Mecamylamine blocks the development of tolerance to nicotine in rats: implications for the mechanisms of tolerance

 Chronic injections of nicotine in rats produce upregulation of nicotinic cholinergic receptors. It has been proposed that this upregulation is a reflection of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicotinic receptors, does not prevent upregulation produced by nicotine injections. This suggests that receptor activation is not a prerequisite for nicotine-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of tolerance to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicotine did block the development of tolerance to nicotine-induced antinociception (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.66 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no evidence that after six pairings of mecamylamine with nicotine, the cues associated with mecamylamine delivery took on conditioned antagonistic properties. These findings suggest that, unlike the receptor upregulation that results from either continuous or repeated nicotine administration, the tolerance following a short series of intermittent nicotine injections is dependent on receptor activation. Received: 20 May 1998 / Final version: 23 July 1998     

Involvement of Cholinergic and Opioid Receptor Mechanisms in Nicotine-Induced Antinociception

Abstract: In this work we have studied the influences of nicotinic agents on the antinociception of morphine in formalin test. Nicotine (0.001-0.1 mg/kg) induced antinociception in mice in a dose-dependent manner in the early phase of formalin test, and also potentiated the morphine effect. The nicotinic receptor antagonist, mecamylamine (0.5 mg/kg), but not hexamethonium decreased the antinociception induced by nicotine (0.1 mg/kg) in both phases. The muscarinic receptor antagonist atropine (5 and 10 mg/kg) also decreased the response of nicotine. Mecamylamine, hexamethonium or atropine did not alter morphine antinociceptive response, while naloxone decreased responses induced by nicotine or morphine. The antagonists by themselves did not elicit any response in formalin test, however, high doses of mecamylamine tend to increase pain response. It is concluded that central cholinergic and opioid receptor mechanisms may be involved in nicotine-induced antinociception.     

Naloxone precipitates nicotine abstinence syndrome and attenuates nicotine-induced antinociception in mice

The present study focused on the evaluation of a role of opioid system in nicotine-induced antinociception and physical dependence in mice. The results indicate that nicotine (3 mg/kg) produced a significant antinociception in the hot plate test. Additionally, the opioid receptor antagonist naloxone (0.5 and 1 mg/kg), dose-dependently attenuated this effect. Our second experimental protocol consisted in intermittent administration of nicotine (2.5 mg/kg, s.c.) four times daily for 7 days. In order to precipitate nicotine abstinence, mice were given one injection of mecamylamine (3 mg/kg) or naloxone (1 mg/kg) one hour after the last nicotine injection on the test day (day 8) in the morning. Interestingly, our findings revealed that both drugs precipitated somatic withdrawal signs in mice, with a slight difference in their influences on the intensity of several signs. These data support the hypothesis that similar opioid-cholinergic interactions are involved in nicotine-induced antinociception and nicotine withdrawal syndrome.     

Caffeine, nicotine and mecamylamine share stimulus properties in the preexposure conditioned taste aversion procedure

RATIONALE: The present study examined whether nicotine and caffeine, two of the most widely used psychoactive drugs, share stimulus properties in the preexposure conditioned taste aversion (CTA) procedure. OBJECTIVES: To determine whether nicotine would attenuate the formation of a caffeine-induced CTA and further assess whether pretreatment with mecamylamine, a nicotinic receptor antagonist, would reverse nicotine's attenuating effect of a caffeine-induced CTA. METHODS: Male Wistar rats were preexposed with one of three doses of nicotine (0.6, 1.2 and 2.0 mg/kg, s.c.) for three consecutive days, then 24 h following the final preexposure injection were conditioned with caffeine (20 mg/kg and 30 mg/kg, i.p.) in a standard two-bottle test. There were four conditioning trials and four drug-free test days. In a follow-up study, rats were pretreated with mecamylamine (2 mg/kg, i.p.) prior to preexposure injections with nicotine (0.6 mg/kg, i.p.), then subsequently conditioned with caffeine (20 mg/kg, i.p.) as described above. RESULTS: The lowest nicotine dose (0.6 mg/kg) attenuated the caffeine induced CTAs (20 mg/kg and 30 mg/kg) but the higher nicotine doses showed no such attenuating effect. In addition, mecamylamine reversed the nicotine-induced attenuation of the caffeine-induced CTA and also directly attenuated it. CONCLUSIONS: These results suggested that caffeine, nicotine and mecamylamine share overlapping stimulus properties and that the nature of this relationship may involve action at the nicotinic-cholinergic receptor.     

