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NEUROPHARMACOLOGY

Calcium-Acting Drugs Modulate Expression and Development of Chronic Tolerance to Nicotine-Induced Antinociception in Mice

Department of Pharmacology and Toxicology, Medical Campus, Virginia Commonwealth University, Richmond, Virginia

Received July 11, 2005; accepted August 11, 2005.

	Abstract

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Initial studies in our laboratory suggested that tolerance to nicotine is thought to involve neuronal adaptation not only at the level of the drug-receptor interaction but at postreceptor events such as calcium-dependent second messengers. The present study was undertaken to investigate the hypothesis that L-type calcium channels and calcium-dependent calmodulin protein kinase II are involved in the development and expression of nicotine tolerance. To that end, the effects of modulation of L-type calcium channels (through the use of inhibitors or activators) as well as calcium-dependent calmodulin protein kinase II inactivation were studied in a mouse model of tolerance where mice were infused with nicotine in minipumps (24 mg/kg/day) for 14 days. In addition, the activity of calcium-dependent calmodulin protein kinase II in the lumbar spinal cord region obtained from nicotine-tolerant mice was measured. Our data showed that chronic administration of L-type calcium channel antagonists nimodipine (1 and 5 mg/kg) and verapamil (10 mg/kg) prevented the development of tolerance to nicotine-induced antinociception. In contrast, chronic exposure of BAYK8644 [(±)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester], a calcium channel activator, enhanced nicotine's tolerance. Moreover, a significant increase in both dependent and independent calcium-dependent calmodulin protein kinase II activity was seen in the spinal cord in nicotine-tolerant mice. Finally, spinal administration of 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine (KN-62), a calcium-dependent calmodulin protein kinase II antagonist, reduced the expression of tolerance to nicotine-induced antinociception in mice. In conclusion, our data indicate that calcium-dependent mechanisms such as L-type calcium channels and calcium-dependent calmodulin protein kinase II activation are involved in the expression and development of nicotine tolerance.

Initial studies in our laboratory showed that chronic exposure of nicotine in mice altered the behavioral sensitivity to calcium-modulating drugs such as BAYK8644 in mice, which suggests that functional changes in L-type calcium channels occur after chronic treatment with nicotine (Damaj, 1997). Pretreatment with L-type calcium channel antagonists reduced the expression of locomotor sensitization to nicotine (Biala and Weglinska, 2004) and mecamylamine-precipitated nicotine withdrawal in mice (Biala and Weglinska, 2005). Taken together, these data suggest a role for neuronal L-type calcium channels in the different aspects of nicotine dependence. Other calcium-mediated events such as calcium-dependent calmodulin protein kinase II may also be involved. We have recently reported that nicotine increases calcium-dependent calmodulin protein kinase II activity in the spinal cord membrane after acute exposure of nicotine in mice (Damaj, 2000). Collectively, these studies suggest the possible involvement of calcium-dependent mechanisms in the development tolerance to nicotine.

The present study was undertaken to investigate the hypothesis that L-type calcium channels and calcium-dependent calmodulin protein kinase II are involved in the development and expression of nicotine tolerance. To that end, the effects of modulation of L-type calcium channels (through the use of inhibitors or activators) were studied in a mouse model of nicotine tolerance. The L-type calcium channel antagonists nimodipine and verapamil were tested to prevent the development of tolerance to nicotine-induced antinociception when coadministered with nicotine chronically. The chronic coexposure of BAYK8644, an L-type calcium channel activator, was tested to enhance nicotine's chronic tolerance. Finally, the activity of calcium-dependent calmodulin protein kinase II in the lumbar spinal cord region obtained from nicotine-tolerant mice was measured to investigate whether the activation of this kinase could be changed during the development of tolerance to chronic nicotine. In addition, acute spinal administration of KN-62, a calcium-dependent calmodulin protein kinase II antagonist, was investigated for its ability to prevent expression of tolerance to nicotine-induced antinociception in mice.

	Materials and Methods

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Animals. Male Institute for Cancer Research mice (20-25 g, 10 weeks old) obtained from Harlan (Indianapolis, IN) were used throughout the study. Animals were housed in an Association for Assessment and Accreditation of Laboratory Animal Care-approved facility in groups of three and had free access to food and water. The study was approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University.

