A wide range of techniques have been used to investigate somatodendritic DA release. Initial studies used detection of 3H-DA to indicate somatodendritic release in vitro using midbrain slices (Geffen et al., 1976; Tagerud and Cuello 1979) and in vivo using push-pull perfusion (Nieoullon et al., 1977; Cheramy et al., 1981). Development of more sensitive off-line detection methods, especially HPLC with electrochemical detection, permitted monitoring of endogenous DA release from midbrain slices in vitro (Elverfors et al., 1997). Another advance was seen with the introduction of in vivo microdialysis, which permits evaluation of extracellular levels of either exogenous or endogenous DA when coupled with an appropriate off-line analytical method (Elverfors and Nissbrandt, 1991; Robertson et al., 1991; Santiago and Westerink, 1991, 1992; Heeringa and Abercrombie 1995; Bergquist et al., 2002). Microdialysis measurements have been particularly helpful in elucidating factors that influence somatodendritic DA release. Like other in vivo methods, microdialysis affords the opportunity to study somatodendritic DA release after systemic drug administration or during behaviour in freely moving animals (see Bergquist and Nissbrandt, 2004, this volume). Another advantage of microdialysis is that dialysate analysis is off-line, usually after an HPLC
separation step, which permits selective detection of DA as well as the possibility for concurrent monitoring of DA metabolites or other transmitters. These strengths come with caveats, however. Firstly, the spatio-temporal resolution of microdialysis is limited. Secondly, interpretation of in vivo studies to address the mechanism of somatodendritic DA release or factors regulating local release are complicated by the unavoidable influence of the overall circuitry governing DA cell activity in the SNc or VTA.
A decade ago, we introduced the use of voltammetric recording using carbon-fibre microelectrodes with fast-scan cyclic voltammetry (FCV) for the study of somatodendritic DA release (Rice et al., 1994). FCV is a high-speed, high spatial resolution detection method that is ideal for monitoring release of DA from discrete brain nuclei, including the SNc and VTA. Indeed, many insights into somatodendritic DA release in midbrain over the last decade have been obtained using FCV or other voltammetric methods. A major advantage of FCV is that it permits real-time monitoring of DA release with sub-second and sub-regional resolution. As with microdialysis, there are also caveats to voltammetric recording. In particular, voltammetric studies of somatodendritic DA release in the SN of some species, including rats (Stamford et al., 1993; Iravani and Kruk, 1997; Bunin and Wightman, 1998) and mice (John et al., 2003), have been hindered by the concomitant or predominant detection of 5-HT. The SN receives one of the highest 5-HT innervation densities in the brain; projections from the raphe nuclei provide direct, asymmetric synaptic 5-HT input to both dopaminergic and non-dopaminergic dendrites of SNc and SNr in primates and rodents (SNr>SNc>VTA) (Steinbusch, 1981; Nedergaard et al., 1988; Lavoie and Parent, 1990; Corvaja et al., 1993; Moukhles et al., 1997). Fortunately, the guinea pig SN receives a less dense 5-HT innervation than that found in rat SN, so that pure somatodendritic DA release can be monitored in guinea-pig SNc in vitro, although not in rat SNc (Cragg et al., 1997a). Thus, the guinea pig is the rodent species of choice for the characterisation of somatodendritic DA release in SN and VTA using voltammetry (Cragg et al., 1997a). This is not a concern for microdialysis, because of the separate off-line separation step usually used for DA detection. Interestingly, there are species differences in 5-HT receptor binding profiles, as well, e.g. 5HT4 receptors (Waeber et al., 1994), with the pattern in guinea pig better resembling that in human SN.
3. WHAT IS THE ROLE OF SOMATODENDRITIC DOPAMINE RELEASE? 3.1. Somatodendritic Dopamine is Required for Basal Ganglia-Mediated Movement
The critical role of the nigrostriatal pathway in movement has been convincingly demonstrated by the motor deficits of Parkinson's disease that accompany loss of nigrostriatal DA and which can be ameliorated by the DA precursor, L-DOPA (Wichman and DeLong 1996; Carlsson, 2002). Both somatodendritic and axon-terminal release are required for basal ganglia-mediated movement (Robertson and Robertson, 1989; Timmerman and Abercrombie, 1996; Crocker, 1997; Bergquist et al., 2003). Evidence for this is reviewed in detail in Bergquist and Nissbrandt, 2004. The cellular and receptor targets of somatodendritic dopamine in SN and VTA that underlie these behavioural effects are discussed in the following section.
3.2. Somatodendritic Dopamine Signalling via Volume Transmission
Where does somatodendritically released DA act? Unlike classical synaptic transmission, e.g. subsynaptic receptor activation by glutamate, DA transmission is modulatory and is mediated primarily by extrasynaptic receptors (e.g. Rice, 2000; Pickel, 2000; Cragg and Rice, 2004). Thus, DA in both midbrain and striatum must act via volume transmission (Fuxe and Agnati, 1991; Rice, 2000). As a consequence, understanding DA transmission requires understanding of local diffusion characteristics. Strikingly, the extracellular volume fraction (or) available for DA diffusion in the SN and VTA is 0.30 (Cragg et al., 2001), compared to values of -0.20 that are typical for forebrain structures, including striatum (Rice and Nicholson, 1991). This means that the extracellular concentration of DA ([DA]0) after release of a given number of molecules will be >30% lower in the SN/VTA than in striatum, in the absence of other regulatory mechanisms. This has obvious implications for concentration-dependent receptor activation in SN/VTA versus striatum, as well as for experimental observations of [DA]0 in these regions. The tortuosity factor, A, which governs the apparent diffusion coefficient of a diffusing substance, is similar between midbrain and striatum (Cragg et al., 2001).
Somatodendritically released DA acts on D2 autoreceptors to regulate DA cell activity (Lacey et al., 1988; Chiodo, 1992; Yung et al., 1995; Falkenburger et al., 2001) and subsequent somatodendritic DA release in the SNc (discussed in section 6.1), as well as axonal release in striatum (Santiago and Westerink, 1991; Kalivas and Duffy, 1991). Moreover, somatodendritically released DA in both SN and VTA can act at non-synaptic DA receptors on presynaptic GABAergic and glutamatergic terminals to modulate release of those transmitters (Miyazaki and Lacey, 1998; Radnikow and Misgeld, 1998; Koga and Momiyama, 2000). For example, activation of Di receptors on the terminals of striatonigral efferents increases GABA inhibitory transmission to SNr output neurons which decreases the inhibitory SNr output to thalamus (Radnikow and Misgeld, 1998); this would reinforce motor activation by the striatonigral pathway.
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