Chronic nicotinic stimulation and blockade effects on working memory

Acute and chronic nicotine treatment has been found to improve learning and memory function in a variety of tasks. In several studies we have found that chronic nicotine infusion improves working memory performance. Replicating these results, the current study showed that chronic nicotine treatment (12mg/kg/day) significantly improved working memory performance in the radial-arm maze. The nicotine effect did not diminish during the 2 weeks following withdrawal. The nicotine-induced improvement was eliminated when the nicotinic antagonist mecamylamine (3mg/kg/day) was given concurrently, suggesting that the nicotine effect was mediated via actions on the nicotinic receptor. Surprisingly, when this chronic dose of mecamylamine was given alone, it caused a transient improvement in choice accuracy during the first week of administration. This improvement subsequently became attenuated and was not evident at all by the third and fourth weeks of administration.     

Acute and chronic nicotine effects on working memory in aged rats

Acute and chronic nicotine administration has been repeatedly been found in our laboratory to improve working memory performance of normal adult rats in the radial-arm maze. The current study was conducted to determine if acute or chronic nicotine administration would improve working memory performance in aged rats. Sixteen young adult (3–7 months) and 32 aged (24–28 months) male Sprague-Dawley rats were trained on an eight-arm radial maze. A significant age-related choice deficit was seen during the 21 sessions of training. After training, half of the rats in each age group were implanted with nicotine-containing osmotic minipumps and the other half implanted with vehicle-containing pumps. Consistent with previous work, the young adult rats given chronic nicotine (approximately 5 mg/kg per day as measured as nicotine base) showed a significant improvement in working memory performance. In contrast, the aged rats did not show a significant effect of this dose of chronic nicotine. After a 2 week withdrawal period the remaining rats underwent a series of acute drug challenges with nicotinic and muscarinic agonists and antagonists as well as the dopaminergic antagonist haloperidol. Mecamylamine and haloperidol impaired the memory performance of the young adult rats, whereas the aged rats showed no effect. In contrast, scopolamine impaired performance of both young adult and aged rats in a similar manner. Both pilocarpine and nicotine improved the memory performance of the aged rats, but did not improve the young adult rats, possibly due to a ceiling effect on performance. During the cholinergic agonist drug phase, the aged rats which had previously been given chronic nicotine infusions showed better performance than those which had not. The resistance of the aged rats to chronic nicotine-induced working memory improvements and acute mecamylamine-induced working memory deficits may have resulted from the decline in nicotinic receptors seen with aging. Chronic co-administration of the nicotinic antagonist mecamylamine in a previous study was found to abolish the chronic nicotine-induced working memory improvement. The aged rats were resistant to haloperidol-induced deficits which may have resulted from the decrease in dopaminergic receptors seen with aging. Interestingly, acute cholinergic agonists including nicotine did improve working memory performance in the aged rats and previous chronic nicotine infusion was beneficial during the period of acute cholinergic agonist challenge. This suggests that nicotinic treatment may be of use for treating age associated memory impairments but that special dosing regimens may be required.This work was carried out in partial fulfillment of a BSc (Hons) in Biochemistry at the University of Bath (UK) by D.T.     

Ventral hippocampal alpha4beta2 nicotinic receptors and chronic nicotine effects on memory