Drugs. (-)-Nicotine was obtained from Aldrich Chemical Co. (Milwaukee, WI) and converted to the ditartrate salt as described by Aceto et al. (1979). Other drugs were obtained as follows. Nimodipine, verapamil, and BAYK8644 were obtained from Sigma/RBI (Natick, MA). KN-62 and KN-04 were purchased from Calbiochem (San Diego, CA). Nicotine ditartrate and verapamil were dissolved in physiological saline (0.9% sodium chloride). KN-62 and KN-04 were prepared in dimethyl sulfoxide (25%). Nimodipine and BAYK8644 were prepared in Emulphor/ethanol/saline (1:1:18). Emulphor (EL620) was obtained from Rhône-Poulenc (Crambury, NJ). Solutions of BAYK8644 were refrigerated in foil-lined containers. All doses are expressed as the free base of the drug.

Intrathecal Injections. Intrathecal injections were performed free-hand between the L₅ and L₆ lumbar space in unanesthetized male mice according to the method of Hylden and Wilcox (1980). The injection was performed using a 30-gauge needle attached to a glass microsyringe. The injection volume in all cases was 5 µl. The accurate placement of the needle was evidenced by a quick flick of the mouse's tail.

Tolerance Induction. Mice were implanted with Alzet osmotic minipumps (model 2002 for 14 days; Alza, Palo Alto, CA) filled with either (-)-nicotine or sterile physiological saline solutions. The concentration of nicotine solution in minipumps was adjusted according to animal weight, resulting in 24 mg/kg/day for 14 days. The minipumps were surgically implanted s.c. under sterile conditions with pentobarbital anesthesia (50 mg/kg i.p.). An incision was made in the back of the animals, and a pump was inserted. The wound was closed with wound clips, and the animal was allowed to recover before being returned to its home cage. At day 15, animals were injected with various doses of nicotine. To test the effects of L-type calcium channel modulators on nicotine tolerance development, mice implanted with minipumps received vehicle (1:1:18) or nimodipine (1 and 5 mg/kg i.p.), verapamil (10 mg/kg i.p.), and BAYK8644 (0.1 and 0.5 mg/kg i.p.) twice a day for 14 days. For the studies with calcium-dependent calmodulin protein kinase II inhibitors, minipumps were removed at day 15, and 12 h later, animals were injected with different i.t. doses of calcium-dependent calmodulin protein kinase II inhibitors. Mice were challenged 12 h later with a dose of 2.5 mg/kg nicotine.

Tail-Flick Test. Antinociception was assessed by the tail-flick method of D'Amour and Smith (1941). Briefly, mice were lightly restrained while a radiant heat source was shone onto the upper portion of the tail. Latency to remove the tail from the heat source was recorded for each animal. A control response (2-4 s) was determined for each mouse before treatment, and test latency was determined after drug administration. To minimize tissue damage, a maximum latency of 10 s was imposed. Antinociceptive response was calculated as percent maximum possible effect (%MPE), where %MPE = [(test - control)/(10 - control)] x 100. The mice were tested 5 min after injection of nicotine.

