The effects of nicotine on locomotor activity in non-tolerant and tolerant rats.

1--Rats were tested for locomotor activity in photocell cages, for 80 min starting immediately after subcutaneous injection of (-)-nicotine bitartrate or 0.9% w/v NaCl solution (saline). In non-tolerant subjects, nicotine (0.1 to 0.4 mg/kg base) depressed activity and induced ataxia in the first 20 min, but increased activity later in the session; these actions were dose-dependent. 2--Tolerance was studied by comparing rats given nicotine (0.4 mg/kg s.c.) every day with control rats given saline instead. Each week, every subject was tested once with nicotine (0.4 mg/kg) and once with saline. With daily or even weekly injections of nicotine, the initial depressant action of the drug was replaced by a dose-dependent stimulant action which occurred throughout the session. In these tolerant animals, little ataxia was seen except when a larger dose of 0.8 mg/kg was given. Tolerance to the depressant action of nicotine persisted for at least 3 weeks. 3--In non-tolerant subjects, mecamylamine (0.5, 1.0 mg/kg s.c.) prevented the initial depressant action of nicotine (0.4 mg/kg). In tolerant rats, the locomotor stimulant action of nicotine (0.4 mg/kg) was prevented by mecamylamine (0.1, 0.32, 1.0 mg/kg s.c.) in a dose-related way; the quaternary ganglion blocker, hexamethonium (0.2, 1.0, 5.0 mg/kg s.c.) had little or no such effect. Neither mecamylamine nor hexamethonium altered activity when given alone. 4--It is suggested that a few treatments with nicotine can unmask a stimulant action of the drug, probably of central origin, which possibly reflects a stimulation of nicotine receptors.     

Cue properties of oral and transdermal nicotine in the rat

In a standard two-lever drug discrimination paradigm, rats were trained to discriminate nicotine 0.5 mg/kg PO from saline. Injections occurred 15 min before the session. Subjects reached the training criterion in a mean of 38 sessions. Nicotine PO, SC, and IP generated similar dose-effect curves (ED₅₀=0.073 mg/kg PO, 0.076 mg/kg SC, 0.090 mg/kg IP); the dose-effect curve for transdermal (TD) administration fell approximately 1 log unit to the right (ED₅₀=1.34 mg/kg). The percentage of rats choosing the nicotine-appropriate lever peaked at 15 min and gradually decreased to 50% or less by 180 min for nicotine PO and TD, a time-decay function similar to that previously shown for SC administration. The nicotinic cholinergic agonist cytisine (0.5–8.0 mg/kg) PO and TD produced up to 56% nicotine-appropriate responding, while the muscarinic cholinergic agonist arecoline (1.0–4.0 mg/kg) PO and TD produced only saline-appropriate responding. The nicotine cue did not generalize to the cholinergic antagonist mecamylamine (0.125–0.5 mg/kg) PO or TD; mecamylamine 0.5 mg/kg PO but not TD completely blocked the PO and TD nicotine cues. These results show that an approximately equal cue occurs with PO, IP, and SC administration, and that the TD cue is considerably weaker. The significance of the procedure as an animal analog of human transdermal nicotine intake is discussed.     

Conditioned taste aversions in rats after intracerebral administration of nicotine

Previous studies suggested that the conditioned taste aversion (CTA) produced by nicotine was of central origin. The aims of the present work were to identify neural substrates that mediate nicotine-induced CTA, and to examine the relationship between the CTA and locomotor depressant effects of nicotine. After two conditioning trials with 0.1 or 0.4mg/kg nicotine (s.c.), significant CTA was apparent. In contrast, CTA was absent when nicotine (4 or 32μg) was administered into a lateral ventricle or when nicotine (4μg) was administered into the fourth ventricle, but decreases in locomotor activity were apparent during the conditioning phase. Nicotine (8μg) produced CTA when administered bilaterally into the nucleus accumbens. This finding was confirmed in a second experiment, but was not found in rats pretreated with the nicotine antagonist mecamylamine (2mg/kg s.c.). Bilateral administration of nicotine into the striatum, ventral tegmental area, dorsal hippocampus or the mesopontine tegmentum failed to produce CTA, and administration of nicotine into the interpeduncular nucleus produced CTA in one of two experiments only. It was concluded that the aversive effects produced by systemically administered nicotine may be mediated in part through nicotinic receptors located in the nucleus accumbens. The locomotor depression associated with intraventricular administration of nicotine could be dissociated from the aversive effect as measured by the CTA procedure.     

