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Iptakalim Preferentially Decreases Nicotine-induced Hyperlocomotion in Phencyclidine-sensitized Rats: A Potential Dual Action against Nicotine Addiction and Psychosis.

Volf N, Hu G, Li M - Clin Psychopharmacol Neurosci (2012)

Bottom Line: Acute nicotine treatment attenuated the PCP-induced hyperlocomotion and PCP-induced disruption of PPI, whereas repeated nicotine treatment potentiated these effects.Importantly, pretreatment with iptakalim (10-20 mg/kg, intraperitoneally) reduced nicotine-induced hyperlocomotion in a dose-dependent fashion.This reduction effect was highly selective: it was more effective in rats previously sensitized to the combination of PCP and nicotine, but less effective in rats sensitized to saline, nicotine alone or PCP alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, USA.

ABSTRACT

Objective: Iptakalim is a putative ATP-sensitive potassium (K(ATP)) channel opener. It is also a novel nicotinic acetylcholine receptor (nAChR) blocker and can antagonize nicotine-induced increase in dopamine release in the nucleus accumbens. Our recent work also shows that iptakalim exhibits a clozapine-like atypical antipsychotic profile, indicating that iptakalim may possess a dual action against nicotine addiction and schizophrenia.

Methods: The present study examined the potential therapeutic effects of iptakalim on nicotine use in schizophrenia. We created an animal model of comorbidity of nicotine addiction and schizophrenia by injecting male Sprague-Dawley rats with nicotine (0.40 mg/kg, subcutaneously[sc]) or saline, in combination with phencyclidine (PCP, 3.0 mg/kg, sc) or saline daily for 14 consecutive days.

Results: During the PCP/nicotine sensitization phase, PCP and nicotine independently increased motor activity over time. PCP also disrupted prepulse inhibition (PPI) of acoustic startle response. Acute nicotine treatment attenuated the PCP-induced hyperlocomotion and PCP-induced disruption of PPI, whereas repeated nicotine treatment potentiated these effects. Importantly, pretreatment with iptakalim (10-20 mg/kg, intraperitoneally) reduced nicotine-induced hyperlocomotion in a dose-dependent fashion. This reduction effect was highly selective: it was more effective in rats previously sensitized to the combination of PCP and nicotine, but less effective in rats sensitized to saline, nicotine alone or PCP alone.

Conclusion: To the extent that the combined nicotine and PCP sensitization mimics comorbid nicotine addiction in schizophrenia, the preferential inhibitory effect of iptakalim on nicotine-induced hyperlocomotion suggests that iptakalim may be a potential useful drug for the treatment nicotine abuse in schizophrenia.

No MeSH data available.


Related in: MedlinePlus

Effects of iptakalim treatment (IPT; 0, 10 and 20 mg/kg, ip) on the expression of nicotine locomotor sensitization in the familiar environment during the nicotine challenge test in the four groups of rats (n=16/group) that were previously treated with SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC. Each rat was injected with nicotine 0.2 mg/kg, sc and locomotor activity was recorded for 90 minutes. Locomotor activity (mean+SEM) was separated into (A) first 30 minutes, (B) second 30 minutes, and (C) last 30 minutes. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its SAL control; ‡p<0.05 significantly different between one of the SAL+NIC groups and one of the PCP+NIC groups. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean.
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Figure 4: Effects of iptakalim treatment (IPT; 0, 10 and 20 mg/kg, ip) on the expression of nicotine locomotor sensitization in the familiar environment during the nicotine challenge test in the four groups of rats (n=16/group) that were previously treated with SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC. Each rat was injected with nicotine 0.2 mg/kg, sc and locomotor activity was recorded for 90 minutes. Locomotor activity (mean+SEM) was separated into (A) first 30 minutes, (B) second 30 minutes, and (C) last 30 minutes. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its SAL control; ‡p<0.05 significantly different between one of the SAL+NIC groups and one of the PCP+NIC groups. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean.

