Pavlovian conditioning of multiple opioid-like responses in mice

Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, IL 60637, USA.
Drug and alcohol dependence (Impact Factor: 3.42). 08/2009; 103(1-2):74-83. DOI: 10.1016/j.drugalcdep.2009.03.016
Source: PubMed


Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2mg/kg, i.p.) in a novel context and subsequently given a vehicle injection. In separate experiments, locomotor activity, Straub tail, hot plate sensitivity, and conditioned place preference (CPP) were measured. Mice exhibited multiple conditional opioid-like responses including conditional hyperlocomotion, a conditional pattern of opioid-like locomotion, Straub tail, analgesia, and place preference. Modulating drug expectation via administration of fentanyl to "demonstrator" mice in the home cage did not affect the expression of conditioned place preference or the concomitant locomotor activity in "observer" mice. In summary, Pavlovian conditioning of an opioid in a novel context induced multiple conditional opioid-like behaviors and provides a model for studying the neurobiological mechanisms of the placebo response in mice.


Available from: Michael Fanselow
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    • "Following OXY training, OXY-CPP (D8-D1 time) loaded onto the same factor as change in distance and rotations for both strains (Tables 2A,B). Opioid-induced rotations (Figure 1A), or " circling " is a stereotypic behavior that is induced by opioid administration (Iwamoto and Way, 1977; Morihisa and Glick, 1977; Seidel et al., 1979; Mickley et al., 1990; Bryant et al., 2009; Hodgson et al., 2010) and its behavioral pattern can be expressed as a conditioned opioid-like placebo response (Bryant et al., 2009). Our observations indicate that mice expressing drug-free "

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    • "1977; Morihisa and Glick. 1977; Seidel et al. 1979; Mickley et al. 1990; Bryant et al. 2009; Hodgson et al. 2010) and its behavioral pattern can be expressed as a conditioned opioid-like placebo response (Bryant et al. 2009). Our observations indicate that mice expressing drug-free conditioned opioid reward behave in a manner that is similar to having received an opioid injection. "
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    ABSTRACT: Drug liking versus drug disliking is a subjective motivational measure in humans that assesses the addiction liability of drugs. Variation in this trait is hypothesized to influence vulnerability versus resilience toward substance abuse disorders and likely contains a genetic component. In rodents and humans, conditioned place preference (CPP) / aversion (CPA) is a Pavlovian conditioning paradigm whereby a learned preference for the drug-paired environment is used to infer drug liking whereas a learned avoidance or aversion is used to infer drug disliking. C57BL/6 inbred mouse substrains are nearly genetically identical, yet demonstrate robust differences in addiction-relevant behaviors, including locomotor sensitization to cocaine and consumption of ethanol. Here, we tested the hypothesis that B6 substrains would demonstrate differences in the rewarding properties of the mu opioid receptor agonist oxycodone (5 mg/kg, i.p.) and the aversive properties of the opioid receptor antagonist naloxone (4 mg/kg, i.p.). Both substrains showed similar degrees of oxycodone-induced CPP; however, there was a three-fold enhancement of naloxone-induced CPA in agonist-naïve C57BL/6J relative to C57Bl/6NJ mice. Exploratory factor analysis of CPP and CPA identified unique factors that explain variance in behavioral expression of reward versus aversion. “Conditioned Opioid-Like Behavior” was a reward-based factor whereby drug-free locomotor variables resembling opioid treatment co-varied with the degree of CPP. “Avoidance and Freezing” was an aversion-based factor, whereby the increase in the number of freezing bouts co-varied with the degree of aversion. These results provide new insight into the behavioral architecture of the motivational properties of opioids. Future studies will use quantitative trait locus mapping in B6 substrains to identify novel genetic factors that contribute to the marked strain difference in NAL-CPA.
    Frontiers in Behavioral Neuroscience 12/2014; accepted. DOI:10.3389/fnbeh.2014.00450 · 3.27 Impact Factor
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    • "A number of psychological theories to explain placebo effect have been put forth, including expectation of improvement, conditioning of response based on prior consistent therapy with an active modality followed by replacement of the active therapy with placebo,28 and emotional state. Expectancy theory involves a sense of achieving forthcoming improvement which precedes the initiation of therapy in the clinical trial. "
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    ABSTRACT: Ongoing efforts to improve clinical trial design in irritable bowel syndrome have been hindered by high placebo response rates and ineffective outcome measures. We assessed established strategies to minimize placebo effect as well as the various ap-proaches to placebo effect which can affect trial design. These include genetic markers such as catechol-O-methyltransferase, opioidergic and dopaminergic neurobiologic theory, pre-cebo effect centered on expectancy theory, and side effect unblinding grounded on conditioning theory. We reviewed endpoints used in the study of IBS over the past decade including adequate relief and subjective global relief, emphasizing their weaknesses in fully evaluating the IBS condition, specifically their motility effects based on functional net value and relative benefit-harm based on dropouts due to adverse events. The focus of this review is to highlight ongoing efforts to improve clinical trial design which can lead to better outcomes in a real-world setting.
    Journal of neurogastroenterology and motility 04/2014; 20(2):163-170. DOI:10.5056/jnm.2014.20.2.163 · 2.30 Impact Factor
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