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Mecamylamine is a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist that has been prescribed for hypertension and as an off-label smoking cessation aid. Here, we examined pharmacological mechanisms underlying the interoceptive effects (i.e., discriminative stimulus effects) of mecamylamine (5.6 mg/kg s.c.) and compared the effects of nAChR antagonists in this discrimination assay to their capacity to block a nicotine discriminative stimulus (1.78 mg/kg s.c.) in rhesus monkeys. Central (pempidine) and peripherally restricted nAChR antagonists (pentolinium and chlorisondamine) dose-dependently substituted for the mecamylamine discriminative stimulus in the following rank order potency (pentolinium > pempidine > chlorisondamine > mecamylamine). In contrast, at equi-effective doses based on substitution for mecamylamine, only mecamylamine antagonized the discriminative stimulus effects of nicotine, i.e., pentolinium, chlorisondamine, and pempidine did not. NMDA receptor antagonists produced dose-dependent substitution for mecamylamine with the following rank order potency (MK-801 > phencyclidine > ketamine). In contrast, behaviorally active doses of smoking cessation aids including nAChR agonists (nicotine, varenicline, and cytisine), the smoking cessation aid and antidepressant bupropion, and the benzodiazepine midazolam did not substitute for the discriminative stimulus effects of mecamylamine. These data suggest that peripheral nAChRs and NMDA receptors may contribute to the interoceptive stimulus effects produced by mecamylamine. Based on the current results, the therapeutic use of mecamylamine (i.e., for smoking or to alleviate green tobacco sickness) should be weighed against the potential for mecamylamine to produce interoceptive effects that overlap with another class of abused drugs (i.e., NMDA receptor agonists).

Acetylcholine (ACh) neurotransmission is important for attention, while dopamine (DA) signaling modulates impulsive behavior. Prior studies have established an existing relationship between ACh and DA that mediates dopamine release in the prefrontal cortex of the brain in rats performing the 5-choice serial reaction time task (5-CSRTT). This study is aimed to identify cholinergic and dopaminergic interactions that govern attention and impulsive behavior, using adult Long-Evans rats of both sexes and a 5-CSRTT, with variable short and long cue delays. In Experiment 1, the effects of single cholinergic and dopaminergic drugs were evaluated on 5-CSRTT performance. Drugs like nicotinic ACh receptor (nAChR) agonist nicotine, amphetamine, and GBR12909 that increase the synaptic levels of ACh and DA respectively all increased impulsive behavior. In addition, amphetamine and GBR 12909 decreased attention while nicotine had no effect on attention. The antagonists mecamylamine, a general nAChR antagonist, flupenthixol a DA 1/2 receptor antagonist, and SCH 23390 a DA 1 receptor antagonist, all decreased impulsive behavior, with mixed effects on attention. In contrast, dihydro-β-erythroidine hydrobromide (DHBE), an α4β2 subunit-specific nAChR antagonist, had no significant effects on attention or impulsivity across doses administered. Eticlopride, a DA 2 receptor antagonist, decreased attention at the shortest cue delay but did not affect impulsivity. The acetylcholinesterase inhibitor donepezil decreased both attention and impulsive behavior. Subsequently in Experiment 2, effects of nicotine and amphetamine were determined after pretreatment with SCH 23390 or eticlopride. SCH 23390 attenuated the effects of nicotine and amphetamine to increase impulsivity, while eticlopride only attenuated the effect of nicotine on impulsivity. Minimal effects were seen on attention in the combination trials. This study confirms that dopamine D1 receptor plays an essential role in modulation of impulsive behavior, as measured by the 5-CSRTT. More importantly, it establishes that impulsive behavior is altered by interactions between cholinergic and dopaminergic neurotransmission.

A variety of nicotinic drug treatments have been found to decrease nicotine self-administration. However, interactions of drugs affecting different nicotinic receptor subtypes have not been much investigated. This study investigated the interactions between dextromethorphan, which blocks nicotinic α3β2 receptors as well as a variety of other receptors with sazetidine-A which is a potent and selective α4β2 nicotinic receptor partial agonist with desensitizing properties. This interaction was compared with dextromethorphan combination treatment with mecamylamine, which is a nonspecific nicotinic channel blocker. Co-administration of dextromethorphan (either 0.5 or 5 mg/kg) and lower dose of sazetidine-A (0.3 mg/kg) caused a significant reduction in nicotine SA. With regard to food-motivated responding, 3 mg/kg of sazetidine-A given alone caused a significant decrease in food intake. However, the lower 0.3 mg/kg sazetidine-A dose did not significantly affect food-motivated responding even when given in combination with the higher 5 mg/kg dextromethorphan dose which itself caused a significant decrease in food motivated responding. Interestingly, this higher dextromethorphan dose significantly attenuated the decrease in food motivated responding caused by 3 mg/kg of sazetidine-A. Locomotor activity was increased by the lower 0.3 mg/kg sazetidine-A dose and decreased by the 5 mg/kg dextromethorphan dose. Mecamylamine at the doses (0.1 and 1 mg/kg) did not affect nicotine SA, but at 1 mg/kg significantly decreased food-motivated responding. None of the mecamylamine doses augmented the effect of dextromethorphan in reducing nicotine self-administration. These studies showed that the combination of dextromethorphan and sazetidine-A had mutually potentiating effects, which could provide a better efficacy for promoting smoking cessation, however the strength of the interactions was fairly modest.

Electronic-cigarette's (ECIGs) popularity has grown over the last decade and changed the way individuals administer nicotine. Preclinical research is imperative for understanding the addictive properties and health-risks associated with ECIG use; however, there is not a standard dosing regimen used across research laboratories. The main objective was to determine how vapor puff durations, administration session length, and flavored e-liquid alter general and mood-disorder related behaviors while providing a foundation of vapor administration parameters. Adult male and female C57BL/6 mice were exposed to several nicotine-free unflavored vapor puff durations (1, 3, 6, or 10 s) and vapor administration session lengths (10 and 30 min) then measured on the following assays: locomotor activity (LMA), tail suspension test (TST), and light-dark test. The effects of mecamylamine and the time-course of vapor-induced depression of LMA also were assessed. Additionally, mice were exposed to flavored (strawberry and adventurers tobacco blend) vapor inhalation and measured on locomotor activity, tail suspension test, and light-dark test. Following both 10 and 30 min vapor administration session, there was a puff duration-dependent decrease in distance traveled, time in center, and rearing. The vapor-induced depression of LMA was not mediated by nicotine or nicotinic acetylcholine receptor (nAChR) activation and lasted 60–90 min. The 10 s puff duration produced an anxiogenic-like effect in the light-dark test by decreasing the time spent in the light side. Vapor inhalation did not significantly alter TST behavior. No significant effects of sex or flavor were found. The anxiogenic-like effects of nicotine-free vapor inhalation are concerning as many adolescents vape nicotine-free flavored e-liquid, and there is an association between ECIGs and mood disorders. Additionally, these studies demonstrate that vapor puff duration, but not vapor administration session length, is an important variable to consider during research design as it can become a confounding variable and alter baseline behaviors.