Nicotine-induced grooming: a possible dopaminergic and/or cholinergic mechanism

The ability of nicotine, to induce grooming in rats was studied. Grooming was induced by i.p. injection of different doses (0.0675-0.5 mg/kg) of nicotine to rats. The effect was dose-dependent. However, the response was decreased with increasing doses of the drug from 0.25-0.5 mg/kg. Administration of the dopamine (DA) D1/D2 receptor agonist apomorphine (0.025-5 mg/kg, i.p.) also caused grooming in a dose-dependent manner. High doses of apomorphine (0.1-0.5 mg/kg, i.p.) also induced a lower degree of response. Combination of a low dose of nicotine (0.0675 mg/kg) with different doses of apomorphine did not show any interaction. However, there was an interaction between a high dose of nicotine and apomorphine. Thus, combination of a higher dose of nicotine (0.125 mg/kg) with apomorphine, reduced apomorphine-induced grooming. The muscarinic receptor antagonist atropine (5 and 10 mg/kg), peripheral nicotinic receptor antagonist hexamethonium (5 and 10 mg/kg), central nicotinic receptor antagonist mecamylamine (1 and 3 mg/kg) and D1 DA receptor antagonist SCH23390 (0.05 and 0.1 mg/kg) all decreased the response to nicotine. Atropine, mecamylamine and SCH23390 by themselves reduced spontaneous grooming. It is concluded that nicotine elicits grooming indirectly through a possible D1 dopaminergic mechanism. However, muscarinic and nicotinic cholinergic mechanism(s) may be involved.     

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．     

Antagonism of AND and AND-OR drug mixture discriminations in rats

It has been suggested that use of the AND-OR training method may be associated with an enhancement of the pharmacological specificity of discriminations based on mixture of drugs. Rats were trained to discriminate a mixture of nicotine (0.4 mg/kg s.c.) plus midazolam (0.2 mg/kg s.c.) from saline (AND-discrimination, n = 8) or to discriminate the mixture from either drug alone (AND-OR discrimination, n = 6). The studies used two-lever operant procedures with food reinforcers presented on a tandem schedule. After discriminations were acquired to 80% accuracy, the nicotine antagonist mecamylamine (0.03–1.0 mg/kg s.c.) and the benzodiazepine antagonist flumazenil (0.32–10 mg/kg i.p.) were tested on the response to the mixture of nicotine plus midazolam. The antagonist effects of either mecamylamine or flumazenil given alone were more marked in rats trained under the AND-OR procedure than in rats trained on the AND-discrimination. Similarly, the antagonist effects of mixtures of mecamylamine plus flumazenil were much more potent under the AND-OR than under the AND-discrimination procedure. The AND-OR method reduced the dose of the antagonist mixture needed to produce complete block by a factor of about 10, as compared with the AND-discrimination. These striking differences in sensitivity to antagonists support the view that AND-OR or related procedures may enhance the pharmacological specificity of complex drug discriminations.     

