Orexin- and Drug-induced Potentiation of Dopamine Neurotransmission and Reward-related Behaviours
Date
2021-01-14
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Abstract
Mesolimbic dopamine (DA) plays a pivotal role in orchestrating numerous motivated behaviours, including seeking and consumption of rewards and the attribution of motivational (incentive) value to reward-related stimuli, such as food and drug cues. Repeated exposure to drugs of abuse produces enduring changes in mesolimbic DA neurotransmission, including potentiated responses to future drug experiences, known as sensitization. A prominent theory of addiction proposes that sensitization of mesolimbic DA by drugs of abuse renders individuals hypersensitive to the motivational properties of drug stimuli (i.e., incentive sensitization), allowing them to gain powerful control over behaviour and ultimately driving addiction. However, it remains unknown how rapidly incentive value can be attributed to drug cues, or if previous drug exposure potentiates cue-evoked mesolimbic DA and attribution of incentive value to drug cues. Furthermore, the hypothalamic neuropeptide orexin (Ox), is hypothesized to sculpt mesolimbic DA and guide reward-related behaviours, including the drug-induced sensitization. However, the effects of endogenous Ox release in the ventral tegmental area (VTA) on mesolimbic DA and reward - related behaviour remains to be characterized. Chapter 1 of this thesis critically evaluates literature regarding motivation and related neurobiology, the effects of drugs of abuse, current theories of addiction, and the influence of Ox. Chapters 2 and 3 of this thesis demonstrate that repeated exposure to drugs of abuse and orexin release in the VTA increase mesolimbic DA and reward-related behaviour. Firstly, pre-treatment with cocaine or the short-acting opioid remifentanil increases rapid attribution of incentive value to a cocaine or remifentanil cue. Secondly, remifentanil pre-treatment potentiates remifentanil-evoked and cue-evoked mesolimbic DA across a single Pavlovian conditioning session. Thirdly, endogenous Ox release in the VTA leads to place preference and increases motivated food-cue directed behaviour. Lastly, Ox release in the VTA potentiates electrically evoked mesolimbic DA. The significance, caveats, and wider implications of this work is discussed chapter 4.
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Keywords
Motivation, Addiction, Dopamine, Sensitization, Orexin
Citation
Thomas, C. S. (2020). Orexin- and Drug-induced Potentiation of Dopamine Neurotransmission and Reward-related Behaviours (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.