The role of nicotinic receptor alpha 7 subunits in nicotine discrimination

The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. The experiments described here use mice lacking the alpha7 subunit of nicotinic receptors to investigate the role of alpha7-containing receptors in nicotine discrimination. Wild-type and alpha7-knockout mice were trained in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement. Mutant mice exhibited baseline rates of lever-pressing as low as 52.2% of rates in wild-type controls (n=21-24). Mutant and wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) at a similar rate (n=10-12) and reached similar final levels of accuracy (71.9 +/- 4.4% and 90.8 +/- 3.1% after 60 training sessions for 0.4 and 0.8 mg/kg training doses, respectively, in mutant mice, as compared with 75.0 +/- 6.5% and 87.6 +/- 4.8% for wild types). The genotypes exhibited similar steep dose-response curves for nicotine discrimination. In both genotypes, dose-response curves for mice trained with 0.8 mg/kg of nicotine were displaced three- to four-fold to the right as compared with those for the mice trained with the smaller dose. The predominant effect of nicotine on the overall rate of responding was a reduction at the largest doses tested and there was no difference between the genotypes. The results suggest that nicotinic receptors containing the alpha7 subunit do not contribute to the discriminative stimulus or response-rate-depressant effects of nicotine, although they may regulate baseline rates of operant responding.     

Threshold doses for nicotine discrimination in smokers and non-smokers

RATIONALE: Tobacco use during initial experimentation often involves modest nicotine exposure, escalating to larger doses and more frequent exposure with the onset of tobacco dependence. Threshold doses for nicotine discrimination therefore may differ between naive and experienced tobacco users. OBJECTIVES: We determined the lowest (threshold) dose of nasal spray nicotine that smokers and non-smokers could reliably discriminate from placebo spray. METHODS: Male and female smokers (n=18) and non-smokers (n=17) were initially trained to discriminate 20 microg/kg from placebo before proceeding to threshold determination sessions, which involved discrimination of progressively lower doses below 20 microg/kg ("descending order" subgroup) or higher doses above 1 microg/kg ("ascending order" subgroup). Threshold was determined by the lowest dose reliably discriminated from placebo (correct on > or =80% of testing trials) and by failure to discriminate the next lowest dose. RESULTS: Threshold doses for nicotine discrimination were low and not different between smokers and non-smokers (median thresholds of 3 versus 2 microg/kg and approximate blood levels of 2.6 versus 1.6 ng/ml, respectively). Thresholds were similar between descending and ascending order subgroups. Several subjective responses differentiated threshold dose from the dose just below threshold, particularly in non-smokers. CONCLUSIONS: Threshold doses for nasal spray nicotine discrimination in humans are low, well below the typical nicotine delivery of most cigarette brands, and may not change after long-term smoking exposure.     

Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats

Rationale Antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists.Objective The present study aimed to evaluate the discriminative-stimulus effects of the NMDA receptor channel blockers (+)MK-801, dextromethorphan, and memantine in rats trained to discriminate nicotine from its vehicle.Methods Adult male Wistar rats were trained to discriminate 0.6 mg/kg nicotine from saline under a two-lever, fixed-ratio 10 schedule of food reinforcement. During test sessions, injections of (+)MK-801 (0.03–0.3 mg/kg, i.p.), dextromethorphan (30 mg/kg, s.c.), or memantine (1–10 mg/kg, i.p.) were co-administered with s.c. nicotine (0.075–0.6 mg/kg; interaction tests) or saline (generalization tests). Additional interaction and generalization tests were conducted with the selective nicotinic receptor antagonists mecamylamine (0.1–3 mg/kg, s.c.) and MRZ 2/621 (0.3–10 mg/kg, i.p.), and the mGlu5 receptor antagonist MPEP (3–10 mg/kg, i.p.).Results In generalization tests, none of the compounds produced any appreciable levels of substitution for nicotine. The nicotine discriminative-stimulus control was dose dependently attenuated by mecamylamine (ED₅₀=0.67 mg/kg) and MRZ 2/621 (ED₅₀=9.7 mg/kg). Both agents produced a marked downward shift in the nicotine dose–response curve. Memantine and MPEP slightly attenuated nicotine discriminative-stimulus effects, while (+)MK-801 and dextromethorphan did not affect the nicotine-appropriate responding.Conclusions NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.     

Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine

Rationale: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed β2-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine’s acute subjective and reinforcing effects. Objective: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Methods: Adult male rats were trained to disciminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Results: Erysodine (0.3–10 mg/kg) and mecamylamine (0.1–1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32–32 mg/kg) and mecamylamine (0.32–3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for α4β2 nACHRs and its selectivity relative to α7 and α1β1γδ receptors, the present data support a critical role of β2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine. Received: 20 March 1999 / Final version: 22 September 1999     

Influence of training dose on nicotine discrimination in humans

Non-human research indicates that drug discrimination results may depend largely on the specific training conditions, including initial training dose. It has recently been shown that humans can discriminate among different doses of nicotine delivered by nasal spray. In this study, we examined the influence of training dose on subsequent behavioral discrimination of a range of nicotine doses. Male (n=17) and female smokers (n=16) were randomly assigned to low (10 µg/kg) versus high (30 µg/kg) nicotine training dose groups and trained reliably to discriminate this dose from placebo (0) on day 1 (80% correct identification). All but six subjects (four in low, two in high) learned this discrimination and continued on to day 2, in which both groups received 0, 5, 10, 20, and 30 µg/kg in ascending order (30 min between dosings) and were tested for generalization with their training dose using quantal and quantitative behavioral discrimination tasks. Subjective responses via traditional self-report measures were also assessed. Nicotine-appropriate responding on day 2 was significantly greater in low- versus high-dose groups, especially at 5 µg/kg. However, this difference due to training dose was seen more in women than in men. Discrimination behavior was associated with subjective effects of head rush in males, and with head rush and decline in urge to smoke in females. These results show that discriminative stimulus effects of nicotine are not fixed properties of the drug, but can be influenced by training conditions, and that effects associated with this discrimination may differ between men and women.     

Evaluation of the role of nicotinic acetylcholine receptor subtypes and cannabinoid system in the discriminative stimulus effects of nicotine in rats

Male Wistar rats were trained to discriminate (−)-nicotine (0.4 mg/kg) from saline under a two-lever, fixed-ratio 10 schedule of water reinforcement. During test sessions the following drugs were coadministered with saline (substitution studies) or nicotine (0.025–0.4 mg/kg; combination studies): the ₄β₂ nicotinic acetylcholine receptor subtype antagonist dihydro-β-erythroidine (DHβE), the non-selective nicotinic acetylcholine receptor subtype antagonist mecamylamine, the ₇ nicotinic acetylcholine receptor subtype antagonist methyllycaconitine (MLA), the ₄β₂ nicotinic acetylcholine receptor subtype agonist 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-IA), the cannabinoid CB₁ receptor antagonist/partial agonist rimonabant, the cannabinoid CB₂ receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methybenzyl)pyrazole-3-carboxamide (SR 144528), the cannabinoid CB_1/2 receptor agonists (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP 55,940) or R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)-methanone mesylate (WIN 55,212-2), the endogenous cannabinoid agonist and non-competitive ₇ nicotinic acetylcholine receptor subtype antagonist anandamide, the anandamide uptake and fatty acid amide hydrolase inhibitor N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM-404), the fatty acid amide hydrolase inhibitor cyclohexylcarbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB 597), AM-404 + anandamide or URB 597 + anandamide. 5-IA (0.01 mg/kg) fully substituted for nicotine, while other drugs were inactive. In combination studies, DHβE and mecamylamine dose-dependently attenuated the discriminative stimulus effects of nicotine and the full substitution of 5-IA, while MLA, rimonabant, SR 144528, CP 55,940, WIN 55,212-2, and URB 597 did not alter the nicotine cue. Pretreatment with AM-404 + anandamide or URB 597 + anandamide weakly enhanced nicotine-lever responding. Our pharmacological analyses demonstrates that the expression of nicotine discrimination is under the control of nicotinic acetylcholine receptor subtypes composed of ₄β₂ (but not of ₇) subunits. Furthermore, we excluded the involvement of either cannabinoid CB₁ and CB₂ receptors or increases in the endocannabinoid tone in the nicotine discrimination.     

