Effects of sex and remifentanil dose on rats’ acquisition of responding for a remifentanil-conditioned reinforcer

Abstract

Opioid-conditioned reinforcement is thought to exacerbate opioid abuse and dependence. Sex/gender can influence opioid abuse behaviors, but the effects of sex/gender on opioid-conditioned reinforcement, specifically, are unclear. In this study we compared new-response acquisition with opioid-conditioned reinforcement in male and female rats. First, separate groups received response-independent remifentanil injections (0.0-32.0 μg/kg, IV) and presentations of a light–noise stimulus. In experimental groups, injections and stimulus presentations always co-occurred (“paired PAV”); in control groups, the two occurred independently of each other (“random PAV”). Next, in instrumental acquisition (ACQ) sessions, two novel nose-poke manipulanda were introduced. All animals (regardless of sex, dose, PAV type) could respond in the active nose-poke, which produced the stimulus alone, or the inactive nose-poke. Both males and females dose-dependently acquired nose-poke responding (active > inactive) after paired PAV, but not after random PAV. Therefore, the stimulus was a conditioned reinforcer. We identified three sex differences. First, only females acquired responding after PAV with 32.0 μg/kg remifentanil. Second, using a progressive ratio schedule for ACQ, both sexes acquired responding, but females made significantly more active responses. Third, when a single session of PAV was conducted, only males acquired responding. Thus, rats’ sex interacts with pharmacological and environmental factors to determine opioid-conditioned reinforcement.

Effects of dose on acquisition and persistence of a new response for a remifentanil-associated stimulus

“…We found that animals that had a Paired Pavlovian conditioning history showed a higher level of active responding relative to animals assigned to the Random control group, in particular for animals conditioned with 3.2 and 10.0 μg/kg/infusion of remifentanil. These findings are consistent with Bertz and colleagues (2013;2016) and indicate that a Paired Pavlovian conditioned history engendered a higher level of conditioned reinforcing properties. We extended the findings of Bertz and colleagues by characterizing persistence and by using an effect size analysis.…”

“…These data should be interpreted with a consideration in mind that we did not include a control condition in which saline was used (instead of remifentanil) during the Pavlovian conditioning phase. We determined the range of doses of remifentanil based on the findings of Bertz et al (2016), who did include a saline control. They found that pairing saline infusions with stimulus presentations did not engender the stimulus with conditioned reinforcing properties.…”

“…For the Pavlovian conditioning phase, we assigned rats to one of three dosing conditions: 1.0, 3.2, or 10.0 μg/kg/ infusion. These doses were selected based on the findings of Bertz et al (2016). Within each dosing condition, rats were assigned to Paired Pavlovian (n = 8 per dose) or Random control (n = 8 per dose) conditioning.…”

“…The new response acquisition procedure has been proposed as a particularly rigorous procedure for evaluating conditioned reinforcement (Davis and Smith, 1976;Bertz and Woods, 2013;Bertz et al, 2015;Bertz et al, 2016). The new response acquisition procedure is divided into two phases.…”

Elucidating the role of D4 receptors in mediating attributions of salience to incentive stimuli on Pavlovian conditioned approach and conditioned reinforcement paradigms

“…Furthermore, consistent with former investigations, there do not appear to be any sex differences in either the acquisition or expression of motivated behaviours to conditioned stimuli. [2,12]. The failure of a D 4 agonist to alter behaviour here is in some regards surprising, in that a canon of evidence implicates D 4 receptor dysfunction in multiple disease states that are characterised by inappropriate or maladaptive attributions of salience.…”