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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 repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on locomotor activity (mean+SEM). A total of 64 rats were randomly assigned to one of four groups (n=16/group): SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC and tested on day 1, 6, 11 and 13 of drug treatment. *p<0.05 significantly different from the SAL+SAL control group; †p<0.05 significantly different between two PCP groups (NIC vs. SAL). SAL, saline; PCP, phencyclidine hydrochloride; NIC, nicotine; SEM, standard error of the mean.
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Figure 1: Effects of repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on locomotor activity (mean+SEM). A total of 64 rats were randomly assigned to one of four groups (n=16/group): SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC and tested on day 1, 6, 11 and 13 of drug treatment. *p<0.05 significantly different from the SAL+SAL control group; †p<0.05 significantly different between two PCP groups (NIC vs. SAL). SAL, saline; PCP, phencyclidine hydrochloride; NIC, nicotine; SEM, standard error of the mean.

Mentions: Data for one rat in the SAL+SAL group on the last motor activity test was missing due to a technical error and were not entered in the analysis. As can be seen in Fig. 1, both PCP and nicotine treatment progressively increased motor activity throughout the four test days. Repeated measures ANOVA revealed a main effect of PCP, F(1, 59)=332.68, p<0.001, and nicotine, F(1, 59)=12.88, p=0.001, but no PCP×nicotine interaction, F(1, 59)=1.7879, p=0.187. Both PCP and nicotine also induced behavioral sensitization as evidenced by the significant PCP×test day, F(3, 177)=11.104, p<0.001, and nicotine×test day interaction, F(3, 177)=16.980, p<0.001. One-way ANOVA followed by the post hoc LSD tests on each test day showed that both PCP groups showed greater numbers of activity than the SAL+SAL group on all test days, p<0.001. Nicotine treatment alone also significantly increased motor activity, as evidenced by the significant group differences between the SAL+NIC and SAL+SAL groups on the last three days of testing, p<0.011. Interestingly, on the first day of testing, the PCP+NIC group had significantly lower motor activity than the PCP+SAL group, p=0.034, suggesting an acute inhibitory effect of nicotine on PCP-induced hyperlocomotion. This effect was in contrast to the potentiated effect seen in the latter part of testing. The PCP+NIC group showed significantly higher motor activity than the PCP+SAL group on the last two testing days, p=0.009 and p<0.001, respectively.


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 repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on locomotor activity (mean+SEM). A total of 64 rats were randomly assigned to one of four groups (n=16/group): SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC and tested on day 1, 6, 11 and 13 of drug treatment. *p<0.05 significantly different from the SAL+SAL control group; †p<0.05 significantly different between two PCP groups (NIC vs. SAL). SAL, saline; PCP, phencyclidine hydrochloride; 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 1: Effects of repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on locomotor activity (mean+SEM). A total of 64 rats were randomly assigned to one of four groups (n=16/group): SAL+SAL, SAL+NIC, PCP+SAL, and PCP+NIC and tested on day 1, 6, 11 and 13 of drug treatment. *p<0.05 significantly different from the SAL+SAL control group; †p<0.05 significantly different between two PCP groups (NIC vs. SAL). SAL, saline; PCP, phencyclidine hydrochloride; NIC, nicotine; SEM, standard error of the mean.
Mentions: Data for one rat in the SAL+SAL group on the last motor activity test was missing due to a technical error and were not entered in the analysis. As can be seen in Fig. 1, both PCP and nicotine treatment progressively increased motor activity throughout the four test days. Repeated measures ANOVA revealed a main effect of PCP, F(1, 59)=332.68, p<0.001, and nicotine, F(1, 59)=12.88, p=0.001, but no PCP×nicotine interaction, F(1, 59)=1.7879, p=0.187. Both PCP and nicotine also induced behavioral sensitization as evidenced by the significant PCP×test day, F(3, 177)=11.104, p<0.001, and nicotine×test day interaction, F(3, 177)=16.980, p<0.001. One-way ANOVA followed by the post hoc LSD tests on each test day showed that both PCP groups showed greater numbers of activity than the SAL+SAL group on all test days, p<0.001. Nicotine treatment alone also significantly increased motor activity, as evidenced by the significant group differences between the SAL+NIC and SAL+SAL groups on the last three days of testing, p<0.011. Interestingly, on the first day of testing, the PCP+NIC group had significantly lower motor activity than the PCP+SAL group, p=0.034, suggesting an acute inhibitory effect of nicotine on PCP-induced hyperlocomotion. This effect was in contrast to the potentiated effect seen in the latter part of testing. The PCP+NIC group showed significantly higher motor activity than the PCP+SAL group on the last two testing days, p=0.009 and p<0.001, respectively.

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