Effects of training dose and two- versus three-choice testing procedure on nicotine discrimination responding in humans

Rationale: Discrimination of a drug’s interoceptive stimulus effects often depends substantially on training and testing conditions. Objectives: We examined changes in nicotine discrimination behavior in humans as a function of lowering the training dose and of varying the discrimination testing procedure. Methods: Smokers and never-smokers (n=10 each) were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) and tested on generalization of discrimination responding across a range of doses from 0 to 20 μg/kg. Each subsequently learned to reliably discriminate progressively smaller doses of nicotine from placebo until his or her threshold dose for discrimination was identified (mean=2.7 μg/kg). A repeat testing of generalization responding across 0–20 μg/kg was then conducted, using placebo and the subject’s threshold dose as training doses. Generalization testing involved both two-choice and three-choice (novel response option) quantitative procedures. Results: A significant shift to the left was seen in nicotine-appropriate responding in the two-choice procedure when the nicotine training dose was lowered (i.e. from the first to the second test of generalization). In the three-choice procedure, however, there was no such leftward shift. Instead, in never-smokers, a flattening of nicotine-appropriate responding occurred with a lowering of the training dose, while novel-appropriate responding significantly increased. The subjective effects of ”head rush” and, in never-smokers only, ”jittery” also showed a shift to the left in their relationship with nicotine generalization dose when the training dose was lowered. Conclusions: These results confirm the importance of training and testing conditions on discrimination behavior and subjective drug responses within subjects and demonstrate the utility of the novel-response, three-choice procedure for assessing qualitatively different stimulus effects of novel drug doses. Received: 21 December 1998 / Final version: 11 March 1999     

Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist

Tobacco addiction requires activation by nicotine of a variety of central nicotinic acetylcholine receptors (nAChRs). In animals, both nAChR antagonists and immunization against nicotine can reduce nAChR activation by nicotine and block a variety of addiction-relevant behaviors. However, clinical use of nAChR antagonists for smoking cessation is limited by dose-related side effects, and immunization does not reliably produce sufficient antibody levels in smokers to enhance smoking cessation rates. Combining these approaches may be one way of addressing the limitations of each while enhancing overall efficacy. This study examined the individual and combined effects of passive immunization with the monoclonal nicotine-specific antibody Nic311 and the nicotinic receptor antagonist mecamylamine (MEC) on nicotine's discriminative stimulus effects. Rats were trained to discriminate 0.4 mg/kg of nicotine from saline using a two-lever operant discrimination procedure. Antagonism of nicotine discrimination by Nic311 (160 mg/kg i.v.) and ascending doses of MEC (0.03, 0.1, 0.3, and 1.0 mg/kg s.c.) was assessed across four consecutive daily 2-min extinction test sessions using a 2 × 2 design. Nic311 alone produced a 24-48% reduction in % nicotine-lever responding (%NLR) across all four test sessions. MEC produced a dose-dependent decrease in %NLR, with no effect at the two lowest doses and 80-93% attenuation at the two highest doses. Nic311 combined with MEC significantly suppressed %NLR at every MEC dose (85-92% reduction across all four test sessions). Very low doses of MEC that were ineffective alone completely blocked nicotine discrimination when combined with Nic311. These data demonstrate that nicotine-specific antibodies and MEC can work synergistically to suppress the subjective effects of nicotine and suggest that low doses of MEC may significantly enhance the efficacy of immunotherapy.     

Evidence that nicotine can acutely desensitize central nicotinic acetylcholinergic receptors

Current concepts concerning nicotine's CNS mechanism(s) of action suggest that this drug produces its effects via an interaction at nicotinic-cholinergic receptors (nAChRs) sensitive to acetylcholine. In vitro research further suggests that, following its initial agonist effect, this cholinergic drug may also induce a rapid desensitization of the nAChR similar to that of acetylcholine, resulting in termination of its pharmacological effect. Research described in this paper provides evidence of this secondary desensitization process in vivo by demonstrating nicotine's ability to induce acute tolerance in a Discriminative Stimulus (DS) paradigm. The ability of nicotine (400 µg/kg, SC) to elicit DS control of behavior in a two-lever operant procedure was significantly reduced via a challenge dose (800 µg/kg, SC) of nicotine administered 15–180 min before the training dose. Twenty-three of 52 rats demonstrated this phenomenon. The time to develop acute tolerance varied, providing additional evidence that these effects may be contingent upon individual rat variability. In addition, physostigmine was also observed to induce a similar desensitization in a random population of desensitizing rats. Lastly, there were no differences between desensitizers and non-desensitizers in relation to the ability of mecamylamine (1000 µg/kg, SC) to antagonize the DS, while in both populations of rats scopolamine (100 µg/kg, SC) failed to antagonize the DS.Supported by The German Research Council on Smoking and Health     

