stress alleviation. Previous studies had shown that sensory cues are important for the consumptive aspects of smoking (i.e., smoking satisfaction and craving reduction). The current study shows that sensory cues are important for other effects of smoking as well.

Adolescent↗
PubMed1991

Interactive effects of D1 and D2 agonists with scopolamine on radial-arm maze performance.

Pharmacological blockade of muscarinic cholinergic (ACh) receptors has been found to impair choice accuracy in a variety of tasks including the radial-arm maze. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the dopaminergic (DA) antagonist haloperidol as well as the selective D1 antagonist SCH 23390. In the current study, interactions were studied between scopolamine and selective agonists of D1 (SCH 38393) and D2 (quinpirole) receptors. Surprisingly, the D1 agonist SKF 38393 was found to significantly alleviate the scopolamine-induced choice accuracy deficit. In contrast, the D2 agonist quinpirole was not found to significantly alter the effects of scopolamine on choice accuracy but did have supra-additive effects of increasing choice latency. Both the D1 agonist SKF 38393 and the D1 antagonist SCH 23390 have been found to reverse the choice accuracy deficit caused by scopolamine and the deficit resulting from lesions of the medial projection from the basal forebrain to the cortex. Possible mechanisms for these effects are discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Impairment of radial-arm maze performance in rats following lesions involving the cholinergic medial pathway: reversal by arecoline and differential effects of muscarinic and nicotinic antagonists.

Pharmacologic studies have indicated that accurate performance on the radial-arm maze depends upon the integrity of both nicotinic and muscarinic cholinergic neurotransmitter systems and that these systems interact in a complex fashion. Although numerous studies have suggested that pathways deriving from the basal nuclear complex of the forebrain are critical for the cholinergic modulation of learning and memory, most have focussed on the septohippocampal projection, and none have specifically targeted the medial or lateral systems. In Experiment 1, cortical knife cuts interrupting the medial cholinergic pathway were made at the level of the caudate-putamen nucleus. Such transections produced a robust but temporary disruption of choice accuracy performance in the radial-arm maze. Recovery of this behavior occurred within 10 days and before cholinergic fiber regeneration, suggesting that compensatory changes could have taken place in non-ablated neuronal circuits. In Experiment 2, daily postsurgical administration of arecoline, an agonist with predominantly muscarinic actions, was found to virtually eliminate the adverse behavioral effects of medial pathway transections, indicating that the deficit could be attributable, in part, to disruption of cholinergic projections. In Experiment 3, the effects of scopolamine, a muscarinic antagonist, and mecamylamine, a nicotinic antagonist, were examined in rats with medial cholinergic pathway transections after behavior had returned postsurgically to control levels. Although both drugs attenuated radial-arm maze performance before knife cuts, only scopolamine reduced choice accuracy following surgery. We conclude that the medial cholinergic pathway, particularly its nicotinic actions, plays an important role in cognitive function, at least as exemplified by radial-arm maze performance. Muscarinic mechanisms associated with other telencephalically projecting cholinergic networks, as well as possibly with the medial pathway itself, appear to operate interactively with nicotinic influences.

Animals↗
PubMed1991

Nicotinic and muscarinic interactions and choice accuracy in the radial-arm maze.

Muscarinic acetylcholine (ACh) systems have long been known to be necessary for accurate performance in cognitive tests. Nicotinic ACh systems have been shown to be involved as well. However, there is only a limited amount of information concerning the interactions of these two branches of the ACh transmitter system. The current study was conducted to investigate the improvement in choice accuracy caused by muscarinic and nicotinic agonists and how it is affected by antagonists of these systems. Adult female Sprague-Dawley strain rats (N = 11) were trained on a working memory task in an 8-arm radial maze. Acute injections of the muscarinic and nicotinic agonists, pilocarpine (PILO, 1.0 mg/kg) and nicotine (NIC, 0.2 mg/kg), were made alone or in combination with the muscarinic and nicotinic antagonists, scopolamine (SCOP, 0.1 mg/kg) and mecamylamine (MEC, 10 mg/kg). NIC administration caused a significant improvement in choice accuracy compared with saline (p less than 0.01) and PILO caused a marginally significant improvement in choice accuracy (p less than 0.06). The combination of these nicotinic and muscarinic agonists did not cause an additive improvement. However, the improvement caused by either agonist was reversed by both nicotinic or muscarinic antagonists. This reversal was more complete for NIC than PILO despite the fact that NIC caused a greater improvement than PILO. These results suggest that muscarinic and nicotinic components of the ACh system, which are both important for cognitive function, interact in important ways. These interactions may be critical to consider when devising treatments for cognitive dysfunction associated with cholinergic hypofunction such as with Alzheimer's disease.