Background and Aim The cholinergic system can affect drug reward. The present study aimed to examine the roles of muscarinic acetylcholine receptor (mAChR) and nicotinic acetylcholine receptor (nAChR) in morphine-induced behavioral sensitization. Methods To analyze the roles of mAChR and nAChR in behavioral sensitization induced by morphine (5 mg/kg), seven experiments were designed. Experiment 1 , Experiment 2 examined the effects of 3, 1, and 0.3 mg/kg scopolamine and 0.2, 0.1, and 0.05 mg/kg scopolamine, respectively, on the locomotor activity when administered alone. Experiment 3 , Experiment 4 explored the effect of scopolamine on morphine-induced behavioral sensitization. Experiment 5 studied the effect of mecamylamine on morphine-induced behavioral sensitization. Experiment 6 , Experiment 7 investigated the effects of scopolamine + huperzine A and mecamylamine + huperzine A, respectively, on morphine-induced behavioral sensitization. Results The results revealed that 3 mg/kg scopolamine, which significantly enhanced locomotor activity when administered alone, inhibited the acquisition of morphine-induced sensitization. However, mecamylamine (0.5, 1, 2 mg/kg) did not have these effects. The co-administration of scopolamine (0.05 mg/kg) + huperzine A (0.4 mg/kg) or mecamylamine (1 mg/kg) + huperzine A (0.4 mg/kg) did not affect the acquisition of morphine-induced behavioral sensitization. Scopolamine (0.05 mg/kg) which did not affect the locomotor activity when administered alone, but not mecamylamine (1 mg/kg), reversed the acute attenuation effect of huperzine A (0.4 mg/kg) on morphine-induced locomotor activity at the acquisition stage and reversed the inhibition of huperzine A on the expression of morphine-induced sensitization. Conclusion The mAChR might play a more important role in morphine-induced locomotor activity and the expression of morphine-induced behavioral sensitization. The mechanisms of mAChR and nAChR were relatively separate in morphine-induced sensitization.

Nicotine is only mildly rewarding, but after becoming dependent, it is difficult to quit smoking. The goal of these studies was to determine if low-nicotine cigarettes are less likely to cause dependence and enhance the reinforcing effects of nicotine than regular high-nicotine cigarettes. Male and female rats were exposed to tobacco smoke with a low or high nicotine level for 35 days. It was investigated if smoke exposure affects the development of dependence, anxiety- and depressive-like behavior, and nicotine-induced behavioral sensitization. Smoke exposure did not affect locomotor activity in a small open field or sucrose preference. Mecamylamine precipitated somatic withdrawal signs in male rats exposed to smoke with a high level of nicotine, but not in male rats exposed to smoke with a low level of nicotine or in females. After cessation of smoke exposure, there was a small decrease in sucrose preference in the male rats, which was not observed in the females. Cessation of smoke exposure did not affect anxiety-like behavior in the large open field or the elevated plus maze test. Female rats displayed less anxiety-like behavior in both these tests. Repeated treatment with nicotine increased locomotor activity, rearing, and stereotypies. Prior exposure to smoke with a high level of nicotine increased nicotine-induced rearing in the females. These findings indicate that exposure to smoke with a low level of nicotine does not lead to dependence and does not potentiate the effects of nicotine. Exposure to smoke with a high level of nicotine differently affects males and females.

Cigarette smoking and resultant nicotine dependence remain major public health problems. Most smokers begin before the age of 18, yet preclinical models have insufficiently characterized the development of nicotine dependence in adolescence. To categorize the short-term effects of chronic nicotine administration throughout adolescence and adulthood, we exposed male Sprague Dawley rats to 14 days of continuously delivered nicotine (0, 1.2 or 4.8 mg/kg/d) using a subcutaneous osmotic minipump, starting between postnatal day 33 (p33) and p96. Next, to explore the effects of extended exposure to chronic nicotine, we exposed male Sprague Dawley rats to 42 days of continuous nicotine starting in adolescence (p33) or early adulthood (p68). Somatic and affective signs of precipitated withdrawal (PW) were observed after a mecamylamine (1.5 mg/kg, i.p.) challenge as compared to a saline injection. Short term nicotine exposure starting at p96, well within the adult period, elicited a significant increase in somatic PW as measured by a composite behavioral score. In contrast, adolescent exposure to nicotine elicited a unique behavioral profile, dependent on the starting age of exposure. Late adolescence exposure was characterized by scratching while adult exposure was characterized by facial tremors and yawns. Extended exposure to nicotine resulted in age specific characteristic nicotine withdrawal behaviors, including scratches, ptosis and locomotion, distinct from the short-term exposure. Thus, nicotine dependence severity, based on the expression of total somatic PW behaviors, is not observed until the adult period, and differences between adolescents and adults are observed using a more nuanced behavioral scoring approach. We conclude that age of nicotine initiation affects somatic withdrawal signs and their magnitude. These data serve as a foundation for understanding the underlying brain mechanisms of nicotine dependence and their development over adolescence and early adulthood.

