Neurochemical evidence that AMPA receptor-mediated tonic inhibition of hypothalamic dopaminergic neurons occurs via activation of inhibitory interneurons

Blockade of -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors with 6-nitro-7-sulfamoyl-benzo-[f]quinoxaline-2,3(1H,4H)-dione (NBOX) activates tuberoinfundibular (TIDA) and periventricular-hypophysial dopaminergic (PHDA) neurons suggesting that these neurons are tonically inhibited by endogenous excitatory amino acid neurotransmitters acting at AMPA receptors. The purpose of the present study was to identify prospective inhibitory neurotransmitters mediating this effect by examining the ability of γ-aminobutyric acid (GABA)_A and κ-opioid receptor agonists to reverse the stimulatory effects of NBQX on the activity of these neurons (estimated from concentrations of 3,4-dihydroxyphenylacetic acid [DOPAC] in the median eminence and intermediate lobe of the pituitary). The GABA_A receptor agonist isoguvacine prevented the NBQX-induced increase in DOPAC concentrations in the median eminence but not in the intermediate lobe. The κ-opioid receptor agonist U-50,488 had no effect in the median eminence, but attenuated the NBQX-induced increase of DOPAC concentrations in the intermediate lobe. These results suggest that excitatory amino acid neurotransmitters activate AMPA receptors and increase release of GABA, which by acting at GABA, which by acting at GABA_A receptors tonically inhibits TIDA neurons. On the other hand, AMPA receptor-mediated tonic inhibition of PHDA neurons occurs, at least in part, by a mechanism involving endogenous κ-opioids.