Tonic Activation of NMDA Receptors Causes Spontaneous Burst Discharge of Rat Midbrain Dopamine Neurons In Vivo

Abstract

Midbrain dopamine neurons in vivo discharge in a single-spike firing pattern or in a burst-firing pattern. Such activity in vivo strikingly contrasts with the pacemaker activity of the same dopamine neurons recorded in vitro. We have recently shown that burst activity in vivo of midbrain dopamine neurons is due to the local activation of excitatory amino acid receptors, as microapplication of the broad-spectrum antagonist of excitatory amino acids, kynurenic acid, strongly regularized the spontaneous firing pattern of these dopamine neurons. In the present study, we investigated which subtypes of excitatory amino acid receptors are involved in the burst-firing of midbrain dopamine neurons in chloral hydrate-anaesthetized rats, iontophoretic or pressure microejections of 6-cyano, 7-nitroquinoxaline-2,3-dione (CNQX), a non-N-methyl-D-aspartate (NMDA) receptor antagonist, did not alter the spontaneous burst firing of dopamine neurons (n = 36). In contrast, similar ejections of (+-)2-amino,5-phosphonopentanoic acid (AP-5), a specific antagonist at NMDA receptors, markedly regularized the firing pattern by reducing the occurrence of bursts (n = 52). In addition, iontophoretic ejections of NMDA, but not kainate or quisqualate, elicited a discharge of these dopamine neurons in bursts (n = 20, 12 and 14, respectively). These data suggest that burst-firing of midbrain dopamine neurons in vivo results from the tonic activation of NMDA receptors by endogenous excitatory amino acids. In view of the critical dependency of catecholamine release on the discharge pattern of source neurons, excitatory amino acid inputs to midbrain dopamine neurons may constitute a major physiological substrate in the control of the dopamine level in target areas.

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels

“…As the different patterns are essentially absent in vitro Grace and Onn, 1989; but see Mereu et al, 1997) afferent input is considered to be a crucial modulator of firing pattern. Considerable evidence implicates an important role for glutamatergic input and especially NMDA receptor stimulation in the burst firing pattern Clark, 1992, 1997;Chergui et al, 1993;Christoffersen and Meltzer, 1995). These conclusions are supported by several recent computational modeling studies of burst firing in dopaminergic neurons (e.g., Canavier, 1999;Amini et al, 1999;Wilson and Callaway, 2000;Medvedev et al, 2003;Komendantov et al, 2004;Kuznetsov et al, 2006).…”

Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders

“…43 In rats, electrical or glutamatergic stimulation of medial PFC areas that appear to include the subgenual PFC elicits burst firing patterns of dopaminergic cells in the VTA and increases DA release in the nucleus. [44][45][46][47][48] The burst firing of DA cell activity elicits more terminal DA release per action potential than the non-bursting, pacemaker firing pattern. 46 The phasic, burst firing of DA neurons and accompanying rise in DA release normally occur in response to primary rewards (until they become fully predicted) and reward-predicting stimuli.…”

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

“…Activation of glutamatergic afferents (Geisler et al, 2007;Grace and Bunney, 1984;Omelchenko and Sesack, 2009), and possibly VM VGluT2-containing interneurons (Dobi et al, 2010), control the transition from peacemaker tonic to phasic burst firing of DA neurons. In contrast, blockade of VM ionotropic glutamate receptors disrupts burst firing (Charlety et al, 1991;Chergui et al, 1993). Dopamine burst firing signals the occurrence of salient unconditional and conditional stimuli (Schultz, 2010) and it is believed to convey motivationally relevant information to forebrain structures involved in motor execution (Overton and Clark, 1997).…”