Once weekly administration of nicotine produces long-lasting locomotor sensitization in rats via a nicotinic receptor-mediated mechanism

RATIONALE: Chronic nicotine administration results in dynamic changes in neuronal function, expressed as behavioral sensitization in animals and addiction in smokers. OBJECTIVES: The present study was undertaken to determine whether once-weekly nicotine injection produces sensitization to the locomotor-activating properties of nicotine as a result of nicotinic receptor activation. METHODS: Once weekly for 6 weeks, rats were administered (s.c.) two saline injections or saline and nicotine (0.35 mg/kg), and locomotor activity was monitored. Rats remained in the home cage for 21 days, and subsequently were injected with the appropriate treatment to determine whether sensitization persisted. Rats were also injected with saline or mecamylamine (1.2 mg/kg) followed by saline or nicotine once weekly for 6 weeks to determine the effect of mecamylamine and whether it inhibited nicotine-induced hyperactivity. A separate group was injected with saline and nicotine once weekly for 4 weeks; on week 5, mecamylamine and nicotine were administered to determine whether mecamylamine inhibited the expression of sensitization. Separate groups were injected with mecamylamine and nicotine once weekly for 5 weeks or 6 weeks; on week 6 or week 9, respectively, saline and nicotine were injected to determine whether mecamylamine inhibited the initiation of sensitization. RESULTS: Sensitization to the locomotor-activating properties of nicotine developed following four nicotine injections across a 28-day period and persisted following 21 days of no drug treatment. Mecamylamine did not alter activity but attenuated both the initiation and expression of sensitization. CONCLUSIONS: Nicotinic receptor activation following once-weekly nicotine administration produces long-lasting behavioral sensitization, suggesting that even infrequent nicotine exposure initiates neuroadaptive processes associated with nicotine addiction.     

Different methods of assessing nicotine-induced antinociception may engage different neural mechanisms

Two methods were used to assess nicotine-in-duced antinociception: tail withdrawal from a hot water bath and hind paw withdrawal from a hotplate. Nicotine doses which produced 75–80% maximum response were 0.75 mg/kg (free base) for tail withdrawal and 0.35 mg/kg for paw withdrawal. The peripheral blocker chlorisondamine (0.1 mg/kg, SC) and the central antagonist, mecamylamine (1 mg/kg, SC) were each effective in blocking nicotine-induced increases in tail withdrawal latencies, suggesting that this effect of nicotine depends on either the action of nicotine at peripheral receptors or the functional integrity of those receptors. In contrast, nicotine-induced increases in paw withdrawal latencies were blocked by mecamylamine but not by chlorisondamine, even at other agonist/antagonist dose combinations. The results indicate that these two effects of nicotine involve at least partially separate pathways and may reflect a different mix of the antinociceptive and motor depressing effects of nicotine.     

中枢N受体对M受体介导体温降低作用的调节

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

Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats

Nicotine addiction is a chronic disorder characterized by a relatively high rate of relapse even after long period of abstinence. In the present study, we used the conditioned place preference (CPP) paradigm to investigate the establishment, extinction, reinstatement, and cross-reinstatement of nicotine-induced place conditioning in rats. First, we revealed that nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.175 mg/kg, base, intraperitoneally (i.p.)). Once established, nicotine CPP was extinguished by repeated testing. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.175 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Furthermore, given the important role of alpha4beta2 (a4b2) nicotinic receptor subtype in the acquisition and maintenance of nicotine dependence, we evaluated and compared the efficacy of varenicline, a partial a4b2 nicotinic receptor agonist (0.5, 1, and 2 mg/kg, subcutaneously (s.c.)), and mecamylamine (0.5, 1, and 2 mg/kg, s.c.), a non-selective nicotinic receptor antagonist, in blocking nicotine-induced CPP as well as reinstatement of nicotine CPP provoked by nicotine and morphine. It was shown that both nicotinic receptor ligands attenuated the acquisition and expression of nicotine CPP as well as the expression of reinstatement of nicotine CPP provoked by both drugs. Our results indicate similar cholinergic mechanisms, probably through the a4b2 receptors involved in the rewarding effects of nicotine and morphine in rats and may suggest that nicotinic receptors could be a potential target for developing pharmacotherapeutic strategies to treat and prevent nicotine and/or opioid addiction and relapse.     

Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats

Lobeline inhibits [3H]nicotine binding to rat brain membranes and nicotine-induced [3H]dopamine release from superfused rat striatal slices, indicating that lobeline acts as a nicotinic receptor antagonist. To determine whether lobeline also inhibits the effects of nicotine in vivo, the present study assessed the effect of lobeline pretreatment on nicotine-induced hyperactivity and sensitization. For 12 consecutive days, rats were injected subcutaneously with lobeline (3 mg/kg) or saline, followed 10 min later by nicotine (0.3 mg/kg) or saline injection, and activity was monitored. To determine if lobeline inhibits induction of sensitization to nicotine, 1 or 28 days later, rats were pretreated with saline followed by nicotine or saline. Lobeline attenuated nicotine-induced hyperactivity when both drugs were administered repeatedly. Although an initial injection of lobeline produced hypoactivity, tolerance to this effect developed. Importantly, tolerance did not develop to the lobeline-induced attenuation of nicotine hyperactivity. Lobeline attenuated the induction of sensitization to nicotine 1 day, but not 28 days, after the cessation of lobeline treatment. These results demonstrate that systemic administration of lobeline attenuates the locomotor-activating effects of repeated nicotine injection and the sensitization to nicotine, consistent with lobeline inhibition of nicotinic receptors and/or neurotransmitter transporters.     

Effects of mecamylamine on nicotine-induced conditioned hyperactivity and sensitization in differentially reared rats

Rats reared in an enriched condition (EC) display less sensitization to nicotine than rats reared in an impoverished condition (IC). However, it is unknown what effect differential rearing has on nicotine-induced conditioned hyperactivity. The present study determined whether differential rearing affects nicotine-induced conditioned hyperactivity. This study also examined the effects of mecamylamine on conditioned hyperactivity and sensitization. EC, IC, and social condition (SC) rats were reared from 21 to 51 days of age before receiving repeated nicotine injections (.4 mg/kg) prior to 1-h locomotor sessions. Following the conditioned-hyperactivity test, rats received additional training sessions followed by a drug-free rest period before the sensitization test. Mecamylamine (1.0 mg/kg) was administered prior to the conditioned-hyperactivity test and sensitization test. Nicotine treatment resulted in sensitization and conditioned hyperactivity in all differential rearing groups. EC rats displayed less locomotor activity in response to nicotine than both IC and SC rats. Pretreatment with mecamylamine blocked the expression of conditioned hyperactivity only in EC and SC rats and attenuated sensitization in all three rearing groups. These findings suggest that environmental enrichment may alter nicotinic acetylcholine receptors during development and may be a protective factor in the initiation and relapse of smoking behavior.     

Antinociceptive effect of chronic nicotine and nociceptive effect of its withdrawal measured by hot-plate and tail-flick in rats

Nicotine (6 mg/kg/day) was administered subcutaneously via Alzet osmotic pumps to rats for 28 days. Nociception was measured by the hot-plate and tail-flick methods. A significant antinociceptive effect was demonstrated during the first week of the treatment; after that tolerance developed, lasting for the remaining period of nicotine treatment. This effect was more pronounced in the habituated, rather than in the naive, rats. Rats subjected to nicotine withdrawal tended to exhibit the nociceptive effect for 10 days with an overall P value on the border of significance. This chronic nicotine-induced antinociception and nicotine withdrawal-induced nociception was detectable only by hot-plate but not the tail-flick technique.     

