Investigating the neurochemical basis of action initiation, selection, and inhibition

Thesis

Two central monoamine systems, dopamine and serotonin, are thought to be integral to the promotion or inhibition of goal-directed action respectively, but how this information is conveyed in tandem with reward-related signals is not yet fully understood. In particular, whilst reward prediction error encoding by midbrain dopamine activity and release is well replicated, this contrasts with a wealth of pharmacological evidence emphasising dopamine’s role in activation of behaviour for reward. In Chapter 3, we establish a novel cue-instructed behavioural paradigm where animals must either enact or entirely restrain movement with the promise of receiving a small or large reward: the Go/No-Go task. We show that the phasic dopaminergic signal is shaped both by reward size on offer and by movement required to garner reward. To establish whether this phasic signal is causally driving behaviour, in Chapter 4 we systemically manipulate D1-like receptors – thought to be most sensitive to phasic dopamine release – to show that global modulation of this receptor mediates action initiation, inhibition, and execution, and biases action selection towards highly rewarding responses. In Chapter 5 the ability to initiate or inhibit cue-driven action exclusively is localised to D1-like receptors in the core of the nucleus accumbens. D2-like receptors have been considered important for the inhibition of action, but more recently it has been hypothesised that they may in fact work synergistically with D1-like receptors to promote reward-guided action. In Chapter 6 we show that these receptors indeed gate goal-directed behaviour, but only when movement is required. Finally, the serotonergic 5-HT2C receptor has been demonstrated as key to the ability to wait for reward but whether this is dependent on movement has not yet been explored. Therefore, in Chapter 7, we systemically and locally apply a 5-HT2C receptor ligand to show that disruption of this receptor’s normal function reduces behavioural inhibition whilst simultaneously improving both speed and ability to enact goal-directed behaviour, but that the locus of these effects is extra-accumbens. In Chapter 8, we summarise these findings and discuss their implications for our understanding of how two of the brain’s principal neurotransmitter systems, dopamine and serotonin, regulate motivated behaviour in the context of action and inaction.

Authors: Grima, L

• DOI: 10.5287/ora-ga7bdqyew
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford