Intracerebroventricular nicotine and mecamylamine alter radial-arm maze performance in rats

In rats, the effects of an intracerebroventricular (ICV) nicotinic agonist nicotine (NIC), the nicotinic antagonist mecamylamine (MEC), and combinations of NIC + MEC were assessed in a radial-arm maze (RAM). In experiment 1, exploratory behavior was assessed in untrained rats (N = 13). The rats received 4 μg, 8.65 nmol NIC (NIC 4), 200 μg, 0.98 μmol MEC (MEC), and saline (SAL) ICV infusions. NIC 4 caused a significant increase in choice distribution compared to SAL (P < 0.025). In experiment 2, rats (N = 10) were trained to perform a working memory task for food reinforcement in the RAM. ICV doses of SAL, NIC 4, NIC 8, MEC, MECNIC 4, and MECNIC 8 were administered after completion of the training period. MEC caused a significant deficit in choice accuracy when compared to SAL (P < 0.025). This deficit was reversed when NIC 8 was coadministered with MEC (P < 0.05). There were no significant effects on choice latency for either study. The effects of ICV NIC and MEC on RAM performance are generally similar to their systemic effects in that NIC improves and MEC impairs choice accuracy. The reversal of the MEC-induced choice deficit by ICV NIC administration has not been reported with systemic administration. ICV MEC induces a choice accuracy deficit without increasing choice latency. This has not been seen with systemic MEC administration. The current result implies that the MEC-induced choice accuracy deficit did not result from MEC-induced sedation. The data indicate that previously reported changes in choice accuracy from peripherally administered NIC and MEC result from their central effects. © 1994 Wiley-Liss, Inc.     

Effects of ketazocine, ethylketazocine and phenazocine on schedule-controlled behavior: antagonism by naloxone

Dose-effect curves were determined for phenazocine (0.64-2.5 mg/kg), ketazocine (1.25-80 mg/kg) and ethylketazocine (1.25-80 mg/kg) in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of grain presentation. All three opioid agonists decreased responding with the larger doses. The effects of phenazocine were completely antagonized by small doses of naloxone (0.01-1 mg/kg), whereas the effects of ethylketazocine required larger doses of naloxone (1-10 mg/kg) to be completely antagonized. The behavioral effects of ketazocine were partially attenuated by naloxone, but were not antagonized completely even by a 10 mg/kg dose of naloxone. These data from the pigeon are consistent with previous interpretations that the effects of phenazocine are mediated by actions at a mu opioid receptor, whereas the effects of ketazocine and ethylketazocine are mediated by actions at a kappa opioid receptor.     

Green tobacco sickness: mecamylamine,varenicline, and nicotine vaccine as clinical research tools and potential therapeutics

Introduction: Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting, headache, and abdominal cramps. Prevalence has shifted from the United States and Europe to China, India, and Brazil. Worldwide 8 million individuals are afflicted, including women and children.

Areas covered: Mecamylamine (Inversine®, Vecamyl®), a nicotinic acetylcholine receptor (nAChR) antagonist, should be tested as a remedy for green tobacco sickness. Mecamylamine is approved as an oral tablet for the treatment of hypertension, is safe, and is off-patent. Mecamylamine attenuates many of the effects of nicotine and tobacco including seizures, thereby supporting its use as an effective pharmacotherapy for tobacco dependence. Varenicline (Chantix®) and cytisine (Tabex®) are low efficacy (i.e. intrinsic activity) nAChR agonists, are used as smoking cessation aids, and are viable options to test as remedies against green tobacco sickness. Nicotine immunization strategies may provide further options for future testing.

Expert commentary: Efforts to demonstrate reversal and/or prevention of green tobacco sickness by mecamylamine will underscore the importance of nicotine in this illness and highlight a new medication for effective treatment of tobacco poisoning.     

Interactions between naltrexone and non-opiate drugs evaluated by schedule-controlled behavior

The effects of seven non-opiate drugs were studied, alone and in conjunction with naltrexone, in rats responding under a multiple fixed-interval 5-min, fixed-ratio 30-response schedule of food presentation. The drugs used (selected on the basis of their dopaminergic effects) were d-amphetamine, cocaine, amfonelic acid, bromocriptine (CB154), chlorpromazine, pimozide, and ethanol. Six of the seven drugs produced dose-dependent decreases in the average rate of responding; d-amphetamine increased responding at small doses and decreased responding at larger doses. A 1 mg/kg dose of naltrexone potentiated the rate-decreasing effect of the drugs and antagonized the rate-increasing effect of d-amphetamine, but did not alter responding when given alone. Interactions between naltrexone and non-opiate drugs are discussed in terms of the effects of narcotic antagonists on dopaminergic systems.     

