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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 novel 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 (mean+SEM) was recorded for 30 minutes in a new testing apparatus different from the one used in the inducton of NIC/PCP sensitization. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its saline control. SAL, saline; PCP, phencyclidine; NIC, nicotine.
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Figure 5: Effects of iptakalim treatment (IPT; 0, 10 and 20 mg/kg, ip) on the expression of nicotine locomotor sensitization in the novel 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 (mean+SEM) was recorded for 30 minutes in a new testing apparatus different from the one used in the inducton of NIC/PCP sensitization. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its saline control. SAL, saline; PCP, phencyclidine; NIC, nicotine.

Mentions: The main finding of the present study was that iptakalim dose-dependently reduced nicotine-induced hyperlocomotion. This finding is to some extent expected as evidence from electrophysiological and microdialysis studies shows that iptakalim selectively inhibits α4β2-nAChRs,53) and antagonizes nicotine-induced increase in dopamine release in the accumbens.9) Our finding provides additional behavioral support for iptakalim's inhibitory action on nicotinic receptors. The novel finding is its preferential effect in PCP+NIC sensitized rats: iptakalim was more efficacious in decreasing nicotine-induced increase in motor activity in PCP sensitized rats than in non-sensitized rats or rats sensitized to nicotine alone or PCP alone. During the first 30 minutes of testing in a familiar environment, iptakalim 10 mg/kg only significantly decreased nicotine-induced hyperlocomotion in rats previously sensitized to the combination of PCP and nicotine, but not in rats previously sensitized to saline, nicotine alone or PCP alone. The same pattern was found during the second test in a novel environment. Because nicotine challenge induced as much higher motor activity in rats sensitized to nicotine alone as in those sensitized to both nicotine and PCP (Figs. 4A, 5), the preferential effect of iptakalim could not be attributed to different levels of motor response to nicotine challenge.


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 novel 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 (mean+SEM) was recorded for 30 minutes in a new testing apparatus different from the one used in the inducton of NIC/PCP sensitization. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its saline control. SAL, saline; PCP, phencyclidine; NIC, nicotine.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Effects of iptakalim treatment (IPT; 0, 10 and 20 mg/kg, ip) on the expression of nicotine locomotor sensitization in the novel 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 (mean+SEM) was recorded for 30 minutes in a new testing apparatus different from the one used in the inducton of NIC/PCP sensitization. *p<0.05 significantly different from the SAL+SAL/SAL control group; †p<0.05 significantly different between an iptakalim group and its saline control. SAL, saline; PCP, phencyclidine; NIC, nicotine.
Mentions: The main finding of the present study was that iptakalim dose-dependently reduced nicotine-induced hyperlocomotion. This finding is to some extent expected as evidence from electrophysiological and microdialysis studies shows that iptakalim selectively inhibits α4β2-nAChRs,53) and antagonizes nicotine-induced increase in dopamine release in the accumbens.9) Our finding provides additional behavioral support for iptakalim's inhibitory action on nicotinic receptors. The novel finding is its preferential effect in PCP+NIC sensitized rats: iptakalim was more efficacious in decreasing nicotine-induced increase in motor activity in PCP sensitized rats than in non-sensitized rats or rats sensitized to nicotine alone or PCP alone. During the first 30 minutes of testing in a familiar environment, iptakalim 10 mg/kg only significantly decreased nicotine-induced hyperlocomotion in rats previously sensitized to the combination of PCP and nicotine, but not in rats previously sensitized to saline, nicotine alone or PCP alone. The same pattern was found during the second test in a novel environment. Because nicotine challenge induced as much higher motor activity in rats sensitized to nicotine alone as in those sensitized to both nicotine and PCP (Figs. 4A, 5), the preferential effect of iptakalim could not be attributed to different levels of motor response to nicotine challenge.

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