Calcium-Dependent Calmodulin Protein Kinase II Phosphorylation Assay. Calcium-dependent calmodulin protein kinase II activity was measured using a modified assay kit (Upstate Biotechnology, Lake Placid, NY). Mice implanted with either saline or nicotine minipumps (24 mg/kg/day) for 14 days were used to measure calcium-dependent calmodulin protein kinase II activation. At day 15, mice were killed by cervical dislocation, and the spinal column was isolated and divided in thoracic, cervical, and lumbar regions. The lumbar segment of spinal cord was removed from the spinal column by gentle flushing with ice-cold, isotonic saline. Lumbar spinal cord tissues were homogenized using a microcentrifuge pestle in a calcium-free buffer that contained 20 mM HEPES, pH 7.4, 2.6 mM EGTA, 80 mM -glycerolphosphate, 20 mM magnesium acetate, 0.1 µM okadaic acid, 0.1 µM calyculin, 0.1 mM dithiothreitol, 50 mM sodium fluoride, 1 mM sodium orthovanadate, and 0.01 mg/ml CLAPS (0.1 mg/ml each of pepstatin A, chymostatin, aprotinin, leupeptin, and trypsin-chymotrypsin inhibitor). Homogenates were normalized for protein concentration. Samples were centrifuged to separate the membrane and the cytosol containing-kinase. Supernatant was retained (cytosolic fraction). The pellet was resuspended in homogenization buffer plus 1% NP40 (IGEPAL) and allowed to incubate on ice for 1 h. The tubes were spun again, and supernatant was retained (membrane fraction). Standard phosphorylation reaction solutions contained 15 µg of extract protein, 100 µM CaM kinase II-specific substrate peptide (Autocamtide-2), 0.25 µM protein kinase inhibitors (0.25 µM each of protein kinase A and protein kinase C inhibitor peptides), 75 mM magnesium acetate, 500 µM ATP, 20 mM HEPES, 25 mM -glycerolphosphate, 1 mM sodium orthovanadate, 1 mM dithiothreitol, 1 µCi of [³²P]ATP, 5 µM CaCl₂, and 5 µg of calmodulin for the measurement of calcium-dependent activity. In aliquots used for calcium-independent activity, 5 mM EGTA was added, and CaCl₂ and calmodulin were omitted. Standard reactions were performed in triplicate in a shaking water bath at 30°C for 10 min along with background controls lacking substrate. Activity was quantified by spotting one-half the reaction on phosphocellulose paper squares. Squares were washed in 0.75% phosphoric acid (five times) followed by a brief acetone rinse before analysis by scintillation counting. Calcium-dependent calmodulin protein kinase II activity was expressed in picomoles phosphate per minute per microgram and determined using the following calculations: [(count-specific binding - background) x (correcting factor)]/[(specific radioactivity) x time (10 min)].

Statistical Analysis. Statistical analysis of all analgesic studies was performed using either Student's t test or analysis of variance with Tukey's test post hoc test when appropriate. All differences were considered significant at p < 0.05. ED₅₀ values with 95% confidence limit (CL) for behavioral data were calculated by unweighted least-squares linear regression as described by Tallarida and Murray (1987). Tests for parallelism were calculated according to the method of Tallarida and Murray (1987). If confidence limit values did not overlap, then the shift in the dose-response curve was considered significant.

	Results

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Tolerance to Nicotine-Induced Antinociception: Effects of L-Type Calcium Channel Antagonists. Tolerance to nicotine's effect in the tail-flick test was seen in mice infused with nicotine for 14 days (24 mg/kg/day). Dose-response curves for the nicotine-induced antinociception in chronic nicotine and saline-treated animals are presented in Fig. 1. Animals that received chronic nicotine were less sensitive to the acute nicotine challenge in the tail-flick test, and nicotine's dose-response curve was shifted to the right compared with the vehicle-treated group. The ED₅₀ values (and 95% CL) for saline-treated and nicotine-treated animals were 1.05 (0.5-2.0) and 4.1 (3.4-5.3) mg/kg, respectively (Table 1). In nicotine-infused mice that were chronically treated with nimodipine, tolerance to nicotine was prevented in a dose-dependent manner (Fig. 1). The ED₅₀ value for nicotine-treated animals was reduced from 4.1 to 2.5 and 1.7 mg/kg after chronic treatment with nimodipine at 1 and 5 mg/kg, respectively. A similar prevention of nicotine tolerance was observed with verapamil, a nondihydropyridine L-type calcium channel antagonist (Fig. 2). The ED₅₀ value for nicotine-treated animals was reduced from 4.1 to 1.6 mg/kg after chronic treatment with verapamil at 10 mg/kg.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Blockade of the development of tolerance to nicotine-induced antinociception by nimodipine, an L-type calcium channel blocker, after chronic administration. Dose-response curves of nicotine antinociceptive effects in mice that were infused with nicotine (24 mg/kg for 14 days) and chronically injected with either vehicle or different doses of nimodipine. Mice were tested on day 15 using the tail-flick test. Each point represents the mean %MPE ± S.E. for 8 to 10 mice.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Blockade of the development of tolerance to nicotine-induced antinociception by verapamil, a nondihydropyridine L-type calcium channel blocker, after chronic administration. Dose-response curves of nicotine antinociceptive effects in mice that were infused with nicotine (24 mg/kg for 14 days) and chronically injected with either vehicle or verapamil (10 mg/kg i.p.). Mice were tested on day 15 using the tail-flick test. Each point represents the mean %MPE ± S.E. for 8 to 10 mice.