Morphine-induced place preference: involvement of cholinergic receptors of the ventral tegmental area

In the present study, the effects of intra-ventral tegmental area injections of cholinergic agents on morphine-induced conditioned place preference were investigated by using an unbiased 3-day schedule of place conditioning design in rats. The conditioning treatments with subcutaneous injections of morphine (0.5-7.5 mg/kg) induced a significant dose-dependent conditioned place preference for the drug-associated place. Intra-ventral tegmental area injection of an anticholinesterase, physostigmine (2.5 and 5 microg/rat) or nicotinic acetylcholine receptor agonist, nicotine (0.5 and 1 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant conditioned place preference. Furthermore, intra-ventral tegmental area administration of muscarinic acetylcholine receptor antagonist, atropine (1-4 microg/rat) or nicotinic acetylcholine receptor antagonist, mecamylamine (5 and 7.5 microg/rat) dose-dependently inhibited the morphine (5 mg/kg)-induced place preference. Atropine or mecamylamine reversed the effect of physostigmine or nicotine on morphine response respectively. The injection of physostigmine, but not atropine, nicotine or mecamylamine, into the ventral tegmental area alone produced a significant place aversion. Moreover, intra-ventral tegmental area administration of the higher doses of physostigmine or atropine, but not nicotine or mecamylamine decreased the locomotor activity. We conclude that muscarinic and nicotinic acetylcholine receptors in the ventral tegmental area may critically mediate the rewarding effects of morphine.     

Antagonism of a nicotine plus midazolam discriminative cue in rats

Rats were trained to discriminate nicotine (0.4mg/kg s.c.), midazolam (0.2mg/kg s.c.) or the combination of these drugs from saline (n = 10). The rats were trained to 95% accuracy in a two-bar operant procedure with a tandem schedule of food reinforcement. Testing with the individual drugs in the mixture-trained group showed that nicotine (85% drug-appropriate responding) was a more salient component than midazolam (47%) in the compound stimulus. The rats were tested with benzodiazepine and nicotine antagonists individually and in combination (mecamylamine 0.2-1.6mg/kg s.c.; flumazenil 2.5-20mg/kg i.p.). Results for the mixture-trained animals showed that flumazenil had no effect on its own, however mecamylamine on its own produced a significant but incomplete block in doses of 0.4-1.6mg/kg. The greater salience of the nicotine component of the cue would explain the block by mecamylamine but not flumazenil. The antagonists in combination produced greater blockade than mecamylamine on its own. The selectivity of the antagonist actions on the different cue components was also demonstrated. The results suggest that in drug discrimination experiments, "false negative" results may be obtained with antagonists when a training drug produces a stimulus with more than one component.     

Nicotine attenuates place aversion induced by naloxone in single-dose,morphine-treated rats

Rationale Acute physical dependence refers to the withdrawal syndrome precipitated by an opioid antagonist administered several hours after either a single dose or a short-term infusion of an opioid agonist.Objectives We examined the mechanism of nicotine-induced attenuation of naloxone-precipitated withdrawal syndrome when used to produce an aversive motivational state in a place-conditioning paradigm.Methods The effect of nicotine was investigated through place aversion induced by naloxone in morphine-pretreated rats. Additionally, the mechanism of nicotine action in this model was explored specifically in relation to the dopaminergic system through the use of dopamine receptor antagonist and agonist.Results Place avoidance behavior was potently elicited by naloxone (0.5 mg/kg s.c.) 24 h after a single exposure to morphine (10 mg/kg s.c.). Avoidance behavior was attenuated by pretreatment with a 0.2-mg/kg dose of nicotine 15 min prior to naloxone administration. The effect of nicotine was completely blocked by mecamylamine, but not hexamethonium. The dopamine receptor antagonists haloperidol (0.05, 0.1 mg/kg, s.c.), SCH23390 (0.1 mg/kg, s.c.), raclopride (1.0 mg/kg, s.c.) and eticlopride (0.1 mg/kg, s.c.) showed effects similar to mecamylamine. Additionally, the dopamine receptor agonist apomorphine (0.03, 0.1, 0.3 mg/kg, s.c.) inhibited naloxone-induced place aversion in morphine-treated rats.Conclusion The inhibitory effect of nicotine on place aversion induced by naloxone-precipitated morphine withdrawal may involve a dopaminergic portion of the central nervous system.     