Effects of some typical and atypical antidepressants on schedule-controlled responding in rats

The effects of tricylic antidepressant drugs with diverse chemical structures were studied in rats on responding maintained under a multiple fixed-ratio (30) fixed-interval (5 min) schedule of food resentation. Bupropion, mianserin, and nomifensine increased responding during the first half of the fixed-interval component and during the fixed-ratio component of the multiple schedule. Higher doses decreased rates under both the fixed-ratio component and during the second half of the fixed-interval component. Trazodone and trimipramine also increased rates of responding during the first half of the fixed-interval component. Higher doses of these drugs decreased rates under the fixed-ratio component more than the approximately equal rates during the second half of the fixed-interval component. Iprindole, protryptyline, fluvoxamine, fluoxetine, maprotiline, clomipramine, imipramine, lithium, and chlorpromazine did not increase rates of responding under the fixed-ratio component or under either half of the fixed-interval component. Among these drugs, only imipramine differentially affected the nearly equal rates of responding during the second half of the fixed-interval component and during the fixed-ratio component. The effects of antidepressants depended on both the control rate of responding and the schedule. Rate-increasing effects tended to be associated with antidepressants that interact with dopaminergic systems, but in general, the correlation between behavioral and biochemical effects was low.     

Mutually potentiating effects of mecamylamine and haloperidol in producing catalepsy in rats

Haloperidol and other dopaminergic (DA) blockers have long been known to induce catalepsy. Recently, it has been reported that nicotine potentiates the cataleptic effect of haloperidol. However, this presents a quandary in terms of neural interactions between nicotinic and DA systems. Nicotine promotes the release of DA in the striatum, which should attenuate haloperidol‐induced catalepsy. To resolve this quandary, we assessed haloperidol interactions with nicotine and its antagonist mecamylamine in five studies. With low to moderate doses, we did not find that nicotine potentiated haloperidol‐induced catalepsy. However, in two different studies we found that mecamylamine, a nicotinic antagonist, significantly potentiated the haloperidol‐induced catalepsy. This effect was seen with a dose of mecamylamine which, by itself, did not have any cataleptic effect. These results demonstrate that nicotinic receptor blockade effectively potentiates catalepsy caused by DA blockade. This suggests that previously seen nicotine‐induced potentiation of catalepsy may have been due to its desensitizing effect. Perhaps the use of nicotinic antagonists such as mecamylamine or nicotine + mecamylamine combinations would provide a useful adjunct to DA antagonist therapy in motor disorders such as Tourette's syndrome. Drug Dev. Res. 47:90–96, 1999. © 1999 Wiley‐Liss, Inc.     

CYP2A6多态性对尼古丁代谢及烟草依赖行为的影响

细胞色素P450(cytochrome P450,CYP)超基因家族是人体内最重要的药物代谢酶,其中的一些亚型所具有的基因多态性表现出人体对药物和/或环境化合物毒性、敏感性存在差异,CYP2A6为其一例。     

Effects of phenytoin on schedule-controlled performance of rats

The present study examined the effects of acute administrations of phenytoin on the lever pressing of rats maintained under fixed-ratio, fixed-interval, and interresponse-time-greater-than-T schedules of food delivery. The drug typically produced dose-dependent decreases in response rates under fixed-ratio and fixed-interval schedules, while response rates under the interresponse-time-greater-than-T schedule were affected little by the drug. These findings indicate that phenytoin effects on schedulecontrolled responding differ from those of other anticonvulsants.     