Chronic nicotine administration has been repeatedly shown to facilitate working memory function in rats on the radial-arm maze. The critical neural mechanisms for this effect are still being discovered. The nicotinic nature of the chronic nicotine induced memory improvement is supported by the finding that it is blocked by chronic mecamylamine co-infusion. The hippocampus also appears to be critically important. Hippocampal ibotenic acid lesions block the effect. Within the hippocampus, we have found that the alpha4beta2 nicotinic receptor subtype is involved in memory functioning. Acute ventral hippocampal infusions of the alpha4beta2 nicotinic antagonist dihydro-beta-erythroidine (DHbetaE) significantly decreased working memory performance in the radial-arm maze. The aim of the current study was to determine the importance of alpha4beta2 receptors within the ventral hippocampus for the memory enhancing effects of chronic nicotine treatment. Adult female Sprague-Dawley rats were trained on the 8-arm radial maze and were cannulated bilaterally in the ventral hippocampus. Osmotic minipumps administering chronic nicotine at a rate of 5 mg per kg per day were also implanted in the nicotine treatment rats. Control rats received saline-only minipumps. For a period of 4 weeks after surgery, each rat received bilateral hippocampal infusions of 0, 2, 6 and 18 microg per side of DHbetaE and tested for memory performance on the radial-arm maze. Radial-arm maze choice accuracy was impaired by acute hippocampal DHbetaE infusion in a dose-related fashion. This acute hippocampal DHbetaE-induced choice accuracy impairment was eliminated by chronic systemic nicotine infusion. Chronic nicotine in combination with acute vehicle hippocampal infusion was not seen to alter choice accuracy. Response latency was not found to be altered by acute hippocampal DHbetaE in the absence of chronic nicotine administration, but it did attenuate the response latency reduction induced by chronic nicotine infusion. Wet dog shakes were not found to be affected by hippocampal DHbetaE when given without chronic nicotine. Wet dog shakes were significantly increased by chronic nicotine infusion. Intra-hippocampal DHbetaE significantly potentiated this effect. The results from the current study reinforce the hypothesis that ventral hippocampal alpha4beta2 nicotinic receptors are important for memory function. These receptors may also have a role to play in the development of other aspects of behavior associated with chronic nicotine treatment.     

Chronic nicotine working and reference memory effects in the 16-arm radial maze: interactions with D1 agonist and antagonist drugs

Chronic nicotine infusion has been found in a series of studies in our laboratory to significantly improve choice accuracy of rats in the eight-arm radial maze. The current study was designed to compare the effects of chronic nicotine infusion on working and reference memory in a 16-arm radial maze. Nicotine was administered to female Sprague-Dawley rats at approximately 5 mg/kg per day SC via osmotic minipumps. Controls received saline infusions. Chronic nicotine infusion significantly lowered the number of working memory errors compared to controls, whereas the number of reference memory erros was not significantly affected. The modest nicotine-induced reduction in working memory errors was seen as a main effect over the 4 weeks of infusion, but the clearest effect was seen in weeks 3–4 of nicotine administration. For the 2 weeks after withdrawal, the nicotine effect was no longer evident. Acute D₁ challenges were given with the D₁ agonist dihydrexidine (0, 0.25, 0.5 and 1 mg/kg) and the D₁ antagonist SCH 23390 (0, 0.005, 0.015 and 0.05 μg/kg) during weeks 3–4 of chronic nicotine administration and weeks 1–2 after withdrawal from nicotine. Dihydrexidine caused a modest dose-related increase in reference memory errors but not working memory errors in the nicotine-treated, but not the control rats. The D₁ antagonist SCH 23390 caused a modest though significant decrease in reference memory errors but not working memory errors in the control, but not the nicotine-treated rats. The behavioral specificity of chronic nicotine infusion was demonstrated with selective improvement in working memory function. Pharmacological interactions were seen with chronic nicotine treatment increasing responsivity to D₁ agonist and decreasing responsivity to a D₁ antagonist with regard to reference memory. The mechanisms of this interaction are still undiscovered.     

