The effects of VTA NMDA receptor antagonism on reward-related learning and associated c-fos expression in forebrain

The mechanisms whereby reward-associated stimuli come to function as conditioned stimuli and acquire the capacity to activate the same neural regions activated by primary rewards (i.e., dopamine terminal regions) is not fully understood. We hypothesized that NMDA receptor stimulation in the VTA is necessary for the acquisition by a CS to both produce conditioned approach and activate dopamine terminal regions. Rats were tested in a conditioned approach protocol that consisted of light stimulus-food conditioning sessions (30 randomly presented light stimulus-food pellet pairings), a session with no stimuli or food and 1 session with only light stimulus (CS-only) presentations. Food trough head entries during the CS and just prior to the CS were recorded and a CS/pre-CS ratio indicating the conditioned approach response was calculated. Brain tissue was harvested after the CS-only session and processed for c-fos expression in prefrontal cortex area 2, nucleus accumbens core and shell and medial and lateral caudate. When bilateral intra-VTA microinjections of AP-5 (0, 0.25 or 0.5 μg) were made prior to each of the conditioning sessions the 0.5 μg AP-5 dose prevented the acquisition of conditioned approach; when 0.5 μg AP-5 injections were made prior to the CS-only test they failed to affect expression of the response. Also, 0.5 μg AP-5 prior to conditioning significantly reduced c-fos expression in response to the CS in nucleus accumbens core. These results suggest that VTA NMDA receptor stimulation is necessary for both the acquisition of reward-related learning and acquisition by the CS to activate dopamine terminal regions.