In the present study, the effects of repeated intra-ventral hippocampal (intra-VH) microinjections of nicotinic acetylcholine receptor agonist or antagonist on morphine-induced anxiolytic-like behavior were investigated in morphine-sensitized mice using elevated plus-maze. Intraperitoneal (i.p.) administration of different doses of morphine (5, 7.5 and 10mg/kg) increased the percentage of open arm time (%OAT), open arm entries (%OAE), but not locomotor activity, indicating an anxiolytic-like response to morphine. The maximum response was obtained by 7.5mg/kg of the opioid. The anxiety-like behavior which was induced by a lower dose of morphine (5mg/kg) was significantly increased in mice that had previously received once daily injections of morphine (10 and 20mg/kg, i.p.) for 3 days. It should be considered that this treatment also increased locomotor activity in morphine-sensitized mice. Furthermore, the response to an ineffective dose of morphine (5mg/kg, i.p.) in the EPM was significantly increased in the animals that had previously received nicotine for 3 days (0.1, 0.3, 0.5 and 0.7 μg/mouse; intra-VH), 5 min prior to the injections of morphine (5mg/kg/day × 3 days; i.p.). On the other hand, the increase of morphine-induced anxiolytic-like effect in animals that had previously received the 3-day morphine (20mg/kg) was dose dependently suppressed by once daily injections of mecamylamine (0.5, 1 and 2 μg/mouse/day × 3 days; intra-VH). It is important to note that repeated intra-VH administrations of the same doses of nicotine or mecamylamine alone caused no significant change in morphine (5mg/kg)-induced anxiety-like parameters in the EPM. In conclusion, it seems that morphine sensitization affects the anxiety-like behavior in the EPM and the cholinergic system in the ventral hippocampus, via nicotinic receptors, may play an important role in this effect.

Beneficial effects of nicotine on cognition and behavioral control are hypothesized to relate to the high rates of cigarette smoking in Attention-Deficit/Hyperactivity Disorder (ADHD). Given that ADHD is associated with both impulsivity and elevated risk taking, we hypothesized that nicotine modulates risk taking, as it does impulsivity. 26 non-smoking young adults (15 controls with normal impulsivity and 11 ADHD with high impulsivity) received 7 mg transdermal nicotine, 20 mg oral mecamylamine, and placebo on separate days, followed by the Balloon Analog Risk Task (BART). Statistical analyses found no group differences in baseline risk taking. Reexamination of the data using a median split on baseline risk taking, to create high (HRT) and low (LRT) risk taking groups, revealed significant effects of nicotinic drugs that differed by group. Nicotine reduced risk taking in HRT and mecamylamine increased risk taking in LRT. This finding supports the hypothesis that nicotinic receptor function modulates risk taking broadly, beyond those with ADHD, and is consistent with rate dependent cholinergic modulation of other cognitive functions. Further, the results demonstrate that high impulsivity is separable from high risk taking in young adults with ADHD, supporting the utility of these differential behavioral phenotypes for neurobiological studies.

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.

Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H₃ antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer's disease and schizophrenia.

This experiment examined the effects of mecamylamine, a nicotinic acetylcholine receptor antagonist, on flash-evoked potentials (FEPs) recorded from the visual cortex (VC) and superior colliculus (SC) of chronically implanted male Long-Evans rats, and on body temperature and open field behavior. FEPs were recorded at 20 and 35 min following intraperitoneal injections of saline, and of 0.3, 3.0, and 10.0 mg/kg mecamylamine on separate days. The 0.3 mg/kg dose did not produce significant effects. The amplitude of VC components N30, P48, and P87 increased, N150 and P231 decreased, and P23, N40, N58, and N68 were unchanged following administration of the 10.0 mg/kg dose. In the SC, component P28 was unaffected, P39 was reduced, and N49 was augmented by the 10.0 mg/kg dose. All component peak latencies were increased by the 3.0 and 10.0 mg/kg doses. Significant hypothermia was also produced by the 3.0 and 10.0 mg/kg doses, suggesting that this was the basis for the increased latencies. The 10.0 mg/kg dose produced a significant decrease in movement during the recording sessions. In subsequent open field observations, both line crossings and rearings were reduced by the 3.0 and 10.0 mg/kg doses. The results suggest that endogenous acetylcholine acting on nicotinic acetylcholine receptors plays at most a modest role in producing FEPs recorded from the VC and SC.

Several evidences have indicated the involvement of neuronal nicotinic acetylcholine receptors (nAChR) in behavioral effects of drugs of abuse, including ethanol. nAChRs are implicated in ethanol-induced behaviors as well as neurochemical responses to ethanol. Recently, it is demonstrated that mecamylamine, a nAChR antagonist blocks cocaine-, d-amphetamine-, ephedrine-, nicotine-, and methylphenidate-induced psychomotor sensitization. However, no reports are available on its role in ethanol-induced psychomotor sensitization. Therefore, an attempt was made to evaluate its effect on ethanol-induced locomotor sensitization using a model previously described by us. The results revealed that acute administration of mecamylamine (1 and 2 mg/kg, i.p.) blocked the acute stimulant effect of ethanol (2.0 g/kg, i.p.). In addition, treatment with mecamylamine (0.5–2.0 mg/kg, i.p.), 30 min prior to the challenge dose of ethanol (2.0 g/kg, i.p.) dose dependently attenuated expression of sensitization to locomotor stimulant effect of ethanol. Moreover, administration of mecamylamine (1 and 2 mg/kg, i.p.) during development (prior to each ethanol injection on days 1, 4, 7, and 10) blocked acquisition as well as expression (day 15) of sensitization to locomotor stimulant effect of ethanol. Mecamylamine per se did not affect locomotor activity. Further, it also did not influence blood ethanol levels and rotarod performance in mice. These results support the hypothesis that neuroadaptive changes in nAChRs may participate in the development and the expression of ethanol-induced locomotor sensitization.

The present study examined the antinociceptive effect of the ethanolic extract from Melissa officinalis L. and of the rosmarinic acid in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. The extract (3-1000 mg/kg), given orally (p.o.) 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with ID50 value of 241.9 mg/kg. In the formalin test, the extract (30-1000 mg/kg, p.o.) also caused significant inhibition of both, the early (neurogenic pain) and the late (inflammatory pain), phases of formalin-induced licking. The extract (10-1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of glutamate-induced pain, with ID50 value of 198.5 mg/kg. Furthermore, the rosmarinic acid (0.3-3 mg/kg), given p.o. 1 h prior, produced dose-related inhibition of glutamate-induced pain, with ID50 value of 2.64 mg/kg. The antinociception caused by the extract (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with atropine (1 mg/kg), mecamylamine (2 mg/kg) or l-arginine (40 mg/kg). In contrast, the extract (100 mg/kg, p.o.) antinociception was not affected by i.p. treatment with naloxone (1 mg/kg) or D-arginine (40 mg/kg). It was also not associated with non-specific effects, such as muscle relaxation or sedation. Collectively, the present results suggest that the extract produced dose-related antinociception in several models of chemical pain through mechanisms that involved cholinergic systems (i.e. through muscarinic and nicotinic acetylcholine receptors) and the L-arginine-nitric oxide pathway. In addition, the rosmarinic acid contained in this plant appears to contribute for the antinociceptive property of the extract. Moreover, the antinociceptive action demonstrated in the present study supports, at least partly, the ethnomedical uses of this plant.

