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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 the expression of PCP locomotor sensitization during the PCP 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 PCP 1.5 mg/kg, sc, and locomotor activity (mean+SEM) was recorded for 90 minutes. *p<0.05 significantly different from the SAL+SAL control group. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean; SEM, standard error of the mean.
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Figure 3: Effects of repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on the expression of PCP locomotor sensitization during the PCP 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 PCP 1.5 mg/kg, sc, and locomotor activity (mean+SEM) was recorded for 90 minutes. *p<0.05 significantly different from the SAL+SAL control group. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean; SEM, standard error of the mean.

Mentions: Fig. 3 shows motor activity in the four groups of rats challenged with PCP 1.5 mg/kg. Two-way ANOVA revealed a main effect of PCP, F(1, 60)=12.242, p=0.001, confirming the PCP-induced behavioral sensitization. The nicotine effect was not significant, F(1, 60)=2.572, p=0.114, indicating that repeated nicotine treatment did not have a long-term impact on PCP sensitization. One-way ANOVA followed by post hoc LSD tested on the four groups showed that both PCP+SAL and PCP+NIC groups showed significantly greater motor activity than the SAL+SAL group, p<0.007.


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 the expression of PCP locomotor sensitization during the PCP 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 PCP 1.5 mg/kg, sc, and locomotor activity (mean+SEM) was recorded for 90 minutes. *p<0.05 significantly different from the SAL+SAL control group. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean; 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 3: Effects of repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on the expression of PCP locomotor sensitization during the PCP 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 PCP 1.5 mg/kg, sc, and locomotor activity (mean+SEM) was recorded for 90 minutes. *p<0.05 significantly different from the SAL+SAL control group. SAL, saline; PCP, phencyclidine; NIC, nicotine; SEM, standard error of the mean; SEM, standard error of the mean.
Mentions: Fig. 3 shows motor activity in the four groups of rats challenged with PCP 1.5 mg/kg. Two-way ANOVA revealed a main effect of PCP, F(1, 60)=12.242, p=0.001, confirming the PCP-induced behavioral sensitization. The nicotine effect was not significant, F(1, 60)=2.572, p=0.114, indicating that repeated nicotine treatment did not have a long-term impact on PCP sensitization. One-way ANOVA followed by post hoc LSD tested on the four groups showed that both PCP+SAL and PCP+NIC groups showed significantly greater motor activity than the SAL+SAL group, p<0.007.

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