Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons.
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.
Margolis
Elyssa B
EB
Ernest Gallo Clinic and Research Center, 5858 Horton St., Suite 200, Emeryville, CA 94608, USA. elyssam@egcrc.net
Hjelmstad
Gregory O
GO
Bonci
Antonello
A
Fields
Howard L
HL
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000528:radiation effects; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology*
D000701:Analgesics, Opioid; D044482:Benzeneacetamides; D011759:Pyrrolidines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D018698:Glutamic Acid; C045444:U 69593