Deficits in brain reward function during nicotine withdrawal may serve as an important substrate for negative reinforcement that contributes to the persistence of the tobacco habit in human smokers. The ability to assess withdrawal-associated reward deficits in genetically modified mice may facilitate understanding of the neurobiological mechanisms of nicotine dependence. Here, we assessed the effects of nicotine withdrawal on brain reward function in mice, as measured by intracranial self-stimulation (ICSS) thresholds. Male C57BL6 mice were trained in a discrete-trial current-threshold ICSS procedure until stable reward thresholds were obtained. Mice then received experimenter-administered saline or nicotine (2 mg/kg/injection salt; × 4 daily) injections for 7 consecutive days, and ICSS thresholds assessed for 3 days after cessation of injections. Thresholds were unaltered in nicotine- and saline-treated mice after cessation of injections, indicating that this treatment regimen was not sufficient to induce withdrawal-associated reward deficits. Next, mice were implanted subcutaneously with osmotic minipumps delivering a constant daily amount of saline or nicotine (24 mg/kg/day; free-base), with pumps surgically removed 13 days later. The nicotinic receptor antagonist mecamylamine (2 mg/kg) elevated ICSS thresholds in nicotine- but not saline-treated mice when administered 8–10 days after pump implantation. Similarly, reward thresholds were elevated in nicotine-treated mice 12–72 h after minipump removal. These data demonstrate that antagonist-precipitated or spontaneous withdrawal from nicotine delivered via osmotic minipumps induced reward deficits in mice. Further, these findings highlight the potential utility of the ICSS procedure for assessing this important affective component of nicotine withdrawal in genetically modified mice.

This study evaluates the effects of three nitric oxide synthase (NOS) inhibitors (L-NNA, L-NAME, L-NMMA) in attenuating the precipitated nicotine withdrawal syndrome in rats. Male albino Wistar rats were made dependent on nicotine by subcutaneous infusion of nicotine (9.0 mg/kg/day) via a 7 day osmotic pump, whereas control rats received saline via osmotic pumps. Test doses of each NOS inhibitor were administered 30 min prior to mecamylamine (1 mg/kg) challenge in control and test rats on the 7th day. Somatic signs of withdrawal were scored for 15 min by using the global Gellert-Holtzman rating scale followed by a measurement of motor activity. A comparison of NOS inhibitors treated rats with the mecamylamine-precipitated nicotine rats showed that at highest dose L-NNA appears to produce a more complete attenuation of all aspects of withdrawal syndrome. On the other hand, L-NAME appears to do so both at moderate and highest doses. This could be due to an incomplete reversal of some signs of withdrawals by L-NMMA. However, motor activity increased in nicotine dependent rats with the administration of NOS inhibitors. This study demonstrates that NO plays an important role in the expression of behavioral signs of nicotine withdrawal syndrome and suggests a potential use of NOS inhibitors as an aid in tobacco smoking cessation.

The compound LXM-10 (2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro [5.5]undecane chloride) is a new spirocyclopiperazinium salt compound. This is the first article to evaluate its antinociceptive effect in the abdominal constriction test induced by acetic acid and the hot-plate test. In the abdominal constriction test, LXM-10 had a significant dose-response effect, and the maximal inhibition ratio was 79.2%. In the hot-plate test, LXM-10 had significant dose-response and time-response effects. The antinociceptive effect began at 1.0 h, peaked at 2.0 h, and persisted 3.0 h after s.c. administration. The hot-plate latency was increased by 126.8% at the dose of 12.0 mg/kg. The antinociceptive effect of LXM-10 was blocked by mecamylamine (a central and peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.25, 0.5, 1.0 mg/kg, i.p.), hexamethonium (a peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), atropine (a central and peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), and atropine methylnitrate (a peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.) in a dose-dependent fashion. In contrast, the effect was not blocked by naloxone (a non-selective opioid receptor antagonist, 2.0 mg/kg, i.p.) or yohimbine (a alpha(2)-adrenergic receptor antagonist, 1.0, 2.5, 5.0 mg/kg, i.p.) in the hot-plate test. Therefore, the antinociceptive effects of LXM-10 involve the peripheral neuronal nicotinic and muscarinic acetylcholine receptors; they are not related to opioid receptors or alpha(2)-adrenergic receptors. LXM-10 did not affect motor coordination, spontaneous activity, or body temperature. These findings with LXM-10 suggest that spirocyclopiperazinium derivatives could provide insight on new analgesics.

The effects of intra-basolateral amygdala (intra-BLA) injections of physostigmine, atropine, nicotine and/or mecamylamine on morphine-induced conditioned place preference (CPP) in rats was investigated by using an unbiased 3-day schedule of place conditioning design. Animals that received 3 daily injections of morphine (0.5-10 mg/kg) subcutaneously (s.c.) or saline (1.0 ml/kg, s.c.) showed a significant preference for compartment paired with morphine. The maximum response was observed with 7.5 mg/kg of the opioid. Administration of the anticholinesterase drug, physostigmine (1, 3 and 5 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. Injections of antimuscarinic receptor agent, atropine (1, 4 and 7 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. The injections of nicotine (0.75, 1 and 2 microg/rat) potentiated the morphine (0.5 mg/kg)-induced place preference, while the nicotinic receptor antagonist, mecamylamine (1, 3 and 6 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. Furthermore, administration of atropine (7 microg/rat) but not mecamylamine (6 microg/rat) reduced the response induced by different doses of physostigmine plus morphine. Moreover, mecamylamine (6 microg/rat) but not atropine (7 microg/rat) reduced the response induced by different doses of nicotine plus morphine. It is concluded that the muscarinic and nicotinic receptor mechanisms in the BLA may be involved in the acquisition of morphine-induced place preference.