Effect of intracerebroventricular bradykinin,angiotensin II,and substance P on multiple fixed-interval fixed-ratio responding in rabbits

The dose-effect relationships of intraventricularly injected bradykinin, angiotensin II, and substance P on lever-lifting behavior of rabbits in a multiple fixed-interval 2-min, fixed-ratio 15 responses (mult. FI 2 FR 15) schedule of sweetened water presentation were determined. Bradykinin, in doses of 30 and 56 ng, increased FI response rates, with lower rates being relatively more increased than higher rates while FR responding was not affected. Conversely, 3 ng of angiotensin II increased only FR response rates. Higher doses of both peptides, up to 1.7 and 1.0 g, respectively, caused dose-dependent decreases in both FI and FR response rates, mainly as a consequence of complete response supression at the beginning of the experimental session. Doses of 0.1, 0.3, and 1.0 g of substance P caused dosedependent decreases in FI and FR response rates with no initial pause, FI response rates being more affected than FR rates. But 3.0 g of substance P caused an initial response suppression as well as comparable decreases in both FI and FR rates. Combined treatments of bradykinin with selected doses of amphetamine, haloperidol, atropine, morphine, and naloxone caused effects on multiple FI FR performance that did not consistently differ from the effect of bradykinin alone. These results show that small amounts of bradykinin, angiotensin II, and substance P cause specific and selective effects on operant behavior when injected into the cerebral ventricles, indicating that these endogenous peptides may play functional roles in behavioral regulation.     

Effects of nicotinic agonists and antagonists on spatial working memory in normal adult and aged rats

The present study had two goals (1) to examine the effects of treatments with nicotinic agonist (nicotine) and antagonist (mecamylamine) on working memory in normal adult rats (14 months of age), and (2) to determine if treating aged (36 to 42 months of age), memory-impaired rats with nicotine could improve their memory function. Memory testing was carried out using a delayed non-matching to position paradigm in a T-maze. Rats were trained to run down one arm of the maze (e.g., right) on an information run and then, after a variable memory delay period of 10, 90, or 180 sec, run down the other arm (e.g., left). In normal adult rats after water injection, memory accuracy was inversely related to memory delay (> 90, 75, and 67% accuracy at the 10, 90, and 180 sec delays, respectively). Administration of nicotine (0.1 or 0.4 mg/kg), or mecamylamine (2.5 or 5 mg/kg), or combinations of these drugs had no significant effects on memory in these rats. However, mecamylamine alone or in combination with nicotine reduced running speed in the T-maze in normal adults, indicating that the drugs did produce some behavioral effects. In aged rats, memory accuracy after water injection was much lower than that of younger adults, averaging 64, 57, and 50% at 10, 90, and 180 sec delays. Interestingly, nicotine injections of 0.1 or 0.4 mg/kg resulted in highly significantly improved accuracy in the memory task. The deficit in memory accuracy in aged rats, evident even at the shortest delay period (10 sec), suggests that the rats may have had impairments in attention or visual discriminatory ability. If this is so, then the beneficial effects of nicotine observed in this study may be more related to its effects on attention rather than memory directly. © 1994 Wiley-Liss, Inc.     

Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium and naloxone

The rate and pattern of lever pressing were studied in 18 rats during 24-h sessions in which responding resulted in intravenous infusions of nicotine. There were four indications of the positive reinforcing effect of nicotine: (1) a greater number of lever presses when nicotine was response-contingent compared to when saline was available; (2) a greater number of responses on the lever resulting in an infusion of nicotine than on the control lever; (3) systematic decreases in the number of contingent nicotine infusions when nicotine was delivered noncontingently; and (4) systematic changes in the frequency of lever pressing as a function of dose. Under a fixed ratio 1 (FR 1) schedule, the number of infusions first increased and then decreased as the dose of nicotine was decreased (64, 32, 16, and 8 microg/kg infusion) and nicotine intake (mg/kg every 24 h) was directly related to the infusion dose. As the FR size was increased from 1 to 6, the number of lever presses increased and the number of infusions (32 microg/kg) remained stable. At FR values greater than 6, both the number of lever presses and infusions decreased. Presession injections of mecamylamine (0.75, 1.5, and 3.0 mg/kg, s.c.) decreased the number of infusions in a dose-related manner. Presession injections of hexamethonium (1.5 and 3.0 mg/kg, s.c.) or naloxone (0.75, 1.5, and 3.0 mg/kg, s.c.) did not alter the within- or between-session patterns of nicotine self-administration. Under the conditions of the present experiment, nicotine served as an effective reinforcer and the behavior was shown to be sensitive to both FR size and infusion dose. In addition, the results suggest that nicotine self-administration involves central nicotinic receptors and that opioid receptor antagonism has no effect on nicotine's reinforcing effects in rats.     

