Excitatory amino acid pathways in brain-stimulation reward

A range of agonists and antagonists active at different glutamate/aspartate (Glu/Asp) receptor subtypes were injected into rat ventral tegmental (VTA) sites downstream from self-stimulation electrodes in the medial forebrain bundle. Control injections were made into the contralateral tegmentum. Variable-interval (VI 10 s) self-stimulation was not significantly affected by a specific antagonist of N-methyl-D-aspartate (NMDA)-type receptors (D,L-2-amino-5-phosphonovaleric acid (2-AP5), 10 and 50 nmol). Broad-spectrum excitatory amino acid (EAA) antagonists viz cis-2,3-piperidine dicarboxylate (cPDA) (10 and 50 nmol), gamma-D-glutamylaminomethyl sulphonic acid (GAMS) (10 nmol) and p-chlorobenzoyl-2,3-piperazine dicarboxylic acid (pCB PzDA) (2.0 and 10 nmol), active at kainate, quisqualate, as well as NMDA receptors, all produced significant depression of responding when injected into the ipsilateral, but not the contralateral, tegmentum. Compounds inhibiting Glu/Asp reuptake had variable effects: strong depression with dihydrokainic acid (7.5 nmol), or no significant effect (L-threo-3-hydroxyaspartic acid, 2.0 and 10 nmol). The receptor agonist, NMDA (10 nmol), depressed responding regardless of injection side; kainic and responding regardless of injection side; kainic and quisqualic acid elicited myoclonic and other non-specific responses in preliminary tests, and were not examined further; enhanced responding was not seen. The side-specific blockade of responding by non-NMDA antagonists indicates the existence of non-NMDA EAA terminals in the VTA, signalling the receipt of hypothalamic brain-stimulation reward. Caudally directed EAA projections terminating on A10 dopamine cell bodies may account for depression of self-stimulation by EAA antagonists.