Tolerance to Nicotine-Induced Antinociception: Effects of BAYK8644, an L-Type Calcium Channel Activator. In contrast to L-type calcium channel antagonists that prevented the development of tolerance, BAYK8644 increased the degree of tolerance after chronic administration in nicotine-tolerant mice. Dose-response curves for the nicotine-induced antinociception in chronic administration of BAYK8644 are presented in Fig. 3. In nicotine-infused mice that are chronically treated with BAYK8644, tolerance to nicotine was enhanced in a dose-dependent manner. The ED₅₀ value for nicotine-treated animals was increased from 4.3 to 5.3 and 7.7 mg/kg after chronic treatment with BAYK8644 at 0.1 and 0.5 mg/kg, respectively (Table 1). The increase in the degree of tolerance was only significant at the higher dose of BAYK8644 (0.5 mg/kg) since the confidence limits between the nicotine-treated mice and the BAYK8644-treated animals did not overlap.

View larger version (19K): [in this window] [in a new window]   Fig. 3. Enhancement of the development of tolerance to nicotine-induced antinociception by BAYK8644, an L-type calcium channel activator, after chronic administration. Dose-response curves of nicotine antinociceptive effects in mice that were infused with nicotine (24 mg/kg for 14 days) and chronically injected with either vehicle or different doses of BAYK8644. Mice were tested on day 15 using the tail-flick test. Each point represents the mean %MPE ± S.E. for 8 to 10 mice.

View larger version (22K): [in this window] [in a new window]   Fig. 4. Increase in spinal calcium-dependent calmodulin protein kinase II activity (membrane) after chronic administration of nicotine (24 mg/kg/day for 14 days) or vehicle. Each point represents the mean activity ± S.E. of six mice (*, p < 0.05 versus saline).

View larger version (16K): [in this window] [in a new window]   Fig. 5. Effects of KN-62, a calcium-dependent calmodulin protein kinase II inhibitor, on the expression of tolerance to nicotine-induced antinociception. Mice were infused with nicotine (24 mg/kg for 14 days) and injected i.t. with vehicle, KN-62, or KN-04 (inactive analog) at day 15. Mice were tested 12 h later in the tail-flick after a challenge dose of nicotine (2.5 mg/kg). Each point represents the mean %MPE ± S.E. for 8 to 10 mice. *, p < 0.05 versus Sal/Sal; , p < 0.05 versus Sal Nic (2.5).

	Discussion

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The present study examined the role of L-type calcium channels and calcium-mediated second messenger systems in the development and expression of chronic tolerance to nicotine. We have shown that chronic pretreatment with L-type calcium channel antagonists nimodipine and verapamil, which decrease the intracellular calcium level, prevented the development of tolerance to nicotine's antinociceptive effects. In contrast, chronic exposure to L-type calcium channel activator BAYK8644, which increases the intracellular calcium level, enhanced the degree of tolerance to nicotine. In addition, the present study demonstrates that inhibition of spinal calcium-dependent calmodulin protein kinase II by i.t. injection of its specific inhibitor KN-62 strongly attenuated the expression of nicotine tolerance in response to chronic administration of the drug. Furthermore, spinal calcium-dependent calmodulin protein kinase II activity was significantly increased in nicotine-tolerant mice as compared with those in saline-infused mice. Taken together, these findings indicate a substantial role of activated calcium-dependent calmodulin protein kinase II in the development of tolerance to nicotine-induced antinociception. This contention can be strongly supported by the fact that KN-62 inhibited expression to tolerance induced by nicotine. The present study extends our previous findings in which we reported that L-type calcium channels and calcium-dependent calmodulin protein kinase II inhibitors reduced nicotine antinociception after acute administration (Damaj et al., 1995; Damaj, 2000). Furthermore, pretreatment with L-type calcium channel antagonists was reported to reduce the expression of locomotor sensitization to nicotine (Biala, 2004) and mecamylamine-precipitated nicotine withdrawal in mice (Biala and Weglinska, 2005). The involvement of L-type calcium channels in nicotine's dependence and tolerance is similar to that reported with other drugs of abuse such as alcohol, morphine, and sedatives (Little, 1991; Littleton and Brennan, 1993).