Animals↗
PubMed1991

Inter-relationships between conditioned and primary reinforcement in the maintenance of cigarette smoking.

Research on smoking cessation has increasingly focussed on pharmacological aspects of nicotine and nicotine withdrawal. However, cigarette smoking also provides a characteristic set of sensory cues. These sensory aspects of smoking are important to address in that they may be potent conditioned reinforcing stimuli linked to the actions of nicotine. The repetition of the smoking act thousands of times per year by a moderately heavy smoker leads to a strong conditioned association between the sensory aspects of smoking (the putative CS) and the pharmacological effects of nicotine (the putative UCS). Strategies for disrupting CS-UCS associations may be useful in developing more effective smoking cessation treatments. These include: counterconditioning of the CS; presenting the CS alone; presenting the CS with the UCS but pharmacologically blocking the UCS; and presenting the CS and UCS in an unconnected fashion. The role of sensory cues in alleviating craving for cigarettes is discussed, and specific techniques for duplicating relevant sensory aspects of smoking without delivering significant doses of nicotine are described. The combination of nicotine and nicotinic antagonists to block primary reinforcement and hasten extinction of conditioned reinforcement is also considered.

Arousal↗
PubMed1990

Long-term effects of developmental halothane exposure on radial arm maze performance in rats.

Chronic exposure of rats to low levels of halothane during development, a treatment which retards synaptogenesis, was found to cause a long-term impairment of choice accuracy in the radial-arm maze. In Expt. 1, the relative importance of dose level and dosing regimen was examined. Dose level seemed the more critical variable for causing impaired choice accuracy. Exposure to 100 parts per million (ppm) of halothane in the air either on an intermittent or continuous schedule from day two of conception until 60 days after birth significantly impaired choice accuracy, whereas exposure to 25 ppm on a continuous schedule did not cause a deficit, even though with this condition the total amount of halothane exposure was about the same as with 100 ppm given intermittently. In Expt. 2, the 100 ppm intermittent exposure regimen was used to examine the relative importance of exposure during early and late developmental periods for producing the cognitive effects of halothane. Groups were divided into those exposed to halothane during gestation and until 30 days after birth (early exposure), those exposed from day 31 until day 90 (late exposure) and those exposed during both early and late periods (combined exposure). Adverse effects on choice accuracy were seen with all 3 types of exposure, but surprisingly, it was the late exposure that caused the most severe effects. These results show that developmental exposure to halothane which impairs synaptogenesis also causes long-lasting cognitive impairment. Halothane exposure can be a useful experimental tool for examining the relationship between synaptic and behavioral development.

Age Factors↗
PubMed1990

d-Amphetamine-induced "floating limb" syndrome in young rhesus monkeys.

Acute d-amphetamine administration to young rhesus monkeys (N = 10) caused a motor syndrome of hypoactivity and chorea-like postures and motor movements which we have termed "floating limb". Frequently after subcutaneous injections of 0.3 or 0.6 mg/kg d-amphetamine, an affected monkey raised one or both legs or arms and held the limb(s) motionless in the air. Affected limbs were usually returned to a normal position if they appeared to enter the animal's visual field. In other cases, the monkey assumed bizarre and contorted postures which were held for prolonged periods. Such postures were often accompanied by gentle repetitive brushing of the ears and facial hair with extremities of the affected limbs. Quantification of the frequency of these movements showed that they occurred regularly for 90-150 min after d-amphetamine. Hydroxyamphetamine, a peripherally-acting amphetamine analog, did not induce floating limb, indicating that the behavior was probably mediated by central actions of d-amphetamine. A similar disorder has been reported occasionally in other studies with monkeys and cats. It may be related to the chorea that is seen in humans after the use of amphetamine and other stimulants. d-Amphetamine treatment in young monkeys may provide a viable model of human choreoathetoid disorders induced by disease or drug use.

Animals↗
PubMed1990

Contrasting effects of centromedial and basolateral amygdaloid lesions on stress-related responses in the rat.