Working memory impairments in the n-back task in schizophrenia have been linked to sustained deficiency in mesocortical dopamine function. More recently, abnormalities in the cholinergic system have also been documented in schizophrenia, with cortical reductions in both nicotinic and muscarinic receptors. While the cholinergic hypothesis of memory is well established, the role of cholinergic receptors in modulating n-back working memory is not known. We investigated the effects of selective and simultaneous muscarinic and nicotinic antagonism on spatial and object n-back working memory performance. The study was a double-blind, placebo-controlled repeated-measures design in which 12 healthy subjects were tested under four acute treatment conditions; placebo (P), mecamylamine (M), scopolamine (S) and mecamylamine+scopolamine (MS). Muscarinic antagonism with scopolamine significantly impaired both object and spatial n-back working memory, whereas nicotinic antagonism with mecamylamine had little effect. Simultaneous antagonism of both muscarinic and nicotinic receptors produced greater impairments in both object and spatial n-back working memory performance than muscarinic or nicotinic antagonism alone. These results suggest that: (1) both muscarinic and nicotinic receptors may functionally interact to synergistically modulate n-back working memory, and (2) that n-back working memory impairments in schizophrenia may in part be due to reductions in both muscarinic and nicotinic receptors.

Nicotine has been shown to have additive as well as antagonistic effects on behavior stimulated by ethanol. Here, we examine the effects of nicotine, ethanol, and the coadministration of each drug on acoustic startle responding in C57BL/6J mice. Mice were tested at a range of decibel levels (80-115 dB, 5 dB increments), with administration of 0.031, 0.062, 0.125, and 0.25 mg/kg nicotine or 0.5, 1.0, 1.5, and 2.0 g/kg ethanol. Nicotine and ethanol each caused an increase in the acoustic startle response at the highest and lowest doses tested, respectively. Mecamylamine, a nicotinic receptor antagonist, administered in combination with nicotine or ethanol attenuated these increases in acoustic startle responding. Nicotine and ethanol, administered together, did not produce greater enhancement of startle than when administered alone. Haloperidol (1 mg/kg) was administered in combination with nicotine or ethanol to investigate if dopamine modulated nicotine or ethanol enhancement of acoustic startle. It was found that the increase in acoustic startle responses observed with ethanol or nicotine was attenuated by haloperidol. Thus, ethanol or nicotine may enhance the acoustic startle reflex through a common dopaminergic mechanism.

18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.

The acquisition of morphine and nicotine conditioned place preference (CPP) and cross-tolerance between the response of two drugs was studied in mice. A biased CPP paradigm was used to study the effect of the agents. Morphine (5 mg/kg) and nicotine (1 mg/kg) induced CPP. Naloxone (0.5, 1 and 2 mg/kg), but not mecamylamine (0.025, 0.05 and 0.1 mg/kg), induced conditioned place aversion (CPA). Both antagonists reversed CPP induced by morphine and nicotine. Administration of one daily dose of morphine (12.5, 25 or 50 mg/kg) for 3 days or nicotine (0.5, 1 or 2 mg/kg) three times a day for 12 days, in order to develop tolerance to the drugs, reduced the conditioning induced by morphine (5 mg/kg) or nicotine (1 mg/kg). CPA-induced by naloxone was reduced in animals, which were rendered tolerant to morphine (50 mg/kg) or nicotine (2 mg/kg). Mecamylamine, however, which did not induce any response in the nontolerant mice, elicited CPP in the tolerant animals. It is concluded that there may be a cross-tolerance between morphine- and nicotine-induced CPP.

Cholinergic blockade has been shown to impair performance in delayed nonmatching to position (DNMTP) paradigms in rats. In this study, a murine operant DNMTP task was used to assess the effects of cholinergic antagonism in two strains of mice (DBA/2 and C57BL/6) differing in spatial learning abilities. DNMTP was scheduled in operant chambers with retractable levers, where mice were trained until high levels of accuracy. Subsequently, proactive interference effects were assessed by manipulation of the intertrial interval (ITI), and animals were tested in this task under scopolamine (0.1-1.0 mg/kg) and mecamylamine (0.5-2.0 mg/kg) treatment. Data were analyzed according to the methods of signal detection theory. ITI manipulation decreased accuracy when the time between trials was reduced to 5 s. Cholinergic blockade failed to induce a pure mnemonic impairment but distinguishable effects of both receptor antagonists could be detected: scopolamine disrupted accuracy in a dose-dependent but delay-independent manner, whereas mecamylamine failed to impair accuracy, but decreased responsivity delay- and dose-dependently. Strains mainly differed in responsivity, with DBA/2 showing higher latencies to respond to the levers. These results are comparable to those obtained in rats. Thus, operant DNMTP can be applied to assess working memory in mice.

In the present study, effects of nicotine on catalepsy induced by morphine in mice have been investigated. Morphine but not nicotine induced a dose-dependent catalepsy. The response of morphine was potentiated by nicotine. Intraperitoneal administration of atropine, naloxone, mecamylamine, and hexamethonium to mice reduced catalepsy induced by a combination of morphine with nicotine. Intracerebroventricular injection of atropine, hexamethonium, and naloxone also decreased catalepsy induced by morphine plus nicotine. Intraperitoneal administration of atropine, but not intraperitoneal or intracerebroventricular injection of hexamethonium, decreased the effect of a single dose of morphine. It was concluded that morphine catalepsy can be elicited by opioid and cholinergic receptors, and the potentiation of morphine induced by nicotine may also be mediated through cholinergic receptor mechanisms.

SIB-1553A is a novel ligand with reputed agonist selectivity at nicotinic receptors containing the beta(4) subunit. As such, it represents an interesting pharmacological tool with which to probe the function of nicotine receptor subtypes. In the present studies, we compared SIB-1553A with nicotine in its ability to stimulate locomotion and to enhance attention in rats as assessed using the five-choice serial reaction time task (5-CSRTT). In nicotine-naive rats, SIB-1553A (10-40 mg/kg) induced a comparable increase in locomotion to nicotine (0.4 mg/kg), whereas in nicotine-sensitised rats, an enhanced locomotor response was seen to nicotine (0.4 mg/kg) but not to SIB-1553A (10-80 mg/kg). Similarly, chronic treatment with either SIB-1553A or nicotine did not lead to a cross-sensitised locomotor response. Unlike nicotine, SIB-1553A-induced locomotion was insensitive to antagonism by either mecamylamine (1 mg/kg) or DH beta E (3 mg/kg), suggesting a non-nicotinic mechanism. In young and aged rats, nicotine (0.4 mg/kg) enhanced attention as demonstrated by an increase in response accuracy and speed. SIB-1553A (3-10 mg/kg) did not mimic any of these changes and at the highest dose tended to disrupt performance. These results lend further support to the involvement of a high affinity site, possibly alpha(4)beta(2), in the locomotor and attentional-enhancing properties of nicotine.

