Differential modulation by dopamine of responses evoked by excitatory amino acids in human cortex

Abstract

The responses of human neocortical neurons to iontophoretic application of excitatory amino acids and their modulation by dopamine (DA) were studied in vitro. Brain slices were obtained from children undergoing surgery for intractable epilepsy. Application of N-methyl-D-aspartate (NMDA) to the slices induced slow depolarizations accompanied by decreased input conductances and sustained action potentials in cortical neurons. Glutamate produced rapid depolarizations and firing with few changes in input conductances. Quisqualate also induced depolarization and firing, but input conductances increased during the rising phase of the membrane depolarization. Iontophoretic application of DA alone produced no change in membrane potential or input conductance. However, when DA was applied in conjunction with the excitatory amino acids, it produced contrasting effects. With either bath application of DA or when iontophoresis of DA preceded application of NMDA, the amplitude of the membrane depolarizations and the number of action potentials were increased, whereas the latency of these responses decreased. In contrast, DA decreased the amplitude of the depolarizations and the number of action potentials evoked by glutamate or quisqualate. The fact that DA affects responses to NMDA and glutamate or quisqualate in opposite directions is of considerable importance to the understanding of cellular mechanisms of neuromodulation and the role of DA in cognitive processing and in epilepsy.

Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms

“…In the striatum, for instance, D1 receptors potentiate responses mediated by NMDA receptors, whereas D2 receptors depress AMPA responses (Cepeda et al, 1993). A similar pattern has been reported in human neocortical neurons (Cepeda et al, 1992), and a D1 enhancement of NMDA responses has been observed in the PFC of young rats (Wang and O'Donnell, 2001). Despite the wealth of data indicating that DAglutamate interactions are essential for mature cognitive functions, the few studies conducted to address cellular mechanisms of these interactions have been performed in slices from prepubertal (typically Ͻ40 d old) animals.…”

“Early” and “Late” Effects of Sustained Haloperidol on Apomorphine- and Phencyclidine-induced Sensorimotor Gating Deficits

“…A second possible explanation for the delayed emergence of anti-PCP effects of haloperidol in this paradigm is that these effects may result from a direct augmentation of NMDA receptor processes (Banerjee et al 1995), or via changes in specific interactions between glutamate and DA receptors in frontal cortex (Cepeda et al 1992), striatum (Amalric et al 1994;Smith et al 1994) or nucleus accumbens (Svensson et al 1994) -all regions implicated in the regulation of PPI (Swerdlow et al 1992). Other reports suggest that subchronic perturbations of glutamatergic substrates via repeated injections of PCP are capable of modifying behavioral and neurochemical properties of brain DA systems (Jentsch et al 1997(Jentsch et al , 1998.…”

Activation of D1, but not D2 Receptors Potentiates Dizocilpine-Mediated Disruption of Prepulse Inhibition of the Startle

“…In particular, the strong influence affected by dopamine on responses mediated by N-methyl-D-aspartate (NMDA) receptors (Clow and Jhamandas, 1989) potentially functions as a filtering device for the extraction of relevant information, either by modifying the signal-to-noise ratio (Cepeda et al, 1992) or by promoting orientation of attentional resources toward significant stimuli (Redgrave et al, 1999). Impairment of filtering mechanisms is conjectured to lead to sensory flooding and sensorimotor gating deficits (McGhie and Chapman, 1961;Braff and Geyer, 1990), which characterize several neuropsychiatric disorders (for a review see Braff et al, 2001), such as bipolar disorder (Saccuzzo and Braff, 1986;Perry et al, 2001), Huntington's disease (Swerdlow et al, 1995), obsessive-compulsive disorder (Swerdlow et al, 1993), Tourette's syndrome (Castellanos et al, 1996), and, particularly, schizophrenia (Braff et al, 1978).…”