The mechanisms by which L-type calcium channels and calcium-dependent calmodulin protein kinase II affect nicotine tolerance remain unclear. Although there are few reports on the contributions of calcium-dependent signaling pathways in nicotine tolerance, recent studies have focused on the modulation of CREB following chronic treatment with nicotine, often with dissimilar results. Brunzell et al. (2003) reported that phosphorylated CREB decreased in the nucleus accumbens in mice following chronic oral consumption of nicotine, whereas Pluzarev and Pandey (2004) showed that, in rats, nicotine withdrawal (but not chronic treatment with nicotine itself) significantly reduced the levels of CREB in rat cortex and amygdala. More recently, chronic exposure to nicotine was reported to increase Ca²⁺ entry into cortical neurons through L-type calcium channels and levels of [³H]verapamil binding sites after chronic nicotine exposure (Katsura et al., 2002). Moreover, chronic injection of nicotine in mice increased [³H]diltiazem binding sites and expression of ₁ and ₂/₁ subunits in the cerebral cortex. Consistent with these findings, L-type calcium channels are found on the terminals of dopaminergic afferents in the basal forebrain, and activation of nAChRs is known to increase calcium conductance of membranes of central neurons resulting in dopamine release (Marshall et al., 1997). In addition, studies with neuronal preparations showed that significant amounts of Ca²⁺ enter the neuron following activation of nAChRs, causing a rise in [Ca²⁺]_i concentration (Mulle et al., 1992; Barrantes et al., 1995). This effect is sufficient to activate calcium-dependent protein kinases like calcium-dependent calmodulin protein kinase II (Damaj, 2000). Furthermore, nAChR-mediated depolarization can activate voltage-operated Ca²⁺ channels, which augments the primary Ca²⁺ signals generated by nicotinic receptors (Dajas-Bailador and Wonnacott, 2004). We therefore can hypothesize that after chronic exposure to nicotine a greater calcium influx, through voltage-operated Ca²⁺ channels and possibly N-methyl-D-aspartate receptors, leads to an activation of calcium-dependent kinases such as calcium-dependent calmodulin protein kinase II during tolerance. Also, given that chronic nicotine exposure causes an increase in the number of L-type calcium channels in different brain regions, antagonists could prevent the induction of synaptic neuroadaptation processes and the expression of nicotine tolerance syndrome in mice. It is almost certain that enhanced calcium-dependent calmodulin protein kinase II activity can phosphorylate and modulate functions of other proteins that could play a role in modulating nicotine tolerance. For example, one can speculate that sustained activation of calcium-dependent calmodulin protein kinase II modulates the onset and recovery of nAChR desensitization. Desensitization of nAChRs after chronic nicotine leads to a decrease in direct calcium influx through these receptors. This decrease will prompt adaptive changes and functional up-regulation in other calcium-regulating mechanisms such as voltage-gated calcium channels and the intracellular calcium stores and, in turn, triggers an increase in intracellular calcium and sustained calcium-dependent calmodulin protein kinase II activation. Taken together, our data strongly support the idea that the long-lasting activation of calcium-dependent calmodulin protein kinase II in the spinal cord may lead to the synaptic plasticity associated with the development and/or maintenance of nicotine tolerance.

In conclusion, our data indicate that calcium-dependent mechanisms such as L-type calcium channels and calcium-dependent calmodulin protein kinase II activation are involved in the expression and development of nicotine tolerance. Since L-type calcium channel antagonists can reduce tolerance to nicotine, they offer potential new strategies for treating nicotine dependence.

	Acknowledgements

 
I greatly appreciate the technical assistance of Tie Han and Travis Roberts.

	Footnotes

 
This work was supported by National Institute on Drug Abuse Grants DA-12610 and DA-05274.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.105.092460.

ABBREVIATIONS: nAChR, acetylcholine nicotinic receptor; BAYK8644, (±)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester; KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine; KN-04, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine derivative; %MPE, percent maximum possible effect; CL, confidence limit; CREB, cAMP response element-binding protein.

Address correspondence to: Dr. M. Imad Damaj, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613. E-mail: mdamaj{at}hsc.vcu.edu

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This Article Abstract Full Text (PDF) All Versions of this Article: jpet.105.092460v1 315/2/959    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Damaj, M. I. Search for Related Content PubMed PubMed Citation Articles by Damaj, M. I.