Mesostriatal dopaminergic neurons possess extensively branched axonal arbours. Whether action potentials are converted to dopamine output in the striatum will be influenced dynamically and critically by axonal properties and mechanisms that are poorly understood. Here, we address the roles for mechanisms governing release probability and axonal activity in determining short‐term plasticity of dopamine release, using fast‐scan cyclic voltammetry in the ex vivo mouse striatum. We show that brief short‐term facilitation and longer short term depression are only weakly dependent on the level of initial release, i.e. are release insensitive. Rather, short-term plasticity is strongly determined by mechanisms which govern axonal activation, including K+‐gated excitability and the dopamine transporter, particularly in the dorsal striatum. We identify the dopamine transporter as a master regulator of dopamine short‐term plasticity, governing the balance between release‐dependent and independent mechanisms that also show region‐specific gating.

Key Findings: 13 Short-term plasticity in dopamine release is only weakly governed by initial release 14  Short-term depression is strongly dependent on axonal excitability and activation 15  The dopamine transporter controls short-term plasticity and drives short-term depression 16  Dopamine transporters govern the balance between release-dependent and -independent 17 mechanisms 18 Condon et al 2 Abstract 19Mesostriatal DA neurons possess extensively branched axonal arbours. Whether action potentials are 20 converted to DA output in striatum will be influenced dynamically and critically by axonal properties and 21 mechanisms that are poorly understood. We addressed the roles for mechanisms governing release 22 probability and axonal activity in determining short-term plasticity of DA release, using fast-scan cyclic 23 voltammetry in ex vivo mouse striatum. Brief short-term facilitation (STF) and longer short-term depression 24 (STD) were only weakly dependent on the level of initial release, i.e. were release-insensitive. Rather, short-25 term plasticity was strongly determined by mechanisms which governed axonal activation, including K + -gated 26 excitability and the dopamine transporter (DAT), particularly in dorsal striatum. We identify the DAT as a 27 master regulator of DA short-term plasticity, governing the balance between release-dependent and 28 independent mechanisms that also show region-specific gating. 29 and short-term plasticity [18]. Axons of DA neurons are remarkable: they comprise vast, extensively 43 branched arbours [19,20], that from anatomical observations and a binary tree model [21] can be calculated 44 to form an average of 16,000 branch points per nigrostriatal neuron. Axonal properties are likely to be 45 particularly important in governing axonal activity and striatal DA output. One major influence is the input 46 from striatal cholinergic interneurons onto nicotinic receptors (nAChRs) on DA axons, which influence the 47 pattern of DA release and promote short-term depression (STD) [11,15,[22][23][24]. But even in the absence of 48 nAChR activation, DA release shows an underlying spectrum of short-term plasticity ranging from short-term 49 depression (STD) to short-term facilitation (STF) [11,15,23,25,26] for which the underlying mechanisms are 50 poorly understood. Existing evidence suggests that short-term plasticity might be only weakly related to 51 initial levels of release [17,25,26] but the dominant drivers remain undefined. 52Here, we delineate the roles of three types of intrinsic drivers that could underlie short-term 53 plasticity of DA release from striatal DA axons. We examine, firstly, the role for initial release; secondly, the 54 role for K + -dependent mechanisms that will govern overall excitability and repolarization; and thirdly, a 55 potential role for the dopamine transporter (DAT). Besides mediating DA uptake, the DAT generates a 56 depolarising transport-coupled conductance in midbrain DA neurons [27,28], and has been suggested to 57 limit vesicular rel...

Background: Activation of the glutamate N-methyl-D-aspartate receptor with its co-agonist D-serine has been shown to improve subjective mood in healthy volunteers. D-alanine is another potent N-methyl-D-aspartate receptor co-agonist which arises from the natural breakdown of host gut microbes, and is predominantly sequestered in the pituitary. This may suggest that D-alanine influences the neuroendocrine stress response which may then impact on emotion. Aims: The current study explored the effects of D-serine and D-alanine on emotional processing, cognition and the levels of the stress hormone cortisol in healthy volunteers. Methods: In a double-blind, placebo-controlled randomised study, participants ( n=63) received a single oral dose of either D-serine, D-alanine (60 mg/kg) or placebo and then performed the Emotional Test Battery and N-back task (two hours post-administration) and provided saliva samples at fixed intervals. Results: Subjects administered with D-alanine were faster at identifying facial expressions of fear, surprise and anger, and at categorising negative self-referential words. Participants on D-alanine also showed a trend to recall more words than placebo in a memory task. D-serine did not have any meaningful effects in any of the tasks. Neither amino acid had a significant effect on salivary cortisol or working memory. Conclusion: This study is the first to suggest that D-alanine can modulate emotional cognitive processing after a single dose. The lack of findings for D-serine nevertheless contrasts a previous study, emphasising a need for further investigation to clarify discrepancies. A better understanding of the physiological actions of D-amino acids would be beneficial in evaluating their therapeutic potential.