Iptakalim is an ATP-sensitive potassium channel opener, as well as an α 4 β 2 -containing nicotinic acetylcholine receptor (nAChR) antagonist. Pretreatment with iptakalim diminishes nicotine-induced dopamine (DA) and glutamate release in the nucleus accumbens. This neuropharmacological profile suggests that iptakalim may be useful for treatment of nicotine dependence. Thus, we examined the effects of iptakalim in two preclinical models. First, the impact of iptakalim on the interoceptive stimulus effect of nicotine was evaluated by training rats in a discriminated goal-tracking task that included intermixed nicotine (0.4 mg/kg, SC) and saline sessions. Sucrose was intermittently presented in a response-independent manner only on nicotine sessions. On intervening test days, rats were pretreated with iptakalim (10, 30, 60 mg/kg, IP). Results revealed that iptakalim attenuated nicotine-evoked responding controlled by the nicotine stimulus in a dose-dependent manner. In a separate study, the impact of iptakalim on the reinforcing effects of nicotine was investigated by training rats to lever-press to self-administer nicotine (0.03 mg/kg/infusion). Results revealed that pretreatment with iptakalim (1, 3, 6 mg/kg, IV) decreased nicotine intake (i.e., less active lever responding). Neither behavioral effect was due to a non-specific motor effect of iptakalim, nor to an ability of iptakalim to inhibit DA transporter (DAT) or serotonin transporter (SERT) function. Together, these finding support the notion that iptakalim may be an effective pharmacotherapy for increasing smoking cessation and a better understanding of its action could contribute to medication development.
Bibliographical noteFunding Information:
This work was in part supported by NIH research grant DA018114 and DA034389 to RAB and DA019447 to AEF, as well as a grant from the Nebraska Department of Health and Human Services awarded to Ming Li. All MED-PC programs used in the present article are available upon request.
Copyright 2019 Elsevier B.V., All rights reserved.
- Drug discrimination
- Interoceptive stimulus
- Nicotine dependence
- Pavlovian conditioning