Research Project
6400637
The goal of this project is defining the role of serotonin (5-HT) in the brain in reducing the control of eating by environmental stimuli. The studies will test the hypothesis that stimulating 5-HT1B (formerly, 5-HT1Dbeta) receptors inhibits learned ingestive responses. Pavlovian conditioning of jaw movements in rabbits will be used. This well-established model allows precise: definition of the physical properties of the conditioned (external) stimuli (CS's) and the unconditioned (appetitive) stimuli (US's); control of the temporal relationship between presentation of the CS and US; and measurement of the characteristics of the conditioned (CR) and unconditioned (UR) responses. Thus, this model is a powerful tool for analyzing the effects of drugs on associative learning and the mechanisms for these actions. CS's (tones) will be paired with intraoral infusion of the US, sucrose. In initial data, systemic injection of a 5-HT1B agonist selectively decreased expression of appetitively conditioned but not unconditioned jaw movements. Experiments will analyze the actions of 5-HT1B agonists on the: acquisition and expression of CR's; and the threshold intensity for CS's to elicit CR's ("CS excitability"). Stimulating 5-HT1B receptors promotes satiation in rabbits. Thus, controls for nonassociative behavioral effects and pharmacological selectivity of action will be included. We predict that stimulating 5-HT1B receptors will dampen CS excitability and therefore reduce the frequency of CR's. The nucleus accumbens (NAC) contains a shell (involved in primary aspects of reward) and a core (for associating external stimuli with rewards and expressing motor responses to incentive stimuli). We hypothesize that the NAC plays a role in serotonergic control of appetitive CR's. 5-HT1B receptors are distributed throughout the NAC; thus studies will map the critical site(s) in the NAC where 5-HT1B agonists dampen conditioned jaw movements. We will then determine whether: infusing 5-HT1B antagonists will enhance CS excitability; and destroying 5-HT innervation of the NAC will potentiate agonist actions on CR expression and on cellular signaling. Overall, the results will provide new information for elucidating neurochemical bases for cognitive processes that initiate, sustain and terminate eating. Rabbits, unlike rodents, express the human form of 5-HT1B receptors. Thus together, the data should be relevant for developing novel strategies for treating obesity, eating disorders and compulsive disorders underlying self-administration substances such as drugs of abuse.
