Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine

Abstract

Iptakalim is an ATP-sensitive potassium channel opener, as well as an α4β2-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 better understanding its action could contribute medication development.

Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus

“…Infusions were made at a constant rate of 0.1 μl/min and cannula was left in place for an additional 5 min. Anesthesia was terminated using IM injection of 0.5 mg/kg atipamezole diluted in saline (Charntikov et al, 2013; Wee et al, 2006). Buprenorphine hydrochloride (0.1 mg/kg; SC) was injected immediately following surgery and the next day (am and pm) for pain management.…”

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in female rats

“…Indwelling jugular catheters were implanted using our standard protocol [previously described in (Charntikov et al , 2013)]. Briefly, rats were anesthetized with a 1 ml/kg intramuscular (IM) injection of a 2:1 ratio cocktail of ketamine HCl (100 mg/ml) and xylazine HCl (20 mg/ml) and then prepared for surgery and catheter implantation.…”

“…Catheter patency was checked on the last day of recovery by IV infusion of 0.05-ml xylazine (20 mg/ml). Rats that displayed motor ataxia within 20 sec were considered patent(Charntikov et al , 2013; Reichel et al , 2008). Patency was again checked after completion of the self-administration phase; 3rats(saline group) were excluded from the study and analyses for not having patent catheters.…”

Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats

“…Rats were surgically implanted a subcutaneous jugular catheter as previously described (Charntikov et al, 2013) and detailed in Supplementary material 1 . Catheter integrity was tested when patency loss was suspected and/or upon completion of the self-administration phase using an infusion of 0.05 ml xylazine (20 mg/ml IV).…”