Mesolimbic dopamine neurotransmission is increased by administration of mu-opioid receptor antagonists

Microdialysis and high pressure liquid chromatography were used to assess the effects of ventral tegmental area microinjections of the mu-opioid receptor antagonists D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and beta-funaltrexamine (beta-FNA) on extracellular ventral striatal dopamine and metabolite concentrations. While CTOP is known to antagonize the increases in extracellular ventral striatal dopamine and dopamine metabolite concentrations induced by ventral tegmental area microinjections of a mu-opioid receptor agonist, it produced dose-orderly increases in ventral striatal dopamine and dopamine metabolite concentrations when administered by itself. beta-FNA also elevated dopamine and metabolite concentrations. These mu-agonist-like effects of the mu-opioid receptor antagonists were unexpected and suggest that a complex local circuitry mediates opioid-dopamine interactions in the ventral tegmental area. Since mu-opioids are known to act on ventral tegmental neurons that contain gamma-aminobutyric acid (GABA), a model of interactions between GABAergic afferents to the ventral tegmental area and ventral tegmental GABAergic interneurons is proposed.