Abstract
Rationale
Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects.
Objectives
Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting.
Methods
Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design.
Results
The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated.
Conclusions
Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus.
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Acknowledgements
Support for this research was provided by the Canadian Natural Sciences and Engineering Research Council #RGPIN-2019-05147 to JEM. The funding source had no role in study design; data collection, analyses, or interpretation; writing; or decision to submit the article for publication. We are grateful for the skilled technical support of Derek Jacklin.
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CJN and JEM designed the study; DRP, CJN, MAW, JMK, and APS conducted the research; DRP conducted data analyses with JEM input; DRP wrote the first manuscript draft; JEM and APS provided revision feedback; all authors have provided feedback on and approved the final manuscript for submission.
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Peart, D.R., Nolan, C.J., Stone, A.P. et al. Disruption of positive- and negative-feature morphine interoceptive occasion setters by dopamine receptor agonism and antagonism in male and female rats. Psychopharmacology (2024). https://doi.org/10.1007/s00213-024-06584-y
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DOI: https://doi.org/10.1007/s00213-024-06584-y