**1. Introduction**

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consumption and plasma beta-endorphin levels in alcohol-preferring rats chronically treated with naltrexone. *Physiology & behavior,*Vol.93, No.4-5, (Mar 18), The neurotransmitter Dopamine (DA) exerts a dual function in the striatum (STR), the latter comprising the caudate and putamen nuclei, the main structures in the central nervous system from which it is released. During the last 50 years, numerous studies have highlighted the role of DA in sensory/motor loops. Along with a phasic function exerted in synaptic or close apposition structures, a modulatory role for extracellular DA has also been demonstrated based on the slow and tonic extracellular diffusion of the amine. This duality is probably supported by a metabolic polymorphism, particularly of the release mechanism. The present chapter focuses on works carried out *in vivo* over the last two decades on the control of DA homeostasis in the STR during normal and pathological conditions. It is now generally accepted that the level of extracellular DA is not simply the consequence of dribbling from the synapse after phasic (firing-dependent) overflow but is maintained through tonic, largely non–synaptic, regulatory processes.

The duality of DA release *in vivo* will first be described. An example of an experimental situation allowing this situation to be characterized will be given, followed by a brief overview of the relevant literature from the last three decades.

The tonic regulatory process remains incompletely understood and still requires thorough analysis. In recent years, *in vivo* and *in vitro* studies have led to the development of theoretical models based on the concept of the reversion of the well-known uptake mechanism involving the DA transporter protein (DAT). In particular conditions, DAT could be involved in the control of the extracellular DA concentration through its ability to perform what is called reverse DA transport (DA-RT). Psychotropes from the amphetamine family are known to induce the release of DA through this mechanism, but the physiological involvement of DA-RT has rarely been adressed.

A large number of regulatory processes have been described concerning tonic DA release. Only two aspects of these regulatory processes will be considered here. Specific experiments devoted to showing the role of DA synthesis and extracellular calcium ions will be described and discussed.

Normal and Physio-Pathological Striatal Dopamine Homeostasis 243

Dual release can be demonstrated by the simultaneous use of two probes. DPA uses a carbon fiber electrode to detect the DA released following stimulation of the DA axons in the Medial Forebrain Bundle (MFB) in the lateral hypothalamus. Every 4 minutes, a 20 second stimulation-train pulse produces a large increase in the amperometric signal in the STR that is strictly restricted to the stimulation period (Fig. 2, Olivier et al., 1995). The amplitude of the peaks that occur is roughly constant over time. As discussed elsewhere by Gonon (1988) and Suaud-Chagny et al. (1992), the increase in the oxidation current under these conditions is likely to be mainly due to the DA released, despite the fact that some of this increase could be due to dihydroxyphenyl acetic acid (DOPAC), the first DA metabolite. Simulation of the MFB alters the differential oxidation current but is ineffective in terms of the amount of regional extracellular basal DA measured through a cannula close to the probe used for DPA. The DA collected through the superfusion system originates from a region considerably larger than the carbon fiber. The carbon fiber is only sensitive to events occurring in the range of µm from its suface whereas the superfusing probe collects diffusing molecules from within several hundreds of microns. Differences also arise from the duration of the measurements. Stimulation of the MFB only lasts for a short period of the collection time (here 0.08%). Given this short period of time, any increase in the release of the amine remains undetectable in the superfusing fluid. The superfusing methods are particularly useful for detecting 'regional' fluctuations whereas voltammetry reports local

**Regional Response: superfusion**

**Local response: Voltametry**

**2.1 Spontaneous and evoked DA release** 

Superfusion in the presence of cadmium ions:

Fig. 2. The effect of MFB stimulation on tonic (up) and phasic down DA release

**% of the Spontaneous**

**DPA Oxyd.Pic**

 **Release**

events.

The two first paragraphs will be devoted to the duality of normal DA neurotransmission. It is however crucial to understand how the two different mechanisms of release (tonic and phasic) could maintain their equilibrium in pathological situations. Numerous animal models of neurodegeneration have been created. To date, only situations mimicking the early phases of parkinsonian neurodegeneration have been used to explore this equilibrium. Original results will also be presented here. These will provide new information on the regulatory modulation of the tonic and phasic release occurring during the initial presymptomatic compensatory phases of Parkinson's disease.