The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion

The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. These experiments use mice lacking the beta2 subunit of nicotinic receptors to investigate its role in nicotine discrimination and conditioned taste aversion (CTA). Wild-type and mutant mice were trained either in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement, or in a counterbalanced two-flavour CTA procedure. Rates of lever-pressing of wild-type and mutant mice did not differ. Wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) rapidly and exhibited steep dose-response curves. Mutant mice failed to acquire these nicotine discriminations and exhibited flat dose-response curves. Both wild-type and mutant mice acquired discrimination of nicotine (1.6 mg/kg) although discrimination performance was weak in the mutants. Nicotine initially reduced response rates in wild-type and mutant mice, and tolerance developed to this effect in each genotype. Both genotypes acquired discrimination of morphine (3 mg/kg) with similar degrees of accuracy, and dose-response curves for morphine discrimination in the two genotypes were indistinguishable. Nicotine produced dose-related CTA in both genotypes, but the magnitude of the effect was less in the mutants than in the wild-type controls. It is concluded that nicotinic receptors containing the beta2 subunit play a major role in the discriminative stimulus and taste aversion effects of nicotine that may reflect psychological aspects of tobacco dependence. Such receptors appear to have a less crucial role in the response-rate, reducing effects of nicotine and in nicotine tolerance.     

Control of behavior by intravenous nicotine injections in human subjects

Results are summarized from a series of studies in which procedures used to assess the reinforcing and aversive properties of drugs in animals, were extended to a human paradigm. Human volunteers were tested using drug self-administration and avoidance procedures, whereby pressing a lever under a fixed-ratio schedule resulted either in the IV injection of nicotine or in the avoidance of programmed IV injections of nicotine, respectively. Nicotine was found to maintain responding that produced its injection under certain conditions, and to maintain responding that avoided its injection under other conditions. Nicotine produced the same constellation of stimulus properties whether functioning as a positively or negatively reinforcing event. These functional properties of nicotine may be determined by schedule of access to nicotine, dose of nicotine, and past history of the subject.     

Effects of isoarecolone, a nicotinic receptor agonist in rodent models of nicotine dependence

Rationale The nicotinic receptor agonist, isoarecolone, has ‘nicotine-like’ subjective properties as detected by rats in a discrimination paradigm. However, isoarecolone lacks the intra-accumbens dopamine-releasing effects, a feature akin to most abused substances. In the five-choice serial reaction time task, isoarecolone can enhance attention and thus may be developed as a cognitive enhancer.Objective The present experiments assess the dependence profile of isoarecolone in rodent models of nicotine dependence.Method and results Tests for cross-substitution in which isoarecolone is substituted for nicotine [0.3 mg/kg/infusion (inf)] self-administration suggest isoarecolone to have nominal reinforcing properties (0.3 or 1.0 mg/kg/inf); intake of isoarecolone declined over three test sessions in which responding was no different from saline extinction, and behaviour was reinstated by re-presenting nicotine. In a model of nicotine-seeking behaviour, rats having been extinguished by removal of nicotine (0.03 mg/kg/inf) and associated cues, the presentation of priming doses of nicotine (0.1–0.4 mg/kg s.c.) with the cues robustly reinstated responding of nicotine-seeking behaviour. Tests with priming doses of isoarecolone (1–20 mg/kg s.c.) shown previously to generalise to nicotine in discrimination tests produced significant levels of reinstatement but the responses were significantly less compared to nicotine-induced reinstatement.Conclusion Overall, these results suggest that isoarecolone with its unique profile of behavioural activity should be further examined for treating chronic diseases that are characterised by attentional dysfunction.     

Discrimination and self-administration of nicotine by inbred strains of mice

These studies aim to characterize the discriminative stimulus effects of nicotine in two inbred strains of mice that differ in many pharmacological responses, and to investigate the feasibility of IV self-administration studies with nicotine in one of the strains. For discrimination studies, three groups of C57BL/6 and one group of DBA/2 mice were trained in a two-lever operant conditioning paradigm with a tandem VI-30″ FR-10 schedule of food reinforcement. After 40 training sessions, accuracy reached 57.5, 77.5 and 90.0% in C57BL/6 mice trained with (–)-nicotine (SC) in doses of 0.4, 0.8 and 1.6 mg/kg, respectively (n = 8). DBA/2 mice trained with 0.8 mg/kg nicotine attained similar (73.3%) accuracy (n = 9). Results from extinction tests showed that all groups of mice yielded orderly dose-response curves for nicotine (0.03–1.6 mg/kg), but stimulus control remained notably weaker for the mice trained with 0.4 mg/kg nicotine than for any other group. Overall rates of responding in the undrugged state were lower for DBA/2 than for C57BL/6 mice; DBA/2 mice were also slightly less sensitive than C57BL/6 mice to the response rate-reducing effect of nicotine. The nicotine antagonist mecamylamine (1.5 mg/kg SC) blocked the discriminative stimulus effect of the training dose of nicotine in all groups. The results of the IV self-administration study suggest that nicotine (0.1 mg/kg) can serve as a positive reinforcer in drug–naive C57BL/6J mice (n = 13). Behaviour maintained by 0.1 mg/kg nicotine injections was significantly greater than behaviour maintained by vehicle injections, and it was maintained under an intermittent schedule of reinforcement (FR4). The methods described provide possible approaches for genetic analyses of strain differences in sensitivity to the discriminative and reinforcing stimulus properties of nicotine. Received: 11 April 1998/Final version: 28 June 1998     

