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Discriminative Stimulus Effects of the Novel Imidazoline I₂ Receptor Ligand CR4056 in Rats

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Discriminative Stimulus Effects of the Novel Imidazoline I₂ Receptor Ligand CR4056 in Rats

Yanyan Qiu et al. Sci Rep.

Abstract

This study examined whether a novel imidazoline I₂ receptor ligand CR4056 could serve as a discriminative stimulus and whether it shares similar discriminative stimulus effects with other reported I₂ 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 I₂ 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 α₂-adrenoceptor agonist clonidine, the μ-opioid receptor agonists morphine and methadone, and the selective I₂ receptor ligands BU224 and 2-BFI. The α₁ adrenoceptor antagonist WB4101, α₂ 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 I₂ receptors.

Figures

Figure 1
Figure 1. Effects of CR4056 in rats trained to discriminate between 10 mg/kg CR4056 (i.p) and vehicle using a two-lever food-reinforced procedure.
The mean (±1 SEM) percentage of responses on the CR4056-appropriate lever (top panels) and the mean (±1 SEM) rate of responding (bottom panels) are plotted as a function of dose in the left panels and as a function of time after i.p. administration of 10 mg/kg CR4056 in the right panels. Points above “V” indicate vehicle. Each point represents the average (±S.E.M.) of eight rats. Asterisks indicate mean rate of responding that were significantly different from control (95% CLs did not overlap).
Figure 2
Figure 2. Effects of phenyzoline, RS45041, idazoxan, tracizoline, 2-BFI and BU224 in rats trained to discriminate between 10 mg/kg CR4056 (i.p) and vehicle using a two-lever food-reinforced procedure.
See Figure 1 for other details.
Figure 3
Figure 3. Effects of morphine, methadone, ketamine, methamphetamine, agmatine, harmane and clonidine in rats trained to discriminate between 10 mg/kg CR4056 (i.p) and vehicle using a two-lever food-reinforced procedure.
See Figure 1 for other details.
Figure 4
Figure 4. Effects of naltrexone, yohimbine and BU224 on the discriminative stimulus effects of CR4056 in rats trained to discriminate between 10 mg/kg CR4056 (i.p) and vehicle using a two-lever food-reinforced procedure.
Pretreatment drugs were administered 10 min prior to CR4056. See Figure 1 for other details.
Figure 5
Figure 5. Effects of WB4101 on the discriminative stimulus effects of the training dose of CR4056 (10 mg/kg) in rats.
See Figure 1 for other details.

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