Ventral hippocampal α4β2 nicotinic receptors and chronic nicotine effects on memory

Chronic nicotine administration has been repeatedly shown to facilitate working memory function in rats on the radial-arm maze. The critical neural mechanisms for this effect are still being discovered. The nicotinic nature of the chronic nicotine induced memory improvement is supported by the finding that it is blocked by chronic mecamylamine co-infusion. The hippocampus also appears to be critically important. Hippocampal ibotenic acid lesions block the effect. Within the hippocampus, we have found that the α4β2 nicotinic receptor subtype is involved in memory functioning. Acute ventral hippocampal infusions of the α4β2 nicotinic antagonist dihydro-β-erythroidine (DHβE) significantly decreased working memory performance in the radial-arm maze. The aim of the current study was to determine the importance of α4β2 receptors within the ventral hippocampus for the memory enhancing effects of chronic nicotine treatment. Adult female Sprague–Dawley rats were trained on the 8-arm radial maze and were cannulated bilaterally in the ventral hippocampus. Osmotic minipumps administering chronic nicotine at a rate of 5 mg per kg per day were also implanted in the nicotine treatment rats. Control rats received saline-only minipumps. For a period of 4 weeks after surgery, each rat received bilateral hippocampal infusions of 0, 2, 6 and 18 μg per side of DHβE and tested for memory performance on the radial-arm maze. Radial-arm maze choice accuracy was impaired by acute hippocampal DHβE infusion in a dose-related fashion. This acute hippocampal DHβE-induced choice accuracy impairment was eliminated by chronic systemic nicotine infusion. Chronic nicotine in combination with acute vehicle hippocampal infusion was not seen to alter choice accuracy. Response latency was not found to be altered by acute hippocampal DHβE in the absence of chronic nicotine administration, but it did attenuate the response latency reduction induced by chronic nicotine infusion. Wet dog shakes were not found to be affected by hippocampal DHβE when given without chronic nicotine. Wet dog shakes were significantly increased by chronic nicotine infusion. Intra-hippocampal DHβE significantly potentiated this effect. The results from the current study reinforce the hypothesis that ventral hippocampal α4β2 nicotinic receptors are important for memory function. These receptors may also have a role to play in the development of other aspects of behavior associated with chronic nicotine treatment.     

Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature

The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular adminstration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats. Received: 22 November 1995 / Final version: 25 November 1996     

Chronic inhibition of α4β2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response

RATIONALE: Acute and chronic systemic nicotine administration has been shown to cause significant spatial memory improvement. The critical nicotinic receptor subtypes for this effect and their location are still being determined. Nicotinic receptors in the ventral hippocampus have been found to be critically involved in memory. Acute ventral hippocampal infusions of dihydro-beta-erythroidine (DHbetaE), an alpha4beta2 nicotinic receptor antagonist, impaired spatial memory of rats in the radial-arm maze. OBJECTIVES: The current study used chronic ventral hippocampal infusion of DHbetaE as a model of nicotinic receptor loss such as that which occurs in Alzheimer's disease. The therapeutic effect of systemic nicotine treatment in reversing the DHbetaE-induced memory impairment was determined. METHODS: Rats were pretrained to asymptotic levels of performance on the eight-arm radial maze. Then, they were implanted with bilateral infusion cannulae in the ventral hippocampus, through which 0, 33.3, or 100 microg/side/day of DHbetaE was continuously infused for 4 weeks. The rats were retested on the eight-arm maze throughout infusion period and after withdrawal, and the interaction of acute systemic nicotine injections on memory was tested. RESULTS: The higher (100 microg/side/day) but not the lower (33.3 microg/side/day) DHbetaE dose caused a significant spatial memory impairment. Acute systemic nicotine injections (0, 0.1, 0.2, and 0.4 mg/kg, subcutaneous) attenuated the memory impairing effects of 100 microg/side/day of DHbetaE. There was no significant effect on response latency with the chronic DHbetaE infusion. Acute systemic nicotine infusions did significantly speed responding, an effect which was reversed by chronic hippocampal infusions of DHbetaE. After withdrawal there were no significant lasting effects on choice accuracy or response latency. Wet-dog shakes were significantly elevated during chronic hippocampal DHbetaE administration with no effect during the withdrawal period. CONCLUSIONS: These results indicate that chronic inhibition of a subset of nicotinic receptors in the hippocampus results in a significant impairment in the spatial memory choice accuracy. The ability of nicotine to attenuate the impairment supports the development of nicotinic agonist therapy of syndromes, such as Alzheimer's disease, that involve a chronic decrease in the activity of the alpha4beta2 nicotinic receptors and memory impairment.     