Nicotine enhances responding with conditioned reinforcement

Rationale The mesolimbic dopamine system has been implicated in the primary reinforcing properties of drugs of abuse as well as in enhanced responding with conditioned reinforcement produced by psychomotor stimulant drugs. Despite clinical observations that nicotine self-administration (i.e. smoking) depends strongly upon conditioned reinforcement (i.e. cues support smoking behavior), little is known about whether nicotine directly affects motivational processes.Objective In these experiments, we investigated whether acute nicotine would influence responding with conditioned reinforcement and the degree to which pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine would modify any nicotine-induced behavioral effects.Methods After subjects had been trained to associate an initially neutral stimulus with water reward, they received acute nicotine (43,25–350 µg/kg SC; –5 min) or saline injections and were tested on the acquisition of a new response for conditioned reinforcement paradigm. In separate experiments, the effect of pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine (300 or 1000 µg/kg SC; –20 min) alone, or in combination with nicotine (350 µg/kg SC; –5 min), on conditioned reinforcement was also examined.Results Acute nicotine injection produced a selective enhancement of responding with conditioned reinforcement (i.e. on the CR lever), without producing non-selective increases in overall responding. The effect of nicotine (350 µg/kg SC; –5 min) was selectively blocked by mecamylamine (300 µg/kg).Conclusions These findings demonstrate that acute exposure to nicotine augments the control over behavior by a conditioned reinforcer, suggesting that nicotine may enhance motivational processes.     

Blockade of nicotine self-administration with nicotinic antagonists in rats

The reinforcing properties of a variety of drugs abused by humans have been investigated using the technique of intravenous self-administration in the rat. To examine the effect of nicotine dose on nicotine self-administration, Wistar rats were allowed to self-administer various doses of nicotine using a within-subjects Latin square design. An inverted U-shaped dose response curve was obtained, with the highest rates of responding at the 0.03 mg/kg/inf dose. With 1-h daily nicotine self-administration sessions, rats did not appear dependent on nicotine 24 h later, as indicated by the absence of somatic signs of withdrawal after subcutaneous injection of a nicotinic acetylcholine receptor antagonist, mecamylamine (0.57 mg/kg). In another set of studies, pretreatment with subcutaneous mecamylamine or dihydro-beta-erythroidine, two nicotinic acetylcholine receptor antagonists, resulted in significant dose-dependent reductions in nicotine self-administration, at two nicotine doses (0.03 and 0.06 mg/kg/inf). These results indicate that nicotine is an effective reinforcer in Wistar rats under the present parameters, and that these reinforcing effects are mediated by activation of nicotinic acetylcholine receptors.     

Modulation of opioidergic system on mecamylamine-precipitated nicotine-withdrawal aversion in rats

RATIONALE: Several lines of evidence indicate that central opioid systems may be involved in the behavioral effects of nicotine. We previously reported that mecamylamine-precipitated nicotine-withdrawal aversion can be evaluated using the conditioned place preference paradigm. OBJECTIVES: In the present study, modulation of opioidergic systems in mecamylamine-precipitated nicotine-withdrawal aversion was investigated. METHODS: Male Sprague-Dawley rats were chronically treated s.c. with 10 mg/kg/day (-)-nicotine tartrate using an osmotic minipump. After nicotine treatment for 7 days, conditioning sessions were performed. In the morning, the rats were treated with mecamylamine (0.3-3.0 mg/kg, s.c.), hexamethonium (1.0-3.0 mg/kg, s.c.), naloxone (0.1-1.7 mg/kg), or saline (1.0 ml/kg, s.c.) in one compartment for 60 min. In the evening of the same day, rats were treated with the other treatments and confined to the other compartment for 60 min. Rats were treated with morphine (3.0 mg/kg, s.c.) or TAN-67 (56.0 mg/kg, s.c.) 30 min prior to mecamylamine injection in the conditioning session. On the next day of conditioning, tests were performed. RESULTS: Mecamylamine, which is known to pass the blood-brain barrier, produced a dose-dependent place aversion. However, hexamethonium, which fails to penetrate the blood-brain barrier, failed to produce a place aversion. Mecamylamine-precipitated nicotine-withdrawal aversion was significantly attenuated by pretreatment with the mu-opioid receptor agonist morphine and the highly selective delta-opioid receptor agonist TAN-67, which was administered 30 min before mecamylamine injection in the conditioning session. Moreover, naloxone at doses (0.1-1.7 mg/kg) that alone failed to show a place aversion in non-treated rats, produced a dose-dependent place aversion in rats that had been chronically treated with nicotine. CONCLUSIONS: These results suggest that central opioid systems may be involved in nicotine-withdrawal aversion.     

