Elsevier

Neuropharmacology

Volume 42, Issue 3, March 2002, Pages 289-296
Neuropharmacology

Group I metabotropic glutamate receptors activate burst firing in rat midbrain dopaminergic neurons

https://doi.org/10.1016/S0028-3908(01)00192-7Get rights and content

Abstract

We have investigated the changes in the spontaneous firing pattern induced by DHPG ((S)-3,5-dihydroxyphenylglycine) and NMDA (N-methyl-d-aspartic acid) on rat dopaminergic neurons in substantia nigra pars compacta (SNc) using sharp microelectrode recordings in in vitro conditions. Twenty-five out of 33 cells modified the regular single-pacemaker activity in burst firing when exposed to the Group I metabotropic glutamate receptor (mGluR) agonist DHPG (30 μM) and d-tubocurarine (500 μM) (d-TC), whereas they all fired in bursts during NMDA (20 μM) plus d-TC application. The blockade of SK-channels by d-TC and apamin was essential for the production of both types of bursts. Although the two drugs induced a similar number of action potentials per burst, the DHPG-induced bursts had a lower frequency, a longer duration and a longer plateau period without spikes. In addition, the DHPG-induced bursting had a longer wash-out, could be reduced or blocked by the mGluR 1 selective, non-competitive antagonist CPCCOEt (7-cyclopropan[b]chromen-1a-carboxylic acid ethyl ester) (100 μM) while it was not affected by the mGluR 5 selective antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine (10 μM). These results suggest that both the activation of glutamate metabotropic type 1 and NMDA ionotropic receptors induce burst firing in the dopaminergic cells of the ventral midbrain when the activity of the SK-channels is reduced.

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.

References (46)

  • N.B. Mercuri et al.

    Activation of metabotropic glutamate receptors induces an inward current in rat dopamine mesencephalic neurons

    Neuroscience

    (1993)
  • P. Overton et al.

    Burst firing in midbrain dopaminergic neurons

    Brain Research Reviews

    (1997)
  • V. Seutin et al.

    Apamin increases NMDA-induced burst-firing of rat mesencephalic dopamine neurons

    Brain Research

    (1993)
  • P.D. Shepard et al.

    Electrophysiological and pharmacological evidence for the existence of distinct subpopulations of nigrostriatal dopaminergic neuron in the rat

    Neuroscience

    (1988)
  • P. Vezina et al.

    Metabotropic glutamate receptors and the generation of locomotor activity: interactions with midbrain dopamine

    Neuroscience Biobehaviour Reviews

    (1999)
  • T. Wang et al.

    N-methyl-D-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies

    Brain Research

    (1994)
  • C.J. Wilson et al.

    Statistical properties of neuronal spike trains in the substantia nigra: cell types and their interactions

    Brain Research

    (1977)
  • F. Zheng et al.

    Trans-ACPD (trans-D,L-1-amino-1,3- cyclopentanedicarboxylic acid) elicited oscillation of membrane potentials in rat dorsolateral septal nucleus neurons recorded intracellularly in vitro

    Neuroscience Letters

    (1991)
  • M.S. Brodie et al.

    Pharmacological reduction of small conductance calcium-activated potassium current (SK) potentiates the excitatory effect of ethanol on ventral tegmental area dopamine neurons

    Journal of Pharmacology and Experimental Therapeutics

    (1999)
  • B.S. Bunney et al.

    Dopaminergic neurons effect of antipsychotic drugs and amphetamine on single cell activity

    Journal of Pharmacology and Experimental Therapeutics

    (1973)
  • G. Casabona et al.

    Expression and coupling to phosphoinositide hydrolysis of group I metabotropic glutamate receptors in early postnatal and adult rat brain

    European Journal of Neuroscience

    (1997)
  • K. Chergui et al.

    Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo

    European Journal of Neuroscience

    (1993)
  • P.J. Conn et al.

    Pharmacology and functions of metabotropic glutamate receptors

    Annual Reviews in Pharmacology and Toxicology

    (1997)
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