Ventral hippocampal alpha 7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze.

Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the nicotinic antagonists mecamylamine, dihydro-beta-erythroidine (DH beta E) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the alpha 4 beta 2 antagonist DH beta E is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the alpha 7 antagonist MLA. Adult female Sprague-Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 microg/side) were given during 3-4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 microg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DH beta E, equimolar ventral hippocampal DH beta E more effectively impaired memory than MLA, but the DH beta E-induced impairment was more effectively reversed by chronic systemic nicotine administration.     

Castration in rats impairs performance during acquisition of a working memory task and exacerbates deficits in working memory produced by scopolamine and mecamylamine

Rationale Although much research has focused on the effects of ovarian hormones on learning and memory in females, less information is available regarding the effects of testicular hormones on learning and memory in males. Additionally, despite evidence of an interaction of testicular hormones and the cholinergic system in areas of the brain implicated in learning and memory, no information is available regarding the behavioral consequences of that interaction.Objectives We assessed the effect of castration in male rats on working memory during acquisition of a radial maze. We also assessed the interactive effects of castration and scopolamine, a muscarinic receptor antagonist, as well as mecamylamine, a nicotinic receptor antagonist, on behavior.Methods Young adult male rats were castrated or underwent sham surgeries. Beginning 10 days after surgeries, performance on a task of working memory was assessed across 24 days of acquisition in an eight-arm radial maze. Following acquisition, scopolamine and mecamylamine dose–effect curves were established.Results Castration of male rats significantly decreased arm-choice accuracy during acquisition. Castration significantly exacerbated impairments in arm-choice accuracy produced by scopolamine as well as mecamylamine, without altering the disruptive effects of the drugs on the rate at which rats entered the arms of the maze.Conclusions These results indicate that castration in male rats impairs working memory during acquisition of a spatial maze task. Additionally, these results suggest that the absence of testicular hormones increases the sensitivity of male rats to the impairing effects of scopolamine as well as mecamylamine on working memory.     

Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area.

Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 micrograms/0.5 microliter/side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 micrograms mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.     

Interaction of nicotinic and histamine H(3) systems in the radial-arm maze repeated acquisition task

Nicotinic systems have been found in a variety of studies to play important roles in cognitive function. Nicotinic involvement in different aspects of cognitive function such as learning vs. memory may differ. We have found in rats that the spatial repeated acquisition task in the radial-arm maze is significantly improved by low doses of the nicotinic receptor antagonist mecamylamine, the atypical nicotinic receptor ligand lobeline, as well as the alpha7 nicotinic receptor agonist ARR-17779. Interestingly, nicotine in the same dose range that improves working memory in the win-shift radial maze task was not effective in improving repeated acquisition performance. Nicotinic systems interact with a variety of other neural systems. Differential involvement of these extended effects with learning vs. memory may help explain differential effects of nicotinic drugs with these cognitive functions. Histamine H(3) receptor antagonists have been shown by some studies to improve cognitive function, but others have not found this effect and some have found impairment. Nicotine stimulates the release of histamine. This effect may counter other cascading effects of nicotine in the performance of learning and memory tasks. A specific test of this hypothesis involves our study of nicotine (0.1-0.4 mg/kg) interactions with the histamine H(3) receptor antagonist thioperamide (2.5-10 mg/kg) on learning memory in the repeated acquisition test in the radial-arm maze. The highest dose of thioperamide tested caused a significant choice accuracy impairment, which was most evident during the later portions of the learning curve. The highest dose of nicotine did not change overall errors but did cause a significant impairment in learning over trials. The choice accuracy impairment induced by thioperamide was significantly attenuated by nicotine (0.4 mg/kg). The learning impairment caused by the highest dose of nicotine was significantly attenuated by thioperamide. Thioperamide also caused a slowing of response, an effect, which was attenuated by nicotine co-administration. The repeated acquisition test can help differentiate acute drug effects on learning. Nicotine and thioperamide effectively reversed each other's choice accuracy impairment even though each by itself impaired accuracy.     