The NMDA antagonist dizocilpine (M K801) attenuates tolerance to nicotine in rats

The N-methyl-D-aspartate antagonist dizocilpine (MK801) has been shown to attenuate neuroadaptations of the locomotor activity responses seen after chronic nicotine administration in rats. The aim of the present study was primarily to examine the effects of dizocilpine on tolerance to the aversive stimulus effect of nicotine, as measured in a conditioned taste aversion (CTA) paradigm. A second aim was to determine whether the previously reported effect of dizocilpine on tolerance to the locomotor depressant effect of nicotine could be confirmed. CTA was assessed from changes in the consumption of saccharin and salt solutions and locomotor activity was measured during 30 min sessions in photocell cages. In control rats, the administration of nicotine (0.4 mg/kg s.c.) produced strong CTA and a biphasic effect on locomotor activity (depression followed by facilitation). Daily treatment for 7 days with nicotine (0.4 mg/kg s.c.) produced tolerance to the CTA and motor effects. This tolerance was not detectable in rats that had received dizocilpine (0.3 mg/kg s.c.) 30 min before each daily injection of nicotine during the period of chronic treatment. The chronic administration of dizocilpine alone did not prevent locomotor effects and CTA when nicotine was administered subsequently. These results suggest that the NMDA receptor may be involved in adaptation to both unconditioned and conditioned behavioural responses to nicotine.     

Repeated administration of nicotine attenuates the development of morphine tolerance and dependence in mice

Clinical use of morphine in pain management is a controversial issue. Both nicotine and morphine are widely abused. So, investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical view. We investigated the influence of repeated administration of nicotine on the development of morphine tolerance and dependence. Adult male albino mice were rendered dependent on morphine by subcutaneous (s.c.) injections three times daily for 3 days. Repeated intraperitoneal (i.p.) injection of nicotine (0.001-2 mg/kg) or saline (1 ml/kg) was performed 15 min prior to each morphine injection. Maximal possible effect (MPE%) of morphine (50 mg/kg; s.c.) was used on the fourth day as an index for the development of tolerance. Likewise, to assess the occurrence of dependence in drug-treated mice, naloxone (5 mg/kg; i.p.) was injected 2 h after the last dose of morphine. Repeated nicotine administration significantly attenuated the development of tolerance in a dose-dependent manner whereas it significantly decreased withdrawal jumping behavior in a biphasic profile (V-shape) manner. Furthermore, the central nicotinic receptor antagonist mecamylamine (0.01-0.1 mg/kg; i.p.) neither the peripheral nicotinic receptor antagonist hexamethonium (0.01 and 0.1 mg/kg; i.p.) nor the muscarinic receptor antagonist atropine (2.5-10 mg/kg; i.p.), dose-dependently antagonized both the inhibition of withdrawal jumping as well as increase in MPE% which was produced by repeated nicotine administration (0.1 mg/kg; i.p.). On the other hand, 3 days of solely nicotine treatment resulted in significant jumping behavior precipitated by naloxone after single morphine injection on the test day. The data suggests that the inhibitory effect of nicotine on the morphine tolerance and dependence is mediated by central nicotinic receptors and there is a cross-dependence between nicotine and morphine.     

