Restricted Diffusion of Dopamine in the Rat Dorsal Striatum

Abstract

Recent evidence has shown that the dorsal striatum of the rat is arranged as a patchwork of domains that exhibit distinct dopamine kinetics and concentrations. This raises the pressing question of how these distinct domains are maintained, especially if dopamine is able to diffuse through the extracellular space. Diffusion between the domains would eliminate the concentration differences and, thereby, the domains themselves. The present study is a closer examination of dopamine's ability to diffuse in the extracellular space. We used voltammetry to record dopamine overflow in dorsal striatum while stimulating the medial forebrain bundle over a range of stimulus currents and frequencies. We also examined the effects of drugs that modulated the dopamine release (raclopride and quinpirole) and uptake (nomifensine). Examining the details of the temporal features of the evoked profiles reveals no clear evidence for long-distance diffusion of dopamine between fast and slow domains, even though uptake inhibition by nomifensine clearly prolongs the time that dopamine resides in the extracellular space. Our observations support the conclusion that striatal tissue has the capacity to retain dopamine molecules, thereby limiting its tendency to diffuse through the extracellular space. KEYWORDS: Dopamine, dopamine transporter, diffusion, evoked release, voltammetry, dorsal striatum C entral dopamine (DA) systems participate in numerous aspects of brain function, 1,2 and their dysfunction contributes to a broad array of disorders and diseases including Parkinson's disease, 3 schizophrenia, 4 and attention deficit hyperactivity disorder. 5 Broadly speaking, the physiological function of the DA molecules themselves is to bind to post-and presynaptic receptors to modulate the activity of the postsynaptic targets 6 and to self-regulate DAergic activity, 7 respectively. Consequently, numerous drugs act by modulating extracellular DA concentrations (e.g., L-DOPA, MAO inhibitors, and inhibitors of the dopamine transporter (DAT) 8−11 ) or by modulating or mimicking the binding of DA to its receptors (DA agonists and antagonists). 12,13 Some of the drugs that target DA systems have important therapeutic applications 14,15 while others have high potential for illicit abuse: 16−18 some therapeutic drugs are also abused. 19 Thus, it is significant to know the extracellular DA concentration per se, to know the kinetics of DA release and clearance that determine the concentration, and to know the actions of drugs that target DA systems.Recently, we have demonstrated that the DA terminal field in the rat dorsal striatum contains a patchwork of kinetic spatial domains. The fast and slow domains were brought to light by recordings of extracellular DA with fast-scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes during electrical stimulation of the medial forebrain bundle (MFB). The extracellular concentration of DA, the kinetics of DA release and clearance, the short-term plasticity of DA release, and the actions of DA-ta...

Modeling the Kinetic Diversity of Dopamine in the Dorsal Striatum

“…Finally, the red symbols and line show a 12-pulse prenomifensine response and its best-fit kinetic model. According to Figure 10, decreasing only the value of k U reproduces the observed tendency of uptake inhibition to increase both the amplitude and duration overshoot (see also Figure 4 of ref 25). No prior DA model has reproduced this tendency solely by adjusting DA uptake kinetics.…”

“…The amplitude and duration of overshoot are sensitive to DAT inhibitors including nomifensine. [24][25][26]44 Past interpretations of overshoot as a sign of diffusion gaps 21,42 need to be reconsidered given our new data that speak against the presence of diffusion gaps ( Figure 6). …”

A Novel Restricted Diffusion Model of Evoked Dopamine

“…The DG model cannot produce responses with a prominent lag but no overshoot even though such responses are commonplace in slow domains. 18,19 The RD model produces better fits to the fast and slow DS responses (Figure 3B).…”

“…Evoked responses recorded in the fast domains of the DS and NAc exhibit marked distinctions in amplitude and profile (Figure 2A; the symbols and solid lines are the averaged evoked responses, and the dotted lines show the SEM interval ( n = 16 DS; n = 7 NAc); stimulus = 60 Hz, 200 ms, 250 μA; data are from refs (19 and 20)). Lag and overshoot are far more pronounced in the NAc, and the signal decay after the peak is slower in the NAc.…”

A review of the effects of FSCV and microdialysis measurements on dopamine release in the surrounding tissue

“…3 for 1 second examples) depending on the stimulus length. 27 The DA concentration rapidly returns to baseline levels after the stimulus ends due to the actions of the DA transporter, the transmembrane protein that removes DA molecules from the extracellular space and returns them to DA terminals, where they are repackaged into synaptic vesicles and reused at a later time. 28 However, we noticed that if a microdialysis probe is implanted nearby a carbon fiber microelectrode, the amplitude of the evoked DA response decreases in a manner that depends upon the distance of separation between the probe and the carbon fiber (Fig.…”