Nicotine-induced taste aversion: characterization and preexposure effects in rats

Rats were trained to drink their 24 hr water intake during a single daily 30 min period. After stabilization, rats were presented with 0.1% (w/v) of sodium saccharin for 30 min. Immediately after removal of the saccharin solution, the animals were injected with saline, mecamylamine hydrochloride or hexamethonium hydrobromide; thirty minutes later, saline or nicotine, 0.05, 0.16, or 0.50 mg/kg were administered. Twenty-four hr later, rats were allowed access to both water and saccharin. Nicotine caused a dose-related decrease in the proportion of fluid consumed as saccharin solution during the 30 min testing situation. Neither mecamylamine nor hexamethonium alone decreased saccharin preference; however, 3 mg/kg of mecamylamine blocked the decrease of saccharin preference induced by nicotine. Preexposure of drug-naive rats to 0.5 mg/kg of nicotine for 2 or 4 days abolished the nicotine-induced taste aversions to saccharin when tested one day, or one week, after conditioning.     

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.     

Epibatidine induces long-term potentiation (LTP) via activation of alpha4beta2 nicotinic acetylcholine receptors (nAChRs) in vivo in the intact mouse dentate gyrus: both alpha7 and alpha4beta2 nAChRs essential to nicotinic LTP

Activation of nicotinic acetylcholine receptors (nAChRs) induces nocotinic long-term potentiation (LTPn) in vivo in the mouse dentate gyrus. We have found that alpha4beta2 nAChRs activated by epibatidine induce LTPn, the full size of which requires the involvement of alpha4beta2 and alpha7 nAChRs, in the intact mouse dentate gyrus using extracellular recording techniques. Intraperitoneal application of epibatidine, a potent alpha4beta2 nAChR agonist, at 0.3 - 3.0 mug/kg induced a long-lasting increase similar to LTPn induced by choline, a selective alpha7 nAChR agonist, and at 10 mug/kg caused a transient increase followed by a depression. The LTPn induced by epibatidine at 3.0 mug/kg or choline at 30 mg/kg was significantly suppressed by pre-treatment but not post-treatment with mecamylamine (0.5 mg/kg, i.p.), a non-selective neuronal nicotinic antagonist. Post-application of nicotine at 3.0 mg/kg enhanced epibatidine-induced LTPn to the same level of nicotine-induced LTPn, but post-application of epibatidine had no effect on nicotine-induced LTPn. Epibatidine-induced LTPn was additionally increased by post-application of choline, and vice versa, reaching the same level of nicotine-induced LTPn. The present study revealed that epibatidine induced the LTPn via alpha4beta2 nAChRs and that both alpha7 and alpha4beta2 nAChRs were essential for full-sized LTPn, suggesting that both nAChRs play an important role in synaptic plasticity.     

Depressive characteristics of FSL rats: involvement of central nicotinic receptors

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.     

Tolerance to the convulsions induced by daily nicotine treatment in rats.

Development of tolerance to the nicotine-induced convulsions in rats was examined. Acute intraperitoneal (i.p.) administration of nicotine (2.5, 3.75 and 5 mg/kg) produced convulsions in a dose-dependent manner. Mecamylamine (1 mg/kg, i.p.) antagonized the convulsions, but hexamethonium (5 mg/kg, i.p.) did not modify them. Daily nicotine administration (2.5, 3.75 and 5 mg/kg, i.p.) once a day for 6 days developed tolerance to the convulsions induced by nicotine. After the daily administrations of nicotine for 6 days, the effects of a challenge administration of nicotine (2 mg/kg) on the nicotine-induced convulsions were tested on the 7th-day. Further tolerances were also developed by the 7th-day challenge administration. After the 7th-day test, nicotine levels of the brain and blood 15 min after the challenge injection were measured. With nicotine (5 mg/kg once a day)-treatment, nicotine levels of all the brain regions were increased. In contrast, a similar challenge injection had no effect on blood nicotine level. These results indicate that the development of tolerance to the nicotine-induced convulsions is produced relatively earlier and day by day by daily administrations to rats, which is closely related with the increase in brain nicotine level.     