Discrimination of agonist-antagonist mixtures: experiments with nicotine plus mecamylamine

Discrimination of a mixture of an agonist plus an antagonist has been analysed by training rats to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline; in different groups of rats (n = 8), nicotine was administered either alone or in combination with the non-competitive nicotine antagonist mecamylamine (0.1-0.8mg/kg s.c.). Rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. After 50 sessions, rats trained with nicotine alone had acquired the discrimination with an accuracy of about 85%. In combination, mecamylamine blocked accuracy during acquisition in a dose-related manner. In generalization tests, rats trained with nicotine alone yielded a typical dose-response curve for nicotine (ED(50) = 0.082mg/kg), without depression of response rate. In rats trained with nicotine plus 0.2mg/kg of mecamylamine, the ED(50) for the discriminative effect of nicotine was lowered (ED(50) = 0.036mg/kg), again without depression of response rate. In rats trained with nicotine plus 0.4-0.8mg/kg of mecamylamine, nicotine did not acquire stimulus control over behaviour (flat dose-response relationships), but in these animals, nicotine had a pronounced response rate-decreasing effect. These characteristics of discriminations based on nicotine plus mecamylamine differed substantially from those of previously described discriminations of nicotine plus midazolam, supporting the hypothesis that interactions between the latter drugs were based on a behavioural mechanism (overshadowing) rather than on interactions at the level of receptors.     

Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats.

Mecamylamine, a noncompetitive nicotinic cholinergic antagonist, inhibits nicotine self-administration in animals and may attenuate tobacco smoking in humans trying to quit. Our preliminary data suggested that this agent, at a dose of 2 mg/kg (subcutaneous (s.c.)), also attenuates cue-induced relapse to nicotine-seeking behavior in rats. This study determined whether mecamylamine-induced attenuation can be obtained at doses lower than the high 2 mg/kg dose used in the first study, and whether it is specific to nicotine-associated cues. Male Sprague-Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. Each infusion was accompanied by a visual cue (1 s onset of a lever light followed by offset of a house light for 20 s during which time no infusions could be obtained). After the nicotine-maintained responding was extinguished by withholding the delivery of nicotine (saline substitution) and its associated cue, reinstatement tests were conducted. Response-contingent re-presentation of the cue without further availability of nicotine significantly reinstated extinguished responding at the previously nicotine-reinforced lever. Pretreatment with mecamylamine (0.5, 1, and 2 mg/kg, s.c.) dose-dependently attenuated the cue-induced reinstatement of lever responding. Mecamylamine did not change food-taking and -seeking responses, whereas the highest dose (2 mg/kg) decreased nicotine self-administration behavior. The results confirm previous findings that stimuli conditioned to nicotine self-administration effectively elicit reinstatement of nicotine-seeking behavior after extinction and demonstrate that mecamylamine, besides suppressing self-administration of nicotine, effectively attenuates cue-induced nicotine-seeking behavior. These findings suggest that the response-reinstatement procedures used in this study may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and that mecamylamine-like drugs may be potential candidates for pharmacological treatment and prevention of relapse to tobacco smoking in abstinent smokers.     

Nicotine does not improve discrimination of brain stimulation reward by rats

Rats were trained to shuttle between two selected ("ON") arms of a Y maze, to obtain electrical stimulation of the medial forebrain bundle. Each shuttle response was rewarded with a brief pulse train. Repetitive entries into the same "ON" arm were not rewarded, nor were entries made into the third ("OFF") arm. Every 67s, stimulation was made available from a different pair of arms. Test sessions lasted for 80 min, beginning immediately after SC injection. Undrugged subjects responded faster, and with a greater proportion of rewarded responses, the higher the stimulation current. In non-tolerant rats, nicotine (0-0.4 mg/kg) depressed responding and induced ataxia shortly after injection; from 40 min, nicotine increased low rates of responding but decreased high rates. All these effects were dose-dependent. Mecamylamine (2.0 mg/kg) prevented the initial depressant action. With repeated daily injections of nicotine (0.4 mg/kg), a marked stimulant action emerged which replaced the initial depressant action, and this was dose-dependent. However, responding was increased by nicotine even when brain stimulation was not available ("time-out"). In contrast, an additional "rate-free" index based on discrimination showed that nicotine did not augment the rewarding properties of the brain stimulation.     