Nicotine discrimination in male and female smokers

Discriminative stimulus effects of nicotine were evaluated in humans using formal behavioral drug discrimination procedures. Male and female smokers (n=9 each) were trained on day 1 to reliably discriminate 0 versus 12 µg/kg nicotine administered by measured-dose nasal spray. All subjects were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 2, 4, 8, and 12 µg/kg (approximately 0–0.8 mg for typical subject) was then examined on day 2. Nicotine-appropriate responding was linearly related to dose, and subjects were able to distinguish the smallest dose (2 µg/kg) from placebo. Although there were no differences between males and females in behavioral discrimination, subjective effects were correlated with nicotine discrimination in females but not in males. These findings indicate that humans are able to discriminate among low doses of nicotine per se, that males and females may differ in the stimuli used to discriminate nicotine, and that drug discrimination procedures may be more sensitive than traditional subjective effects measures in distinguishing among low doses of nicotine.This research was supported by grant DA-08578 from the National Institute on Drug Abuse. J.E.G. was supported in part by predoctoral training grant HL-07560 from the National Heart, Lung, and Blood Institute.     

Role of training dose in discrimination of nicotine and related compounds by rats

Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. There was partial generalization to the nicotine analogues anabasine and cytisine in rats trained to discriminate either 0.2 or 0.4 mg/kg nicotine from saline. However, generalization was complete in rats trained to discriminate 0.1 mg/kg nicotine and, in a novel procedure, any one of three doses of nicotine (0.1, 0.2, or 0.4 mg/kg). There was no generalization to the muscarinic-cholinergic agonist oxotremorine (0.0025–0.04 mg/kg). Additional experiments were carried to further characterize the response of rats trained with nicotine (0.1 mg/kg). These animals failed to generalize to compounds from a range of pharmacological classes (i.e., apomorphine, cocaine, chlordiazepoxide, picrotoxin, and quipazine), but there was partial generalization to amphetamine. Mecamylamine (0.5 mg/kg) but not hexamethonium (5.0 mg/kg) blocked the discrimination of nicotine and the generalization to cytisine. Anabasine (1.0–4.0 mg/kg) did not block the response to nicotine. The results support the view that the nicotine cue is mediated mainly through central cholinergic mechanisms. The dose of nicotine used for training has a very significant influence on the characteristics of the cue and 0.1 mg/kg of nicotine may be more suitable than 0.4 mg/kg as a training dose in future work.     

Inbred mouse strains vary in oral self-selection of nicotine

Inbred mouse strains differ in sensitivity to a first dose of nicotine and in the development of tolerance to nicotine. The experiments reported here used six inbred mouse strains (A, BUB, C3H, C57BL/6, DBA/2, ST/b) that differ in sensitivity to an acute challenge dose of nicotine to determine whether differences in oral self-selection of nicotine exist. Animals were presented with solutions containing nicotine or vehicle (water or 0.2% saccharin) and their daily intake of the two fluids was measured for 4 days starting with a 10 µg/ml nicotine solution. This was followed by sequential 4-day testing with 20, 35, 50, 65, 80, 100, 125, 160, and 200 µg/ml nicotine solutions. The strains differed dramatically in their self-selection of nicotine and in maximal daily dose (mg/kg); the rank order of the strains was C57BL/6>DBA>BUB>AC3HST/b for both the tap water and 0.2% saccharin choice experiments. Correlations between nicotine consumption and sensitivity to nicotine, as measured by a battery of behavioral and physiological responses, were also calculated. Strain differences in nicotine intake were highly correlated with senstivity to nicotine-induced seizures. As senstivity to nicotine-in-duced seizures increases, oral self-selection of nicotine decreases. This finding may suggest that this toxic action of nicotine serves to limit intake.     