Antagonism by methysergide of the effects of -5-hydroxytryptophan and quipazine on schedule-controlled responding

Dose-effect curves for -5-hydroxytryptophan and quipazine were determined alone and in the presence of small doses (0.3 and 1 mg/kg) of methysergide in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of grain presentation. Both serotonergic agonists produced dose-related decreases in responding in both schedule components. Methysergide produced a 2- to 3-fold shift of the dose-effect curve to the right (antagonism) for both serotonergic agonists. It was concluded that -5-hydroxytryptophan and quipazine decrease rates of responding by an action at a methysergide-sensitive serotonergic receptor.     

Effects of clozapine, chlorpromazine and haloperidol on schedule-controlled behavior

The effects of clozapine, chlorpromazine, and haloperidol were determined in mice and pigeons responding under a multiple fixed-ratio 30, fixed-interval 600 sec schedule of food presentation. In both species, low doses were without effect and moderate to high doses of all three antipsychotics decreased responding. In contrast to other behavioral tests used to predict antipsychotic activity, clozapine was equipotent or more potent than chlorpromazine in decreasing responding under the multiple fixed-ratio 30, fixed-interval 600 sec schedule. The order of potency observed in the mouse was: haloperidol greater than chlorpromazine greater than or equal to clozapine. The order of potency in the pigeon was: haloperidol greater than clozapine greater than chlorpromazine. In mice and pigeons, the rate of responding under the fixed-ratio component was decreased at lower than, or the same doses of clozapine as that required to decrease fixed-interval responding. However, in both species, chlorpromazine and haloperidol decreased fixed-interval responding at lower doses or the same dose as that required to decrease fixed-ratio responding.     

Effects of repeated alcohol administration on human operant behaviour

Nine human subjects were exposed to a multiple fixed-ratio (FR) differential-reinforcement-of-low-rate (DRL) schedule of monetary reinforcement. Presses on a manipulandum requiring relatively high force were occasionally followed by an increased money total displayed on a computer screen. Subjects were exposed to the schedule until their behaviour had stabilized. Prior to each of the next three sessions they were administered 0.85 g/kg alcohol. In eight of the nine subjects the initial effect of alcohol was to increase FR response rate and, consequently, reinforcement rate. Subsequent alcohol administration resulted in sensitization: even greater rate-increasing effects. In two further control sessions behaviour returned towards baseline level. DRL response rate was slightly increased by alcohol, but reinforcement rate remained unchanged. There was no consistent change in DRL response or reinforcement rates from the first to the third alcohol sessions. The effects of alcohol on human behaviour were similar to the effects found in studies with animals. The results were also consistent with the view that the changes in behaviour which occur with repeated drug administration depend in part on whether the initial effect of the drug is to increase, decrease or produce no change in reinforcement rate.     

Antagonism by methysergide of the effects of l-5-hydroxytryptophan and quipazine on schedule-controlled responding

Dose-effect curves for l-5-hydroxytryptophan and quipazine were determined alone and in the presence of small doses (0.3 and 1 mg/kg) of methysergide in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of grain presentation. Both serotonergic agonists produced dose-related decreases in responding in both schedule components. Methysergide produced a 2- to 3-fold shift of the dose-effect curve to the right (antagonism) for both serotonergic agonists. It was concluded that l-5-hydroxytryptophan and quipazine decrease rates of responding by an action at a methysergide-sensitive serotonergic receptor.     

Effects of nicotine and mecamylamine on cognition in rhesus monkeys

Rationale Nicotine and other agonists of nicotinic cholinergic receptors (nAChR) have been shown to improve performance in specific memory domains in rodents and monkeys. Such beneficial effects are observed in preclinical models of age-related cognitive decline, stimulating interest in nAChR ligands as possible therapeutics. Prior work has typically focused on assays of spatial working memory in rodent studies and visual recognition memory in monkey studies.Objective The current study was conducted to determine the role played by nAChRs in multiple types of memory in monkeys.Methods Rhesus monkeys (n=6) were trained to perform a battery of six behavioral tasks and then serially challenged with acute doses of nicotine (3.2–56 g/kg, IM) and the nAChR antagonist mecamylamine (0.32–1.78 mg/kg, IM).Results Nicotine improved performance on tests designed to assay visual recognition memory, spatial working memory and visuo-spatial associative memory, while mecamylamine impaired visuo-spatial associative memory. Ballistic and fine motor performance was not significantly improved by nicotine but fine motor performance was impaired by mecamylamine.Conclusions Although nicotine may improve performance in multiple domains, effects on visuo-spatial associative memory is the most specifically attributable to nAChR signaling.     