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.

In the present study, cross-tolerance between hypothermia induced by morphine and nicotine in mice has been investigated. Different doses of morphine or nicotine induced dose-dependent hypothermia. The sub-maximal doses of both drugs were used for interaction studies. Administration of mecamylamine either intracerebroventricularly (2-6 microg/animal icv) or intraperitoneally (0.5 and 1 mg/kg ip) decreased both morphine- or nicotine-induced hypothermia. Naloxone either intracerebroventricularly (2-6 microg/animal) or intraperitoneally (1 and 2 mg/kg) reduced the response to morphine, but not nicotine's response. Hexamethonium (5 and 10 mg/kg ip) caused a slight decrease in morphine's hypothermia, but not that of nicotine. Nicotine's response was decreased in the animals which were made tolerant to hypothermic effect of morphine. Pre-treatment of the animals with low doses of morphine (12.5 or 25 mg/kg), once daily for 3 days, did not cause significant tolerance to the hypothermic response to morphine or nicotine. However, the administration of low doses of morphine (12.5 or 25 mg/kg) plus nicotine (2 mg/kg), once daily for 3 days, increased levels of tolerance to hypothermia induced by either drug. It is concluded that nicotinic receptor mechanism may play a role in morphine-induced hypothermia and there is cross-tolerance between the two drugs.

Antidepressant effects of acute or chronic nicotine treatments in swim test immobility of Flinders sensitive line (FSL) rats, an animal model of depression, were recently demonstrated (Tizabi et al. Psychopharmacology 142:193, 1999). In the present study we sought to determine whether the antidepressant effects of nicotine could be blocked by the nicotinic antagonist, mecamylamine (MEC). Moreover, the effects of chronic nicotine treatment on [3H]cytisine binding in discrete brain regions of FSL and their control Flinders resistant line (FRL) rats were also evaluated. Adult male FSL rats were treated with MEC (0.5 mg/kg) 20 min prior to an acute or chronic nicotine administration. MEC by itself did not affect the immobility in swim test. However, it completely blocked the acute or chronic nicotine effects. Daily nicotine injection (0.4 mg/kg/day for 14 days) resulted in an increase in [3H]cytisine binding primarily in the FRL rats. An increase in nicotinic receptor binding following chronic nicotine administration is believed to reflect desensitization of these receptors. These findings, coupled with previous observation of higher basal nicotinic receptors in FSL rats, further support the involvement of central nicotinic receptors in depressive characteristics of these rats. Moreover, the data suggest therapeutic potential for selective nicotinic receptor agonists in depressive disorders.

The effects of various drugs were assessed in rats responding under a Differential-Reinforcement-of-Low-Rate 30-s (DRL 30-s) schedule. Atropine, scopolamine, and CEB-1957 (a new muscarinic blocker) increased response rate and decreased reinforcement rate, while methylatropine only decreased reinforcement rate. Physostigmine decreased response and reinforcement rates, when pyridostigmine had few effect on DRL responding. The irreversible acetylcholinesterase (AChE) inhibitors organophosphorus compounds (OPC) soman and sarin, injected at one-third of the LD 50 did not consistently alter DRL performance, suggesting that they produce few behavioral effects in the rat when administered at subtoxic doses. Three oximes—pralidoxime, pyrimidoxime, and HI-6—decreased both response and reinforcement rates. Mecamylamine had few consistent effects on performance, and nicotine, d -amphetamine, diazepam, and the wakening drug modafinil increased response rate and decreased reinforcement rate. These two latter drugs also increased the number of very premature responses. These results, taken together, indicate that a DRL schedule is a useful tool to bring to light the existence of psychotropic effects of a drug. The explanation of drug-induced alterations of DRL performance, in terms of effects on cognition or on mood, is also discussed.

A rodent model of nicotine dependence has been developed based on continuous subcutaneous (SC) infusion of nicotine tartrate. Nicotine abstinence syndrome was precipitated by SC injection of the nicotinic antagonist mecamylamine, which freely crosses the blood–brain barrier. In contrast, the nicotinic antagonist hexamethonium crosses the blood–brain barrier very poorly. This study determined whether central or peripheral administration of hexamethonium could precipitate nicotine abstinence. In the first experiment, 26 nicotine-dependent rats were injected SC with 0.5, 5 or 10 mg/kg hexamethonium dichloride or saline alone and observed for 20 min. Few abstinence signs were observed in any group; there was no significant drug effect. In the second experiment, 18 rats were cannulated in the third ventricle and rendered nicotine dependent. One week later, rats were injected through the cannula with 12 or 18 ng hexamethonium or saline alone and observed for 20 min. Both dose groups differed significantly from the saline-injected group, and there was a significant positive linear trend of signs as a function of dose. The high dose had no significant effect in 14 nondependent rats. We conclude that hexamethonium is much more potent by the central route, and there is a major central nervous system component in nicotine dependence.

Cholinergic neurons of the pedunculopontine tegmental nucleus (Ch5) and laterodorsal tegmental nucleus (Ch6) monosynaptically activate dopamine neurons of the substantia nigra and ventral tegmental area (VTA) via nicotinic and muscarinic receptors. The nicotinic receptors near the VTA have been proposed to be important for nicotine self-administration in rats and for tobacco smoking in humans. Nicotinic and muscarinic blockers were microinjected into the VTA of rats trained to lever-press for lateral hypothalamic stimulation via an ipsilateral electrode. The competitive nicotinic blocker dihydro-beta-erythroidine (DH beta E; 5-60 micrograms) shifted rate-frequency curves to the right by a mean of 6-27% in a dose-related manner; the noncompetitive nicotinic blocker mecamylamine (10-300 micrograms) produced similar shifts of 7-21%. Atropine (30 micrograms) shifted the curves to the right by a mean of 82% in three of the sites tested with DH beta E. All blockers decreased maximum bar-pressing rates significantly in some sites when the shifts were large. Therefore, nicotinic receptors in the VTA make small contributions to the maintained rewarding effect of brain-stimulation reward in rats, but muscarinic receptors in the VTA appear to be more important.