Electrophysiological evidence for nicotinic and muscarinic modulation of spinal cord reflexes

Intravenous administration of physostigmine has been found to produce dose- and time-dependent alterations of the lumbar monosynaptic and polysynaptic reflexes in spinal cats. A small dose of physostigmine (0.8 mg/kg) enhanced the monosynaptic reflex for 3 hr, while a larger dose (2.0 mg/kg) produced a pattern of initial depression which peaked at 5 min, followed by an increase which was maintained for 3 hr after injection. Both doses of physostigmine were found to produce a similar pattern of enhancement of the polysynaptic reflex. Atropine and mecamylamine antagonized the increase of the monosynaptic reflex produced by both doses of physostigmine. The initial depression of the monosynaptic reflex produced by the large dose of physostigmine was blocked by mecamylamine, but unaffected by atropine. The enhancement of the polysynaptic reflex, produced by both doses of physostigmine, was antagonized by atropine but not by mecamylamine. In addition, nicotine and oxotremorine were found to mimic the initial effects of physostigmine in the presence of the appropriate antagonist. These data show that both muscarinic and nicotinic receptors are involved differentially in the modulation of spinal reflexes and that physostigmine had an additional late effect which consistently occurred at 20 min after administration.     

Mecamylamine elicits withdrawal-like signs in rats following a single dose of nicotine

Rationale

The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that symptoms of nicotine withdrawal may occur following only a few cigarettes. Whether acute exposure to nicotine can induce dependence in animals has not been well established.

Objective

The objective of this paper is to examine whether the nicotinic acetylcholine receptor antagonist mecamylamine elicits withdrawal-like signs in rats following acute nicotine exposure.

Methods and Results

Mecamylamine (3.0 mg/kg, s.c.) administered ≈2 h after a single dose of nicotine (0.5 mg/kg, s.c.) elicited increases in intracranial self-stimulation (ICSS) thresholds and somatic signs, two well-established effects of withdrawal from long-term (chronic) nicotine exposure. The magnitude of these effects remained constant across five daily test sessions. A lower dose of mecamylamine (1.5 mg/kg, s.c.) had little or no effect on ICSS thresholds or somatic signs following acute nicotine exposure, but precipitated robust increases in these measures during a chronic nicotine infusion. Finally, rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (0.5 mg/kg, s.c.), possibly reflecting a modest spontaneous withdrawal-like effect.

Conclusions

Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence.     

Possible explanations for the antagonism by nicotine against reserpine-induced depletion of monoamines in mouse brain

Summary The inhibitory effect of nicotine pretreatment on reserpine-induced depletion of monoamines in mouse brain was investigated. The depletion of brain monoamines by 24 h after intraperitoneal injection of reserpine (2 mg/kg) was dose-dependently inhibited by nicotine (0.3 – 10 mg/kg, s.c.) pretreatment 20 min before reserpine injection. This effect of nicotine was more marked on dopamine depletion than on noradrenaline or 5-hydroxytryptamine depletion. The nicotine pretreatment also inhibited the reserpine-induced hypothermia and decrease in the locomotor activity. When reserpine (2 mg/kg) was injected intraperitoneally, the inhibitory effect of nicotine (3 mg/kg, s.c.) on the reserpine-induced depletion of brain monoamines and heart noradrenaline was not antagonized by hexamethonium (8 mg/kg, s.c.) but rather potentiated by mecamylamine (2 mg/kg, s.c.). However, when reserpine (0.5 mg/kg) was injected intravenously, pretreatment with nicotine (3 mg/kg, s.c.) inhibited the reserpine-induced dopamine depletion only, and this effect of nicotine was completely blocked by mecamylamine but not by hexamethonium. These results suggest that inhibitory effect of nicotine on the intraperitoneal reserpine-induced depletion of brain monoamines is due to an inhibition of absorption of reserpine, and that central nicotinic action is also involved in the antagonism by nicotine of reserpine-induced dopamine depletion. Correspondence to R. Oishi at the above address