Margolis EB, Hjelmstad GO, Bonci A, Fields HL. Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons. J Neurophysiol 93: 3086-3093

University of California, San Francisco, San Francisco, California, United States
Journal of Neurophysiology (Impact Factor: 2.89). 07/2005; 93(6):3086-93. DOI: 10.1152/jn.00855.2004
Source: PubMed


The ventral tegmental area (VTA) plays a critical role in motivation and reinforcement. Kappa and mu opioid receptor (KOP-R and MOP-R) agonists microinjected into the VTA produce powerful and largely opposing motivational actions. Glutamate transmission within the VTA contributes to these motivational effects. Therefore information about opioid control of glutamate release onto VTA neurons is important. To address this issue, we performed whole cell patch-clamp recordings in VTA slices and measured excitatory postsynaptic currents (EPSCs). There are several classes of neuron in the VTA: principal, secondary, and tertiary. The KOP-R agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593; 1 microM) produced a small reduction in EPSC amplitude in principal neurons (14%) and a significantly larger inhibition in secondary (47%) and tertiary (33%) neurons. The MOP-R agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO; 3 microM) inhibited glutamate release in principal (42%), secondary (45%), and tertiary neurons (35%). Unlike principal and tertiary neurons, in secondary neurons, the magnitude of the U69593 EPSC inhibition was positively correlated with that produced by DAMGO. Finally, DAMGO did not occlude the U69593 effect in principal neurons, suggesting that some glutamatergic terminals are independently controlled by KOP and MOP receptor activation. These findings show that MOP-R and KOP-R agonists regulate excitatory input onto each VTA cell type.

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    • "The primary effects of opioids on the dopamine system have been thought to result from the inhibition of GABAergic neurons that normally hold their dopaminergic neighbors under inhibitory control (Johnson and North, 1992). However, more recent studies show that m-opioid agonists also exert presynaptic control over glutamate inputs to the VTA, reducing glutamate currents evoked in dopamine neurons (Bonci and Malenka, 1999; Manzoni and Williams, 1999; Margolis et al, 2005). There may be an immediate increase in glutamate level before the first earned injection that is masked, in our 10-min dialysis samples, by the net effect of heroin itself when it arrives a few seconds after the predictive stimuli. "
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    • "A decrease in event frequency in a slice preparation following blockade of action potential activity suggests that a portion of the spontaneous events were driven by locally firing neurons. Since action potential independent spontaneous glutamatergic events are present in most VTA neurons (Margolis et al., 2005; Deng et al., 2009; Xiao et al., 2009), we should observe a decrease in frequency, but not elimination, of glutamatergic events when action potential activity is blocked by TTX. "
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    • "Indeed, KOR agonists produce prolonged decreases in extracellular DA concentrations in the NAc after systemic administration (Di Chiara and Imperato, 1988; Carlezon et al., 2006) or microinfusions directly into the NAc (Spanagel et al., 1992) or dorsal striatum (Gehrke et al., 2008). They also inhibit excitatory inputs to the VTA (Margolis et al., 2005) and VTA afferents to the medial PFC (Margolis et al., 2006). Thus KOR-mediated decreases in DA transmission appear to contribute importantly to the acute prodepressive-like effects of KOR agonists and stress. "
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