Mentions: To examine the time course of the iptakalim effect on nicotine-induced increase in motor activity, we analyzed motor activity in each of 30 minutes blocks (a total of 3 blocks) separately (Fig. 4). During the first 30 minutes of testing, three-way ANOVA revealed a main effect of nicotine, F(1, 52)=39.138, p<0.001, suggesting that rats previously treated with nicotine expressed a nicotine behavioral sensitization. There was also a significant PCP×nicotine interaction, F(1, 52)=12.716, p=0.001, indicating that the nicotine sensitization effect was modulated by PCP sensitization. One-way ANOVA followed by post hoc LSD tests revealed that rats previously sensitized with SAL+NIC had significantly higher motor activity in comparison to the SAL+SAL/SAL group, p<0.012. Iptakalim at both doses (10 and 20 mg/kg) did not decrease the nicotine-induced hyperlocomotion or the expression of nicotine sensitization. Rats previously sensitized with PCP+NIC also showed significantly higher motor activity than the SAL+SAL/SAL rats when tested under saline and iptakalim 20 mg/kg conditions, p<0.006, but not under iptakalim 10 mg/kg condition, p=0.207, suggesting that iptakalim 10 mg/kg reduced the nicotine-induced hyperlocomotion to some extent. This observation was also supported by the finding that the PCP+NIC/IPT 10 group exhibited significantly lower motor activity than the PCP+NIC/SAL group, p=0.045. In addition, rats previously sensitized with PCP+SAL showed significantly higher motor activity than the SAL+SAL/SAL rats, p=0.009 when they were tested under saline condition, indicating a possible cross-sensitization from PCP to nicotine. This significant effect disappeared under iptakalim 10 and 20 mg/kg conditions, p>0.236. The overall pattern of the results indicates that iptakalim was more effective in decreasing nicotine-induced increase in motor activity in PCP sensitized rats than saline rats.


Iptakalim Preferentially Decreases Nicotine-induced Hyperlocomotion in Phencyclidine-sensitized Rats: A Potential Dual Action against Nicotine Addiction and Psychosis.

Volf N, Hu G, Li M - Clin Psychopharmacol Neurosci (2012)

Effects of iptakalim treatment (IPT; 0, 10 and 20 mg/kg, ip) on the expression of nicotine locomotor sensitization in the familiar environment during the nicotine challenge test in the four groups of rats (n=16/group) that were previously treated with SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC. Each rat was injected with nicotine 0.2 mg/kg, sc and locomotor activity was recorded for 90 minutes. Locomotor activity (mean+SEM) was separated into (A) first 30 minutes, (B) second 30 minutes, and (C) last 30 minutes. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its SAL control; ‡p<0.05 significantly different between one of the SAL+NIC groups and one of the PCP+NIC groups. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569163&req=5