氯丙嗪和维拉帕米对大鼠镉肾毒性的影响(英文)

目的研究氯丙嗪(CPZ)和维拉帕米(Ver)对由镉引起的大鼠肾毒性是否有预防作用。方法32只大鼠随机分成4组,分别为对照组、单纯染镉组、CPZ和Ver预处理组。单纯染镉组大鼠sc7μmol·kg-1氯化镉;CPZ和Ver预处理组分别ipCPZ5mg·kg-1和Ver4mg·kg-1,1h后sc7μmol·kg-1氯化镉;对照组在相应时间内给予生理盐水,注射容量均为2mL·kg-1。最后一次注射24h后,收集24h尿样,测定尿乳酸脱氢酶(LDH)活性、尿蛋白、尿镉、肾镉和肾皮质中的Na+K+ATP酶,Ca2+ATP酶和蛋白激酶C(PKC)的活性。结果单纯染镉组与对照组比较,尿镉和肾镉含量明显升高。CPZ和Ver预处理组尿镉明显低于单纯染镉组,但肾镉无明显变化。与对照组比较,单纯染镉组尿LDH活性、尿蛋白和肾皮质中的Na+K+ATP酶,Ca2+ATP酶和PKC活性明显升高。CPZ和Ver预处理组大鼠尿LDH活性、尿蛋白和肾皮质中的Na+K+ATP酶,Ca2+ATP酶和PKC活性明显低于单纯染镉组。结论镉能激活Na+K+ATP酶,Ca2+ATP酶和PKC的活性,而且,CPZ和Ver均可不同程度地减轻肾毒性。     

Modeling the nicotinic receptor loss in dementia using the nicotinic antagonist mecamylamine: Effects on human cognitive functioning

The loss of central nicotinic receptors is a neurochemical hallmark of several degenerative brain disorders, notably Alzheimer's disease (AD) and Parkinson's disease (PD). However, uncertainty has remained about the significance of this loss for the cognitive symptomatology of these disorders. Symptoms of impaired acquisition of information and short-term storage, impaired memory consolidation, attention, visual perception, and speed may reflect nicotinic lesions. Administration of the nicotinic antagonist mecamylamine in young and elderly humans produces significant dose-related impairment of new learning, liberalization of response bias, and slowing of reaction time. These results suggest that mecamylamine may in part model the results of nicotinic receptor loss in AD and that nicotinic augmentation of some aspects of cognitive functioning may be a worthwhile strategy to pursue, particularly if agents can be developed that are more selective than nicotine itself. © 1994 Wiley-Liss, Inc.     

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.     

Conditioning of nicotine effects on motility and behaviour in rats

Summary Nicotine produces behavioural signs which are, in part, characteristic of dopaminergic activation. In the present study, it was investigated, to which degree these signs can be conditioned. The drug produced dose-dependent (0.15–0.60 mg/kg s.c.) increases in locomotor activity, hyperkinesia and stereotyped sniffing. The effects produced by 0.6 mg/kg nicotine were significantly inhibited by mecamylamine (1 mg/kg i. p.), but only in part by haloperidol (0.2 mg/kg i. p.). In a subsequent series, the administration of nicotine (0.6 mg/kg s.c.) was repeatedly associated with well-defined environmental (conditioned) stimuli: a wire cage associated with an auditory and an olfactory stimulus. Another group was pseudoconditioned, a third group remained drug-naive. When the animals were given saline in presence of the conditioned stimuli 24 h after the last conditioning session, locomotor activity, hyperkinesia and stereotyped sniffing were significantly higher in conditioned than in pseudoconditioned and drug-naive rats. Similarly, when the rats were injected with nicotine (0.6 mg/kg s. c.) in presence of the conditioned stimuli 24 h after the last conditioning session, locomotor activity and stereotyped sniffing were most pronounced in the conditioned animals. These results demonstrated that behavioural effects of nicotine can be conditioned. Phenomena of this kind might contribute to the addictive behaviour to nicotine. Send offprint requests to K. Kuschinsky at the above address