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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 PPI of acoustic startle response at the 73 dB prepulse level (A), 76 dB prepulse level (B) and 82 dB prepulse level (C) (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. The PPI tests were conducted on the second habituation day (Hab), and on day 3, 8, 12 and 14 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; NIC, nicotine; PPI, prepulse inhibition; SEM, standard error of the mean.
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Figure 2: Effects of repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on PPI of acoustic startle response at the 73 dB prepulse level (A), 76 dB prepulse level (B) and 82 dB prepulse level (C) (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. The PPI tests were conducted on the second habituation day (Hab), and on day 3, 8, 12 and 14 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; NIC, nicotine; PPI, prepulse inhibition; SEM, standard error of the mean.

Mentions: Data for two rats in the PCP+SAL group and two in the SAL+NIC groups were missing due to a technical error and were not analyzed. Fig. 2 shows PPI performance of the four groups of rats tested throughout the sensitization phase. PCP 3.0 mg/kg disrupted PPI at all three levels. Analysis of PPI data from the 4 drug test days revealed a main effect of PCP, F(1, 56)=120.647, p<0.001, but no main effect of nicotine, F(1, 56)=1.821, p=0.183, nor PCP×nicotine interaction, F(1, 56)=0.086, p=0.770. The effect of prepulse level was significant, F(2, 112)=512.147, p<0.001, but the effect of test day was not, F(3, 168)=2.085, p=0.104. There were also significant interactions between PCP×test day, F(3, 168)=3.012, p=0.032, PCP×prepulse level, F(2, 112)=17.611, p<0.001, and nicotine×test day, F(3, 168)=3.768, p=0.012, suggesting that the effects of PCP and nicotine on PPI performance varied across the test days.


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 PPI of acoustic startle response at the 73 dB prepulse level (A), 76 dB prepulse level (B) and 82 dB prepulse level (C) (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. The PPI tests were conducted on the second habituation day (Hab), and on day 3, 8, 12 and 14 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; NIC, nicotine; PPI, prepulse inhibition; 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 2: Effects of repeated administration of SAL, PCP (3.0 mg/kg, sc), and NIC (0.4 mg/kg, sc) on PPI of acoustic startle response at the 73 dB prepulse level (A), 76 dB prepulse level (B) and 82 dB prepulse level (C) (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. The PPI tests were conducted on the second habituation day (Hab), and on day 3, 8, 12 and 14 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; NIC, nicotine; PPI, prepulse inhibition; SEM, standard error of the mean.
Mentions: Data for two rats in the PCP+SAL group and two in the SAL+NIC groups were missing due to a technical error and were not analyzed. Fig. 2 shows PPI performance of the four groups of rats tested throughout the sensitization phase. PCP 3.0 mg/kg disrupted PPI at all three levels. Analysis of PPI data from the 4 drug test days revealed a main effect of PCP, F(1, 56)=120.647, p<0.001, but no main effect of nicotine, F(1, 56)=1.821, p=0.183, nor PCP×nicotine interaction, F(1, 56)=0.086, p=0.770. The effect of prepulse level was significant, F(2, 112)=512.147, p<0.001, but the effect of test day was not, F(3, 168)=2.085, p=0.104. There were also significant interactions between PCP×test day, F(3, 168)=3.012, p=0.032, PCP×prepulse level, F(2, 112)=17.611, p<0.001, and nicotine×test day, F(3, 168)=3.768, p=0.012, suggesting that the effects of PCP and nicotine on PPI performance varied across the test days.

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