中枢N受体对M受体介导体温降低作用的调节

在清醒大鼠上，可进中枢的Ｎ受体拮抗剂美加明可对抗Ｎ受体激动剂烟碱降低体温的作用，增强Ｍ受体激动剂氧化震颤素降低体温的作用；不进中枢的外周Ｎ受体拮抗剂六甲溴铵不影响烟碱和氧化震颤素的上述作用．每天３次ｓｃ烟碱２．５ｍｇ·ｋｇ－１，连续７ｄ，大鼠对烟碱降低体温的作用产生慢性耐受后，氧化震颤素降低体温的作用无显著变化．提示以体温变化为指标，美加明封闭中枢Ｎ受体功能后，中枢Ｍ受体对其激动剂的敏感性增强；反复给予烟碱诱导中枢Ｎ受体功能失敏后，中枢Ｍ受体对其激动剂的敏感性无显著变化．     

Bridged nicotine,isonicotine, and norisonicotine effects on working memory performance of rats in the radial‐arm maze

Nicotine and other nicotinic agonists have been found to improve performance in a variety of tasks, including the radial‐arm maze to improve memory. There has been an active effort to develop novel nicotinic agonists for the treatment of cognitive dysfunction such as is seen in Alzheimer's disease. These novel ligands can also serve as tools with which to increase our knowledge concerning the involvement of nicotinic systems with cognitive function. The current studies were conducted to assess the actions of three new nicotinic agonists, i.e., bridged nicotine, isonicotine, and norisonicotine, on choice accuracy in the radial‐arm maze. Rats were trained on a win‐shift working memory task in the eight‐arm radial maze. In Experiment 1, the rats were administered (subcutaneously) saline and three doses of bridged nicotine, isonicotine, and norisonicotine (0.5, 1.5, and 4.5 mg/kg). Bridged nicotine did not cause any significant effects on memory performance, although it did significantly increase latency and at the high dose caused severe slowing and nonperformance. Both isonicotine and norisonicotine caused a significant linear dose‐related improvement in choice accuracy, indicative of improved working memory function. In Experiment 2, another set of rats received the effective doses of 4.5 mg/kg of isonicotine and norisonicotine as well as higher doses of 13.5 mg/kg of each compound. These doses were administered alone or in combination with 5 mg/kg of the nicotinic antagonist mecamylamine to determine the nicotinic nature of the effects. As in Experiment 1 the 4.5 mg/kg of isonicotine caused a significant memory improvement. The 4.5 mg/kg dose of norisonicotine caused a more modest rise in performance, which was not significantly different from control in this experiment. When both experiments were considered together, the 4.5 mg/kg doses of both isonicotine and norisonicotine were the most effective in improving working memory performance. Significant improvements in working memory were seen with both drugs (P < 0.025). The higher doses of 13.5 mg/kg of both isonicotine and norisonicotine resulted in nearly control‐level performance. Thus, the typical inverted U‐shaped dose‐effect function was evident for both isonicotine and norisonicotine. Mecamylamine brought performance improved by the 4.5 mg/kg dose back to control levels, providing evidence for the nicotinic nature of the effect. Both isonicotine and norisonicotine show promise for development as memory‐improving nicotinic agonist drugs. Drug Dev. Res. 46:107–111, 1999. © 1999 Wiley‐Liss, Inc.     

Effect of vitamin E on memory retention in rats: possible involvement of cholinergic system.