Anticholinergic sensitivity following chronic nicotine administration as measured by radial-arm maze performance in rats

Chronic nicotine administration in rats has been previously found to improve choice accuracy performance of rats in the radial-arm maze. A nicotine-induced choice accuracy improvement was also seen in the current study. Rats were trained to asymptotic levels of choice accuracy performance on a working memory paradigm in an 8-arm radial maze. During and after 3 weeks of chronic nicotine treatment, rats were tested for sensitivity to acute doses of the nicotinic and muscarinic receptor antagonists, mecamylamine and scopolamine. During the first week of administration, nicotine-treated rats were supersensitive to the sedation caused by mecamylamine. This suggests that nicotine may not have been acting as a simple nicotinic agonist, since in this case, the opposite effect, an attenuated effect of mecamylamine in the nicotine-treated group, would have been expected. Three to 4 weeks after withdrawal from chronic nicotine administration, the treated rats were more sensitive to the choice accuracy deficits caused by the muscarinic blocker scopolamine (0.16 mg/kg) and the nicotinic blocker mecamylamine (10 mg/kg). This supersensitivity may have been due to a lasting change caused by chronic nicotine in the cholinergic bases of memory function.     

Blockade of nicotine-induced locomotor sensitization by a novel neurotensin analog in rats

Neurotensin is a tridecapeptide with anatomic and functional relationships to dopaminergic neurons. Previously we showed that one of our brain-penetrating neurotensin analogs, NT69L (N-met-L-Arg, L-Lys, L-Pro, L-neo-Trp, L-tert-Leu, L-Leu), blocks cocaine- and D-amphetamine-induced hyperactivity in rats. We have now performed a similar study in rats sensitized to nicotine over 15 days of administration. Male Sprague-Dawley rats were randomly assigned to receive daily injections for 15 days with one of the following combinations: saline/nicotine (0.35 mg/kg), NT69L (1 mg/kg)/nicotine, saline/saline, or NT69L/saline with a 30-min period between injections. On day 15 each group was given saline/nicotine or NT69L/nicotine and tested in an activity chamber. One-time administration of NT69L attenuated nicotine-induced activity with an ED(50) of 1.6 microg/kg. Rats injected with nicotine over the 15 days had a significant increase in locomotor activity, consistent with nicotine-induced locomotor sensitization. A single injection of NT69L on day 15 prior to nicotine markedly decreased nicotine-induced hyperactivity. Although daily injections of NT69L lessened its effect, statistically significant reductions in hyperactivity to nicotine persisted throughout the study. There was no significant difference in activity between rats injected with NT69L/saline and saline/saline. Thus, the activity reduction was not due to sedation. Acute and chronic nicotine injection caused an increase in cytisine binding in prefrontal cortex. NT69L significantly reduced the increase caused by acute but not chronic injection of nicotine. Nicotine injection resulted in an increase in dopamine levels in the striatum and dopamine and norepinephrine levels in the prefrontal cortex. NT69L lowered the norepinephrine and dopamine levels in the prefrontal cortex but did not affect striatal dopamine. The present study is the first report, to our knowledge, of a possible role for neurotensin in the development of nicotine dependence, and suggests that neurotensin analogs such as NT69L may be explored as treatment for nicotine and other psychostimulant abuse.     

Nicotine tolerance: an analysis of the time course of its development and loss in the rat

The time course of the development and loss of tolerance to nicotine was measured in female rats that were injected subcutaneously (SC), twice daily with 1.6 mg/kg nicotine. Tolerance to nicotine-induced decreases in locomotor activity and body temperature were observed. Tolerance to the effects of nicotine on both of these measures developed rapidly, with maximal changes occurring within 2–4 days after initiation of treatment. The binding ofl-[³H]-nicotine was measured in six brain regions. Chronic nicotine treatment resulted in increases in binding in most brain regions. The increase in binding correlated significantly with the development of tolerance. Rats that had been injected chronically with nicotine did not lose their tolerance throughout a 7-day post-treatment test period. Control levels of binding were regained in all of the brain regions except cortex by 7 days after nicotine treatment was stopped. These findings indicate that changes in receptor binding may relate to the development of tolerance but the retention of tolerance is clearly not related to the number of brain nicotinic receptors, unless nicotine-induced decreases in body temperature and locomotor activity are controlled by cortical [³H]-nicotine binding sites.     

The possible cross-tolerance between morphine- and nicotine-induced hypothermia in mice

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.