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Both Kappa and Mu Opioid Agonists Inhibit Glutamatergic Input to Ventral Tegmental Area Neurons

¹Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville; and ²Department of Neurology and Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, California

Submitted 18 August 2004; accepted in final form 17 December 2004

The ventral tegmental area (VTA) plays a critical role in motivation and reinforcement. Kappa and µ 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 µM) 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 µM) 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.

This article has been cited by other articles:

				E. B. Margolis, H. L. Fields, G. O. Hjelmstad, and J. M. Mitchell {delta}-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption J. Neurosci., November 26, 2008; 28(48): 12672 - 12681. [Abstract] [Full Text] [PDF]

				H. D. Mansvelder Yin and Yang of VTA Opioid Signaling. Focus on "Both Kappa and Mu Opioid Agonists Inhibit Glutamatergic Input to Ventral Tegmental Area Neurons" J Neurophysiol, June 1, 2005; 93(6): 3046 - 3047. [Full Text] [PDF]