In a previous study, mecamylamine, a centrally active nicotine antagonist, exacerbated EEG signs of tobacco abstinence in abstinent smokers. In the present study, the effects of mecamylamine were compared in non-smokers and nondeprived smokers. Mecamylamine (0, 5 and 10 mg, p.o.) was administered to six smokers and six non-smokers; eight of these subjects were also given a 20 mg dose. Before drug administration, resting EEG was similar in both groups. In both groups, mecamylamine caused dose-related decreases in alpha frequency and increases in delta frequency; beta frequency was increased by the 5 and 10 mg doses. The similarity of effects in smokers and non-smokers suggests a direct pharmacological action rather than precipitated nicotine withdrawal. Significant baseline differences existed between smokers and non-smokers in systolic blood pressure, pulse rate, skin temperature and pupil diameter. Response time slowed in both vigilance and distractibility tasks and delayed recall was impaired. Mecamylamine increased ratings of: “relaxed,” “nodding,” “sleepy” and “coasting.” This small-sample study tentatively suggests that nicotinic cholinergic mechanisms modulate brain electrical activity and cognitive function in smokers and non-smokers. Disruption of these neural systems could mediate the symptoms of tobacco withdrawal and be involved in the pathophysiology of Alzheimer's disease.Published by Elsevier Science Inc., 1997

The present report addressed the hypothesis that withdrawal from chronic nicotine treatment activates the same motivational processes as withdrawal from chronic opiate treatment. Conditioning produced by the nicotine antagonist mecamylamine in nicotine-treated animals was studied and compared to the well-known potentiation by opiate treatment of the aversive conditioning produced by the opiate antagonist naloxone. A sensitive two-flavor, three-trial, taste conditioning procedure was used and it was found that chronic treatment using Alzet minipumps for 1 month with nicotine (8 or 16 mg/kg/day) potentiated the ability of mecamylamine to produce taste conditioning. Thus, in nicotine-placebo control animals, only 1.0 mg/kg mecamylamine (s.c.) produced significant conditioning, whereas in nicotine-treated animals 0.5 and 1.0 mg/kg mecamylamine was effective. However, in contrast to chronic opiate treatment, which increases the aversive effect of an opiate antagonist (as confirmed here using treatment for one month with 0.25 mg/kg/day fentanyl and taste conditioning with 0.1 mg/kg naloxone, s.c.), the nicotine treatment changed the valence of the mecamylamine conditioning. The nicotine-naive animals avoided the mecamylamine-paired flavor, whereas the nicotine-exposed subjects preferred it. These findings indicated that there may be important differences between nicotine and opiate withdrawal. Not all effects of nicotine withdrawal in models of addiction can be assumed to be negatively motivating.

The effects of dynorphin A (1-13) on carbon monoxide (CO)-induced amnesia in mice were investigated. Memory deficiency was apparent during Y-maze testing 5 days after CO exposure (delayed amnesia). Percent alternation in the CO-exposed group was significantly lower than that in the control group. Administration of dynorphin A (1-13) (1.5 nmol, i.c.v.) 15 min before the Y-maze test session reversed the impairment of spontaneous alternation performance in the CO-exposed group. To determine whether this effect was mediated via kappa opioid receptors, we attempted to block the effect of dynorphin A using the kappa opioid receptor antagonist nor-binaltorphimine. Nor-binaltorphimine (5.44 nmol, i.c.v.) blocked the effect of dynorphin A (1-13) on delayed amnesia. Dynorphin A (1-13) did not affect the impairment of alternation induced by the blockade of NMDA-receptors by dizocilpine (MK-801), but significantly prevented the impairment induced by mecamylamine. These results suggest that dynorphin A (1-13) modulates the kappa receptor-mediated opioid neuronal system, and reverses the impairment of spontaneous alternation performance induced by CO exposure.

In normal subjects, if an acoustic startle stimulus is immediately preceded by a small brief change in background noise intensity, the magnitude of the subsequent startle response is decreased. This prepulse inhibition (PPI) of an acoustic startle response has been shown to be associated with sensorimotor gating. PPI is disrupted in schizophrenic patients and has been linked to attentional disorders characteristic of this disease. We tested the effects of (−)-nicotine, (0.19, 0.62, and 1.9 μmol/kg IP) (equivalent to 0.03, 0.1, and 0.3 mg/kg base) and the nicotinic cholinergic receptor (nAChR) channel blocker, mecamylamine (5.0 and 50 μmol/kg IP) (equivalent to 1.0 and 10.0 mg/kg) on PPI of the acoustic startle response in the rat. Nicotine increased the PPI at the lowest prepulse signal levels but not at the stronger levels. Mecamylamine was without effect at 5.0 μmol/kg, but the 50μmol/kg dose decreased the inhibition at both weak and strong prepulse (PP) levels. Mecamylamine (5.0 μmol/kg) pretreatment did not block the (−)-nicotine-induced increase in PPI. Lobeline (0.19, 0.62, 1.9, and 6.2 μmol/kg IP) (equivalent to 0.071, 0.23, 0.71, and 2.3 mg/kg) was without effect. These results are consistent with a mecamylamine-insensitive effect of nicotine to improve gating in normal rats. The nAChR subtype involved in producing nicotine's increase of PPI needs further investigation.

Interest has recently focused on tobacco and/or nicotine in relation to senile dementia of the Alzheimer type because the population of patients with this disease among tobacco smokers is significantly smaller than in nonsmokers. We investigated whether, in relation to the dopaminergic neuronal system, nicotine was effective in ameliorating the impairment of performance in passive avoidance tasks in rats induced by scopolamine, an inhibitor of muscarinic acetylcholine receptors. Scopolamine and nicotine were coadministered to rats 30 min before the acquisition trial. Some rats received scopolamine alone; they showed much shorter step-through latency (STL) than the control group in the retention test. Nicotine significantly prolonged the decreased STL induced by scopolamine. The effects of nicotine were inhibited by the preadministration of mecamylamine, SCH 23390, and (-)sulpiride, which are nicotinic acetylcholine, D1, and D2 receptor antagonists, respectively. These results suggest that nicotine, by activating the nicotinic acetylcholinergic and dopaminergic neuronal systems, ameliorates the impairment of performance in the passive avoidance task induced by a muscarinic acetylcholine receptor blocker.

