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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS024782-01A2
Application #
3409673
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-12-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Lee, K S; Lowenkopf, T (1993) Endogenous adenosine delays the onset of hypoxic depolarization in the rat hippocampus in vitro via an action at A1 receptors. Brain Res 609:313-5
Yamamoto, H; Fukunaga, K; Lee, K et al. (1992) Ischemia-induced loss of brain calcium/calmodulin-dependent protein kinase II. J Neurochem 58:1110-7
Arai, A; Vanderklish, P; Kessler, M et al. (1991) A brief period of hypoxia causes proteolysis of cytoskeletal proteins in hippocampal slices. Brain Res 555:276-80
Lee, K S; Frank, S; Vanderklish, P et al. (1991) Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci U S A 88:7233-7
Lee, K S; Brooks, P; Lowenkopf, T (1991) Transient ischemia attenuates neuronal afterdischarges induced in the absence of synaptic transmission. Brain Res 553:171-4
Arai, A; Kessler, M; Lee, K et al. (1990) Calpain inhibitors improve the recovery of synaptic transmission from hypoxia in hippocampal slices. Brain Res 532:63-8
Seubert, P; Lee, K; Lynch, G (1989) Ischemia triggers NMDA receptor-linked cytoskeletal proteolysis in hippocampus. Brain Res 492:366-70
Lee, K S (1989) Selective neuronal vulnerability and the distribution of N-methyl-D-aspartate (NMDA) receptors. Neurobiol Aging 10:609-11;discussion 618-20