Group I metabotropic glutamate receptors activate burst firing in rat midbrain dopaminergic neurons
Introduction
The discharging pattern of midbrain dopaminergic cells has a profound influence on the overall functioning of the dopamine system. Several studies have already shown that dopaminergic neurons display different mode of activity when recorded in in vivo conditions. In particular, they fire either burst of action potentials or irregular single spikes (Bunney et al., 1973, Grace and Bunney, 1984a, Grace and Bunney, 1984b, Grace and Onn, 1989, Shepard and German, 1988, Wilson et al., 1977). Interestingly, the bursting activity maximizes the release of dopamine (DA) in the brain (Overton and Clark, 1997). In fact, the amount of extracellular DA is enhanced in the striatum, nucleus accumbens and cerebral cortex when dopaminergic neurons switch from a single-spike firing to bursts of action potentials (Gonon, 1988, Gonon and Buda, 1985, Manley et al., 1992, Nissbrandt et al., 1994). This bursting activation is also related to relevant and novel rewarding stimuli (Freeman et al., 1985, Horvitz et al., 1997, Mirenowicz and Schultz, 1996, Schultz, 1998).
The dopaminergic neurons, when recorded in in vitro conditions, are mainly characterized by a regular, single-spike spontaneous firing (Grace and Onn, 1989, Johnson and North, 1992, Lacey et al., 1989, Yung et al., 1991). Thus, the absence of the variety of activity patterns observed in vivo is presumably due to the loss of extrinsic afferents impinging on these neurons. The particular importance of excitatory synaptic inputs has been suggested by the observation that: (a) the stimulation of N-methyl-d-aspartic acid (NMDA)-receptors plays an essential role in the discharge pattern of these cells in in vivo experiments; (Chergui et al., 1993, Tong et al., 1996) (b) the continuous activation of NMDA receptors, when associated with modifications of intrinsic membrane components (Kitai et al., 1999), transforms the typical pacemaker-like discharge of the dopaminergic neurons in a bursting mode in in vitro conditions (Johnson et al., 1992, Wang et al., 1994). However, the tonic activation of ionotropic receptors of the NMDA type may not be the exclusive determinant of the bursting behavior of these cells. For instance, the activation of metabotropic glutamate receptors (mGluRs) could be also involved. Therefore, the purpose of the present study was to determine whether group I mGluRs agonists, that exert an excitatory effect on dopaminergic neurons in in vitro experiments (Mercuri et al., 1993) and increase the frequency of bursts in in vivo conditions (Meltzer et al., 1997), could induce, under particular conditions, bursting activity in these cells. To test for this possibility, in vitro intracellular recording techniques were used and the selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) (Conn and Pin, 1997, Shoepp et al., 1994) was applied, in the presence of tubocurarine (d-TC) or apamin, on the dopaminergic cells of the substantia nigra pars compacta (SNc). Tubocurarine at a high concentration (500 μM), has reversible apamin-like effects, blocking a small Ca++-activated K+ current (SK) and reducing the amplitude of the post-spike afterhyperpolarization (AHP) (Brodie et al., 1999, Ishii et al., 1997, Köhler et al., 1996).
Section snippets
Preparation of the tissue
The method used has been described previously (Mercuri et al., 1995). In brief, Wistar rats (150–250 g) were anaesthetized with ketamine and killed. All efforts were made to minimize animal suffering and the number of animals used. All experiments follow international as well as local guidelines on the ethical use of animals from the European Communities Council Directive of 24 November 1986 (86/609/EEC) and the ethical committee of the University of Tor Vergata (Rome, Italy). The brain was
Properties of the cells
The data presented below were obtained from presumed ‘principal’ dopaminergic neurons of the substantia nigra pars compacta. These cells fired spontaneously in a pacemaker-like mode [Fig. 2(a)] at a rate of 1.2±0.3 Hz (n=34) and presented action potentials longer than 1.4 ms. The mean interspike interval (ISI) was 860.3±65.5 ms (n=34). They also displayed a pronounced time and voltage-dependent rectification Ih, during hyperpolarizing voltage pulses. In addition, the application of DA (10–30
Discussion
The present in vitro study shows that the activation of group I mGluRs, as well as NMDA receptors, can induce a switch of the spontaneous firing activity from a single-spike to a bursting mode in midbrain dopaminergic neurons. These data are in line with the current hypothesis that the glutamatergic synaptic inputs activating NMDA receptors control the firing pattern of dopaminergic neurons (Johnson et al., 1992, Overton and Clark, 1997, Wang et al., 1994). In addition, they also suggest a new
Conclusions
The present study provides the first evidence for a role of mGluRs 1 in the activation of bursting behavior in midbrain DA-containing neurons. This effect is observed in the majority of cells exposed to the mGluR 1 agonist DHPG and require the closure of the SK channels. Since bursts are more effective than single-spike firing to increase DA release in the brain, the involvement of metabotropic glutamate receptors in this phenomenon further strengthen the role of this amino acid in transforming
Acknowledgments
The technical assistance of M. Federici is gratefully acknowledged.
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