The effects of lesions in the centromedial and basolateral amygdala were examined using three different tests sensitive to the following stress-related responses: exploratory behavior, pain reactivity, and immune responses. The most clear-cut results were found with exploratory behavior. Rats with lesions of the centromedial amygdala tended to explore a radial-arm maze more quickly and entered more novel arms of the maze than controls. Those with lesions of the basolateral amygdala were generally too hesitant to explore at all. No significant differences were found between groups on measurements of natural killer cell activity. In tests of pain perception, rats in the control group displayed an analgesic response on the hot plate following an injection of the anxiogenic drug, RO 15-1788, whereas rats with centromedial lesions tended to exhibit a blunted response. These findings provide modest support for the view that the central and lateral regions of the amygdala play complementary roles in aversively motivated behaviors and in stress-related response patterns.

Amygdala↗
PubMed1990

Chronic nicotine and withdrawal effects on radial-arm maze performance in rats.

Rats were tested for choice accuracy in an eight-arm radial maze during and after chronic administration of nicotine via subcutaneously implanted glass and Silastic capsules. Nicotine administration significantly improved choice accuracy relative to controls. The effect gradually became apparent over the first 2 weeks of exposure and persisted through the third week. Surprisingly, the significant facilitation of the nicotine-treated rats relative to controls continued for 2 weeks after the end of nicotine administration. No effects of nicotine were seen on choice latency or the strategy to make adjacent arm entries.

Animals↗
PubMed1990

Cholinergic-dopaminergic interactions in cognitive performance.

Both acetylcholinergic (ACh) and dopaminergic (DA) systems have been found to be crucial for the maintenance of accurate cognitive performance. In a series of studies examining those aspects of cognitive function revealed by the radial-arm maze, we have found that these two neurotransmitter systems interact in a complex fashion. Choice accuracy deficits in the radial-arm maze can be induced by blockade of either muscarinic- or nicotinic-ACh receptors. The choice accuracy deficit induced by blockade of muscarinic receptors with scopolamine can be reversed by the DA receptor blocker, haloperidol. The specific DA D1 blocker SCH 23390 also has this effect, whereas the specific D2 blocker raclopride does not, implying that it is D1 blockade that is critical for reversing the scopolamine effect. On the other hand, the choice accuracy deficit induced by nicotinic blockade with mecamylamine is potentiated by haloperidol. This effect is also seen with the D2 antagonist raclopride, but not with the D1 antagonist SCH 23390, implying that it is the D2 receptor which is important for the potentiation of the mecamylamine effect. The relevance of the D2 receptor for nicotinic actions on cognitive function is emphasized by the finding that the selective D2 agonist LY 171555 reverses the choice accuracy deficit caused by mecamylamine. Nicotinic and muscarinic blockade are synergistic in the deficit they produce. Antagonist doses subthreshold when given alone produce a pronounced impairment when given together. This latter deficit can be reversed by the D2 agonist LY 171555. These studies have outlined the complex nature of ACh-DA interactions with regard to cognitive function. Possible neural circuits for these interactions are discussed. The effectiveness of these selective DA treatments in reversing cognitive deficits due to ACh underactivation suggests a novel approach to treating cognitive dysfunction in syndromes such as Alzheimer's disease.

Acetylcholine↗
PubMed1990

Characterization of the cognitive effects of combined muscarinic and nicotinic blockade.

Choice accuracy performance in the radial-arm maze is dependent upon the integrity of both the nicotinic and muscarinic cholinergic receptors. Pharmacological blockade of either of these subtypes of cholinergic receptors with mecamylamine or scopolamine impairs choice accuracy in the radial-arm maze. We have previously demonstrated that the performance deficit caused by muscarinic blockade is exacerbated in at least an additive fashion by coadministration of the nicotinic antagonist, mecamylamine. In the present study, it was found that mecamylamine and scopolamine act together in a greater than additive fashion in disrupting radial-arm maze choice accuracy. When doses of these drugs which do not by themselves cause significant impairments in choice accuracy are given together, they induce a pronounced impairment. Previous results have shown that the adverse effects of nicotinic blockade could be reversed by the dopaminergic D2 agonist LY 171555. In this study, this drug was found to attenuate the cognitive impairment caused by combined nicotinic and muscarinic blockade. On the other hand, the dopaminergic D1 antagonist SCH 23390 which has previously been shown to reverse the adverse effects of muscarinic blockade was not found in this study to attenuate the impairment of combined nicotinic and muscarinic blockade. Since combined nicotinic and muscarinic blockade approximates generalized cholinergic underactivation, treatments like LY 171555, which attenuate the adverse effects of this combined blockade, may be useful in treating syndromes like Alzheimer's disease, which are characterized by generalized cholinergic loss.

Animals↗