Discriminative stimulus effects of the novel imidazoline I(2) receptor ligand CR4056 in rats

This study examined whether a novel imidazoline I(2) receptor ligand CR4056 could serve as a discriminative stimulus and whether it shares similar discriminative stimulus effects with other reported I(2) receptor ligands. Eight male Sprague-Dawley rats were trained to discriminate 10.0 mg/kg CR4056 (i.p.) from vehicle in a two-lever food-reinforced drug discrimination procedure. Once rats acquired the discrimination, substitution and combination studies were conducted to elucidate the underlying receptor mechanisms. All rats acquired CR4056 discrimination after an average of 26 training sessions. Several I(2) receptor ligands (phenyzoline, tracizoline, RS45041, and idazoxan, 3.2–75 mg/kg, i.p.) all occasioned > 80% CR4056-associated lever responding. Other drugs that occasioned partial or no CR4056-associated lever responding included methamphetamine, ketamine, the endogenous imidazoline ligand agmatine, the monoamine oxidase (MAO) inhibitor harmane, the α(2)-adrenoceptor agonist clonidine, the μ-opioid receptor agonists morphine and methadone, and the selective I(2) receptor ligands BU224 and 2-BFI. The α(1) adrenoceptor antagonist WB4101, α(2) adrenoceptor antagonist yohimbine and μ-opioid receptor antagonist naltrexone failed to alter the stimulus effects of CR4056. Together, these results show that CR4056 can serve as a discriminative stimulus in rats, which demonstrates high pharmacological specificity and appears to be mediated by imidazoline I(2) receptors.