Our hypothesis is that brain dopamine D-1 and/or D-2 receptors mediate the positive reinforcing effect of sucrose on eating. We will study sham feeding of sucrose in rats chronically implanted with gastric cannulas (to eliminate post-ingestive effects) and with brain cannulas (for central drug infusions). Four experiments are proposed, the first three use a pharmacological approach, and the fourth, a neurochemical approach. In Experiment 1, the potent, selective D-1 and D-2 receptor antagonists, SCH 23390 and raclopride, respectively, will be infused unilaterally (in separate groups) into a lateral ventricle (i.c.v.). An ID50 for inhibition of sucrose sham feeding will be determined. Necessary controls include: (1) central versus peripheral locus of inhibitory action (ID50 i.c.v. vs i.p.); (2) stereospecificity of inhibition (active vs. inactive enantiomers i.c.v.), and (3) behavioral specificity (sucrose sham feeding vs. water sham drinking). In Experiment 2, the same sequence of testing described in Experiment 1 will be conducted, but the antagonists will be microninjected bilaterally into forebrain dopaminergic terminal zones. These sites have been implicated in the positive reinforceing effects of sucrose in our previous neurochemical experiments, as well as in reinforcement by foods, drugs and electrical stimulation by others. In Experiment 3, sites at which the local applications of selective D-1 and/or D-2 receptor antagonists are found to inhibit sucrose sham feeding in Experiment 2 will be further studied pharmacologically. The chronic destruction of dopaminergic terminals in these sites identified in Experiment 2 will be performed using 6-OHDA infusions bilaterally and the effects of these lesions on sham feeding of sucrose will be determined. Dopamine agonist replacement with dopamine (DA) itself or the selective D-1 (SKF) 38393) and D-2 (LY-141865) agents will be examined. In Experiment 4, we propose to quantify brain dopaminergic metabolism (DOPAC/DA) in discrete micropunched regions corresponding to those studied in Experiments 2 and 3. This will be measured after 9 min of sham feeding sucrose, using HPLC with electrochemical detection. The results of the four experiments will provide converging pharmacological, behavioral and neurochemical evidence to test the hypothesis that specific brain D-1 and/or D-2 sites mediate the positive reinforcing effect of sucrose on sham feeding.
