, 2006; Tritto et al., 2004). Figure 2. Response to varenicline after antagonists in wild-type (WT) and null mutant mice. Mice were injected ip as indicated; protocol 2 was followed. The first intraperitoneal (ip) injection was saline or an antagonist calculated as freebase (Hex = hexamethonium, … Results shown in Figure 3 demonstrate that varenicline selleck Temsirolimus inhibits the effects of a 0.5 mg/kg dose of nicotine. ID50 values for varenicline inhibition of nicotine at 0.5 mg/kg ip (3.1 ��mol/kg) were similar for inhibition of nicotine-elicited decreases in Y-maze crosses and rears and body temperature (0.004�C0.007 mg/kg or 0.02�C0.03 ��mol/kg), while the ID50 for blockade of nicotine-induced decreases in open-field activity was somewhat higher (0.031 mg/kg or 0.14 ��mol/kg).

On a mole for mole basis, these varenicline ID50 values are considerably lower than the nicotine ED50 values (Tritto et al., 2004) needed to produce effects on Y-maze rears, distance traveled in the open-field, Y-maze crosses, and hypothermia (18-, 25-, 74-, and 110-fold, respectively). It appears that varenicline at low doses acts as a functional antagonist at ��2*-nAChRs and at higher doses as an agonist at ��4*-nAChRs, while nicotine can affect these measures as an agonist at both of these subtypes. Figure 3. Effect of low-dose varenicline on nicotine-induced behaviors. C57Bl/6 mice were injected intraperitoneally (ip) with the indicated dose of varenicline (calculated as freebase), followed by an injection of saline or nicotine (0.5 mg/kg freebase) ip 10 …

Discussion By in vivo tests, measuring the well-known locomotor-depressant and hypothermia-inducing effects of nicotinic agonists, varenicline appears to have two different actions. Varenicline, in vivo, acts effectively as an antagonist at ��2*-nAChRs and as an agonist at ��4*-nAChRs. Acute administration of relatively high doses of varenicline elicits locomotor depression and hypothermia. Nicotine elicits these same effects by activation of either ��2*-nAChRs or ��4*-nAChRs (McCallum et al., 2006; Tritto et al., 2004), but not by activation of ��7-nAChRs (Tritto et al., 2004). The lack of effect of deletion of the ��7 subunit indicates the same is true for varenicline (Figure 1). Nicotine effects mediated by activation of ��2*-nAChRs are seen with lower doses of nicotine than those mediated by activation of ��4*-nAChRs, a result predicted by their relative in vitro concentration for 50% effect (EC50) (Tritto et al.

, 2004). In contrast to the reduced potency of nicotine determined in ��2-null mutant mice (1.4- to 4.0-fold shift to higher ED50 values; Tritto et al., 2004), deletion of the ��2 subunit did not decrease the effectiveness of varenicline (Figure 1). In fact, an increase in effectiveness was seen for Anacetrapib hypothermia in the ��2-null mutant mice at the highest varenicline dose (Figure 1).