Nicotine analog inhibition of nicotine self-administration in rats

RATIONALE: Partial agonists and antagonists of addictive drugs have been useful in the treatment of dependence. OBJECTIVE: The purpose of this study is to determine whether nicotine analogs with partial agonist or antagonist properties at alpha4beta2 nicotinic acetylcholine receptors (nAChRs) inhibit self-administration of nicotine in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained to self-administer nicotine (unit dose 0.017 mg/kg) intravenously contingent upon the completion of five lever presses. Once stable responding was established, rats were administered test agents, either as a subcutaneous injection before the daily session or co-infused with nicotine. RESULTS: The number of nicotine injections taken per session was reduced to approximately 50% of baseline after either pre-treatment with the broad spectrum nicotinic receptor antagonist, mecamylamine, or by substituting saline for nicotine (extinction). 4'-Trans-methyl-nicotine, a strong partial agonist, inhibited nicotine self-administration and substituted for nicotine to support self-administration. Partial agonists, prepared by substitution at the 1'-N-position with either ethyl or cyclopropylmethyl moieties, potently inhibited self-administration. Antagonists formed by 5'-methyl substitution also inhibited self-administration, with the 5'-trans-methyl enantiomer about ten times more potent than the 5'-cis-methyl enantiomer. In contrast, antagonists formed by aryl substitution at the 5 position of the pyridyl ring of nicotine did not inhibit self-administration. Intravenous co-infusions had similar effects to the pre-injections. In most instances, doses of the analogs that reduced nicotine self-administration had no effect on food intake when measured using a similar FR5 protocol. CONCLUSIONS: Nicotine analogs with alpha4beta2 nAChR partial agonist and antagonist efficacies can inhibit self-administration and may be considered as prototypical smoking-cessation agents.     

Quitting cigarette smoking produces minimal loss of chronic tolerance to nicotine

RATIONALE: Long-term exposure to nicotine is associated with chronic tolerance to its acute effects, adaptation that may lead to tobacco dependence. The time course for loss of this tolerance after cessation of exposure is not known in humans but could relate to risk of smoking relapse. OBJECTIVES: We examined changes in responses to nicotine as a function of days, weeks, or years of smoking cessation in formerly dependent smokers to determine at what point sensitivity to nicotine is reinstated (i.e., loss of tolerance). METHODS: Acute subjective, cardiovascular, performance, and reinforcing (self-administration) effects of nicotine nasal spray (0-20 microg/kg) were assessed prospectively in men and women smokers before and then day-by-day (study 1) or 3 weeks (study 2) after stopping smoking. A smoking resumption period (study 1) and a group of non-quitting smokers (study 2) were included to control for the passage of time. These effects were also compared cross-sectionally between those who had quit for 1-4 years and those who had for 6-19 years in a separate sample of long-time ex-smokers to determine whether lengthier abstinence causes greater loss of tolerance (study 3). RESULTS: No clear loss of tolerance was observed on any measure in studies 1 or 2, suggesting that chronic tolerance is fully maintained for at least weeks after quitting smoking. Sensitivity to nicotine's effects was also not different as a function of years quit in study 3. CONCLUSIONS: Chronic tolerance to nicotine is not lost within several weeks of quitting smoking and may not change even after years of abstinence from tobacco use.     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.     

Comparative pharmacology of nicotine and ABT-418, a new nicotinic agonist

ABT-418, a novel cholinergic ligand, was reported to possess potent cognitive-enhancing and anxiolytic properties in animal models with reduced side effects (Decker et al. 1994; Garvey et al. 1994) suggesting selectivity of effects. In this study, the binding properties of ABT-418 to [³H]-nicotine sites were evaluated and its pharmacology investigated in different tests in laboratory animals. ABT-418 binds with high affinity to³H-nicotine binding sites in the brain with, however, a K_i (6 nM) less than that of nicotine (four-fold). In addition, it acts as a full nicotinic agonist in producing hypomotility, hypothermia and antinociception in mice and engendering nicotine-like responding in rat drug discrimination. The potency of ABT-418 is three to four times less than that of nicotine in all of the animal models, except for hypothermia. In addition, its behavioral effects are completely blocked by mecamylamine, a non-competitive nicotinic antagonist. Although activation of nicotinic receptors by ABT-418 produced several behavioral and pharmacological effects, our results do not suggest high selectivity of different effects as reported by Decker et al. (1994) and Garvey et al. (1994). However, it should be noted that we did not perform some of these tests that produced effects at low doses (Decker et al. 1994) and additional pharmacological studies are needed to establish its selectivity at multiple nicotinic receptors.