We investigated the effect of the sigma selective PCP derivative PRE-084 on the impairment of learning induced in mice by the noncompetitive NMDA antagonist MK-801. Learning capacities were evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, the step-down passive avoidance and the elevated plus-maze test for long-term memory. At doses about 1 mg/kg IP, PRE-084 significantly attenuated MK-801 (0.2 mg/kg IP) induced impairment of learning. The dose-response curve was bell-shaped which is typical for cognition enhancers. The effect of PRE-084 was antagonized by BMY-14802 (10 mg/kg IP) and suppressed by a chronic treatment with haloperidol (4 mg/kg/day SC for 7 days). Furthermore, PRE-084 did not affect scopolamine (1 mg/kg SC) induced amnesia but significantly attenuated mecamylamine (10 mg/kg IP) induced amnesia. These results show that sigma sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes. Moreover, the PCP derivative PRE-084, acting selectively at sigma sites, reverses the amnesia induced by a drug acting at the PCP site.

Microinjections of nicotine into the fourth ventricle of rats were reported previously to produce a characteristic prostration syndrome; similar microinjections have been investigated for effects on locomotor activity. It was confirmed that nicotine (4 micrograms) administered into the fourth ventricle of rats produced prostration which was also manifested on a second challenge with the drug. Increasing doses of nicotine produced increasing magnitudes of prostration and dose-related decreases in locomotor activity. In rats pretreated with nicotine (0.4 mg/kg SC) for 10 days, no tolerance was seen to either the prostration response or the locomotor depression. Mecamylamine (1.0 mg/kg SC) completely prevented the prostration response produced by 4 micrograms of nicotine, but the locomotor depression was still evident. The locomotor changes following intraventricular administration of nicotine appeared to be different from the locomotor depression seen following systemic administration because the posture of the animals was different and the latter effects showed tolerance with repeated exposures to nicotine and were fully blocked by mecamylamine. These findings suggested that the prostration response and the locomotor depression were mediated by different mechanisms.

In a three-panel runway task, intrahippocampal injection of the nicotinic receptor antagonist, mecamylamine (10 and 18 micrograms/side), significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in a test of working memory. This increase in errors also occurred after rats were given IP mecamylamine (10 mg/kg). Mecamylamine did not affect the number of errors in a test of reference memory whether it was given at doses up to 18 micrograms/side intrahippocampally or up to 10 mg/kg IP. These results suggest that mechanisms mediated by hippocampal nicotinic receptors play a role in working memory but not in reference memory.

The present experiments were performed to investigate the potential role of central adrenergic neurons in regulating occurrence of yawning in rats. Intraperitoneal injection of tacrine (THA) or 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate HCl (NIK-247), cholinesterase inhibitors, induced yawning, which was markedly increased by pretreatment with the beta-adrenoceptor antagonist, pindolol. The yawning evoked by tacrine or NIK-247 given alone or in combination with pindolol was inhibited by pretreatment with scopolamine but not by mecamylamine or spiperone. Treatment with tacrine or NIK-247 increased acetylcholine content of the striatum, but this effect was not enhanced by pindolol, which per se did not affect basal acetylcholine content. Moreover, pretreatment with the central adrenaline synthesis inhibitors, (+-)-2,3-dichloro-alpha-methylbenzylamine HCl (LY-78335) and 2-cyclooctyl-2-hydroxyethylamine HCl (UK-1187A), increased tacrine-induced yawning. Subcutaneous injection of talipexole (B-HT 920), a dopamine D2 receptor agonist, evoked yawning, which was also increased by pindolol, LY-78335, and UK-1187A. These receptors antagonists and synthesis inhibitors per se did not cause yawning responses. The results suggest that the beta-adrenoceptor blockade and the inhibition of adrenaline synthesis facilitate the occurrence of yawning induced by cholinergic and dopaminergic agonists, and thus the central adrenergic neuronal systems may be implicated in the regulation of yawning responses.

The rewarding effects of nicotine alone and nicotine challenged with mecamylamine, a nicotine receptor blocker, or naloxone were determined using a rate-independent discrete-trial threshold measure of brain-stimulation reward in rats. If nicotine acts as other drugs of abuse, it would be expected to lower the reward threshold, that is, increase an animal's sensitivity to rewarding brain stimulation, and naloxone would be expected to block this effect, as it does other stimulants in this paradigm. Nicotine was found to significantly lower the reward threshold and mecamylamine blocked this effect. However, although naloxone increased the variability of nicotine's effect on the reward threshold, it failed to dose dependently block nicotine's threshold-lowering effect.

The nicotinic antagonist mecamylamine (2.5 and 5 mg/kg/IP) depressed both active (shuttle-box) and passive (step-through) avoidance learning in mice of the DBA/2 strain. The nootropic drug oxiracetam (50 and 100 mg/kg/IP) improved acquisition in the multitrial active avoidance test, but had no effect on one-trial passive avoidance learning. When the two drugs were combined, oxiracetam did not counteract mecamylamine-induced impairment of passive avoidance learning, even if it maintained a facilitating action on shuttle-box avoidance acquisition in mice receiving the nicotinic receptor blocker. Prevention of mecamylamine-induced shuttle-box avoidance depression by oxiracetam indicates that central nicotinic mechanisms are probably involved in the improving effects exerted by nootropic drugs on learning.

This study investigated the effect of para-chlorophenylalanine (pCPA), on nicotine-induced analgesia. pCPA reduces physiological levels of 5-HT, a neurotransmitter that has been linked to pain. The effects of naloxone HCl and mecamylamine HCl on this analgesia were also assessed. Subjects were 24 albino rats. Each group of eight rats was injected subcutaneously (SC) with nicotine sulphate, followed by an intraperitoneal (IP) injection of one of the potential antagonists. Behavioral analgesia was assessed using the tail-flick test. Data analysis revealed that pCPA did not affect nicotine-induced analgesia. Consistent with past research, naloxone also had no effect, and mecamylamine effectively eliminated this analgesia. The results are interpreted in light of current knowledge of this behavioral analgesia and pain perception, in general.

Rats were used to investigate the effect of nicotine on mouse-killing and foot shock-induced attack on conspecifics. It was found that intraperitoneal injections of nicotine (100–1000 μg/kg) suppressed mouse-killing in a dose dependent manner. The suppression of mouse-killing by nicotine was not blocked by hexamethonium (30 mg/kg), a peripheral nicotinic receptor blocking agent. Mecamylamine (30 mg/kg), a nicotinec blocking agent with central effects, did reduce the inhibition of attack produced by nicotine. Both intraperitoneal and intraventricular injections of nicotine suppressed shock-induced attack on conspecifics. Shock-elicited flinch, vocalization, and escape were not influenced by nicotine injections. These findings give further support to the view the muscarinic and nicotinic compounds produce antagonistic effects on certain types of attack behavior.