Figure 4: Effects of iptakalim treatment (IPT; 0, 10 and 20 mg/kg, ip) on the expression of nicotine locomotor sensitization in the familiar environment during the nicotine challenge test in the four groups of rats (n=16/group) that were previously treated with SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC. Each rat was injected with nicotine 0.2 mg/kg, sc and locomotor activity was recorded for 90 minutes. Locomotor activity (mean+SEM) was separated into (A) first 30 minutes, (B) second 30 minutes, and (C) last 30 minutes. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its SAL control; ‡p<0.05 significantly different between one of the SAL+NIC groups and one of the PCP+NIC groups. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean.
Mentions: To examine the time course of the iptakalim effect on nicotine-induced increase in motor activity, we analyzed motor activity in each of 30 minutes blocks (a total of 3 blocks) separately (Fig. 4). During the first 30 minutes of testing, three-way ANOVA revealed a main effect of nicotine, F(1, 52)=39.138, p<0.001, suggesting that rats previously treated with nicotine expressed a nicotine behavioral sensitization. There was also a significant PCP×nicotine interaction, F(1, 52)=12.716, p=0.001, indicating that the nicotine sensitization effect was modulated by PCP sensitization. One-way ANOVA followed by post hoc LSD tests revealed that rats previously sensitized with SAL+NIC had significantly higher motor activity in comparison to the SAL+SAL/SAL group, p<0.012. Iptakalim at both doses (10 and 20 mg/kg) did not decrease the nicotine-induced hyperlocomotion or the expression of nicotine sensitization. Rats previously sensitized with PCP+NIC also showed significantly higher motor activity than the SAL+SAL/SAL rats when tested under saline and iptakalim 20 mg/kg conditions, p<0.006, but not under iptakalim 10 mg/kg condition, p=0.207, suggesting that iptakalim 10 mg/kg reduced the nicotine-induced hyperlocomotion to some extent. This observation was also supported by the finding that the PCP+NIC/IPT 10 group exhibited significantly lower motor activity than the PCP+NIC/SAL group, p=0.045. In addition, rats previously sensitized with PCP+SAL showed significantly higher motor activity than the SAL+SAL/SAL rats, p=0.009 when they were tested under saline condition, indicating a possible cross-sensitization from PCP to nicotine. This significant effect disappeared under iptakalim 10 and 20 mg/kg conditions, p>0.236. The overall pattern of the results indicates that iptakalim was more effective in decreasing nicotine-induced increase in motor activity in PCP sensitized rats than saline rats.

Bottom Line: Acute nicotine treatment attenuated the PCP-induced hyperlocomotion and PCP-induced disruption of PPI, whereas repeated nicotine treatment potentiated these effects.Importantly, pretreatment with iptakalim (10-20 mg/kg, intraperitoneally) reduced nicotine-induced hyperlocomotion in a dose-dependent fashion.This reduction effect was highly selective: it was more effective in rats previously sensitized to the combination of PCP and nicotine, but less effective in rats sensitized to saline, nicotine alone or PCP alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, USA.

ABSTRACT

Objective: Iptakalim is a putative ATP-sensitive potassium (K(ATP)) channel opener. It is also a novel nicotinic acetylcholine receptor (nAChR) blocker and can antagonize nicotine-induced increase in dopamine release in the nucleus accumbens. Our recent work also shows that iptakalim exhibits a clozapine-like atypical antipsychotic profile, indicating that iptakalim may possess a dual action against nicotine addiction and schizophrenia.

Methods: The present study examined the potential therapeutic effects of iptakalim on nicotine use in schizophrenia. We created an animal model of comorbidity of nicotine addiction and schizophrenia by injecting male Sprague-Dawley rats with nicotine (0.40 mg/kg, subcutaneously[sc]) or saline, in combination with phencyclidine (PCP, 3.0 mg/kg, sc) or saline daily for 14 consecutive days.

Results: During the PCP/nicotine sensitization phase, PCP and nicotine independently increased motor activity over time. PCP also disrupted prepulse inhibition (PPI) of acoustic startle response. Acute nicotine treatment attenuated the PCP-induced hyperlocomotion and PCP-induced disruption of PPI, whereas repeated nicotine treatment potentiated these effects. Importantly, pretreatment with iptakalim (10-20 mg/kg, intraperitoneally) reduced nicotine-induced hyperlocomotion in a dose-dependent fashion. This reduction effect was highly selective: it was more effective in rats previously sensitized to the combination of PCP and nicotine, but less effective in rats sensitized to saline, nicotine alone or PCP alone.

Conclusion: To the extent that the combined nicotine and PCP sensitization mimics comorbid nicotine addiction in schizophrenia, the preferential inhibitory effect of iptakalim on nicotine-induced hyperlocomotion suggests that iptakalim may be a potential useful drug for the treatment nicotine abuse in schizophrenia.

No MeSH data available.


Related in: MedlinePlus