This study concerned effects of vitamin E and the cholinergic system on memory retention of passive avoidance learning in rats. Post-training intracerebroventricular (i.c.v.) injections were carried out in all experiments. Administrations of vitamin E (10, 25 and 50 microg/rat), nicotine (0.1 microg/rat) and pilocarpine (0.5 microg/rat), the muscarinic receptor agonist increased memory retention, while mecamylamine (0.01, 0.1 and 0.5 microg/rat), the nicotinic receptor antagonist and scopolamine (0.1, 1 and 5 microg/rat), the muscarinic receptor antagonist decreased memory retention. The combination of vitamin E with nicotine or pilocarpine showed potentiation. Effects of mecamylamine or scopolamine were attenuated by vitamin E. It is concluded that vitamin E has a close interaction with cholinergic system in memory retention process.     

Ventral hippocampal α7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze

Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the nicotinic antagonists mecamylamine, dihydro-β-erythroidine (DHβE) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the α4β2 antagonist DHβE is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the α7 antagonist MLA. Adult female Sprague–Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 μg/side) were given during 3–4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 μg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DHβE, equimolar ventral hippocampal DHβE more effectively impaired memory than MLA, but the DHβE-induced impairment was more effectively reversed by chronic systemic nicotine administration.     

EEG correlates of acute nicotinic and muscarinic cholinergic blockade: separate and combined administration of mecamylamine and scopolamine in normal human subjects

Anticholinergic drugs have been proposed as a possible acute model for human electroencephalographic (EEG) studies focused on dementia but the interactive effects of muscarinic and nicotinic cholinergic receptor system blockade on the regulation of electrocortical activity has yet to be examined. EEG recordings were carried out in 15 normal subjects before and after the double-blind acute administration of a placebo, a centrally acting nicotinic blocker (20 mg of mecamylamine), a centrally acting muscarinic blocker (0·6 mg of scopolamine) and a combination dose of mecamylamine and scopolamine. Mecamylamine decreased absolute and relative beta power and increased relative theta power. Scopolamine increased relative power in both theta and beta frequency bands. Mecamylamine produced greater theta increments than scopolamine, while combined administration of the two central blockers induced changes similar to that observed with mecamylamine administered alone. Results are discussed in relation to electrocerebral activity in normal and pathological aging. © 1997 John Wiley & Sons, Ltd.     

Evaluation of muscarinic and nicotinic receptor antagonists on attention and working memory

Cholinergic receptor antagonists are commonly used to model attentional and mnemonic impairments associated with neuropsychiatric disorders such as Alzheimer's disease. However, few studies have systematically assessed the effects of these drugs following manipulations that affect attention or working memory within the same task. In the present experiment, rats were trained to discriminate visual signals from "blank" trials when no signal was presented. This task was modified to include retention intervals on some trials to tax working memory. During standard task performance, rats received systemic injections of the muscarinic receptor antagonist, scopolamine, or of the nicotinic receptor antagonist, mecamylamine. A second experiment tested the effects on this task of co-administering doses of scopolamine and mecamylamine that, when administered alone, did not significantly affect task performance. Scopolamine (0.3 and 1.0 mg/kg) decreased detection of 500 ms signals but did not affect accurate identification of non-signals. Scopolamine did not differentially affect performance across the retention interval. Elevated omission rates were associated with high doses of scopolamine or mecamylamine. Combination drug treatment was associated with decreased signal detection and elevated omission rates. Collectively, the data suggest that muscarinic and nicotinic receptor antagonists do not exclusively impair working memory.     

Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations

Use of chlorpyrifos (CPF) has been curtailed due to its developmental neurotoxicity. In rats, postnatal CPF administration produces lasting changes in cognitive performance, but less information is available about the effects of prenatal exposure. We administered CPF to pregnant rats on gestational days (GD) 17–20, a peak period of neurogenesis, using doses (1 or 5 mg/kg/day) below the threshold for fetal growth impairment. We then evaluated performance in the T-maze, Figure-8 apparatus and 16-arm radial maze, beginning in adolescence and continuing into adulthood. CPF elicited initial locomotor hyperactivity in the T-maze. Females showed slower habituation in the Fig. 8 maze; no effects were seen in males. In the radial-arm maze, females showed impaired choice accuracy for both working and reference memory and again, males were unaffected. Despite the deficits, all animals eventually learned the maze with continued training. At that point, we challenged them with the muscarinic antagonist, scopolamine, to determine the dependence of behavioral performance on cholinergic function. Whereas control females showed impairment with scopolamine, CPF-exposed females did not, implying that the delayed acquisition of the task had been accomplished through alternative mechanisms. The differences were specific to muscarinic circuits, as control and CPF groups responded similarly to the nicotinic antagonist, mecamylamine. Surprisingly, adverse effects of CPF were greater in the group receiving 1 mg/kg as compared to 5 mg/kg. Promotional effects of acetylcholine (ACh) on cell differentiation may thus help to offset CPF-induced developmental damage that occurs through other noncholinergic mechanisms. Our results indicate that late prenatal exposure to CPF induces long-term changes in cognitive performance that are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus, uncovering the adaptive mechanisms that maintain basal performance.     

Effects of concurrent manipulations of nicotinic and muscarinic receptors on spatial and passive avoidance learning

The present study investigates the effects of concurrent manipulations of nicotinic and muscarinic cholinergic receptors on spatial and passive avoidance learning/retention in rats. Daily pretraining test injections of combinations of the subthreshold doses of muscarinic (scopolamine 0.3 mg/kg) and nicotinic (mecamylamine 2.5 mg/kg or 10 mg/kg) antagonists impaired acquisition of the water-maze task (WM). Drug-induced deficits were also observed during the retention trial: the groups injected with scopolamine 0.3 mg/kg, mecamylamine 10 mg/kg and scopolamine 0.3 mg/kg in combination with mecamylamine 2.5 mg/kg showed reduced spatial bias compared with controls. Single preretention test injections of the combination of subthreshold doses of mecamylamine (10 mg/kg) and scopolamine (0.8 mg/kg) impaired memory retrieval in WM. Combined pretraining injections of subthreshold doses of scopolamine (1.0 mg/kg) and mecamylamine (10 mg/kg) induced a severe passive avoidance impairment comparable to 2.0 mg/kg of scopolamine. However, preretention test injections did not impair passive avoidance retention. Either single or combined injections of hexamethonium (5.0 mg/kg, SC) and methylscopolamine (1.0 mg/kg) did not impair either passive avoidance or water-maze performance. The present results suggest that 1) nicotinic and muscarinic systems jointly modulate performance in spatial and avoidance learning tasks and 2) cholinergic antagonists affect acquisition functions more effectively than retention ability. These findings may be relevant to the clinical disorders, like Alzheimer's disease, which are associated with a loss of both cholinergic neurons and nicotinic receptors.     

Effects of nicotine on memory impairment induced by blockade of muscarinic,nicotinic and dopamine D2 receptors in rats

Scopolamine dose-dependently inhibits passive avoidance latency and decreases spontaneous alternation in the Y-maze, suggesting effects on long-term and short-term memory, respectively. Chlorisondamine (10 mg/kg), a compound which produces a long-lasting central nicotinic receptor blockade, did not affect short-term and long-term memory performance. In normal rats, nicotine at the doses of 0.3, 1.0, and 3.0 mg/kg administered once had a facilitating effect on short-term memory; a higher dose (3.0 mg/kg) did not show a more pronounced effect than a lower one (0.3 mg/kg). Nicotine, by activating the nicotinic acetylcholine receptors, attenuated the impairment of short-term memory induced by muscarinic or dopamine D2 receptor blockade. On long-term memory, a single dose of nicotine (0.3, 1.0, 3.0 mg/kg) did not affect memory performance, but improved it after chronic (10 consecutive days, 0.3 mg/kg) administration. The antiamnesic effect of nicotine administered once was observed in scopolamine-, scopolamine+chlorisondamine- or sulpiride-treated rats. These results suggest that the antiamnesic effect of nicotine can result from an action at nicotinic receptors subtypes not blocked by chlorisondamine or at nonnicotinic receptors.