A large body of evidence indicates that cells in the lateral hypothalamus (LH) and dopamine cells in the ventral midbrain both play an important role in the control of food and water intake. Damage to either of these systems, in fact, results in remarkably similar sets of deficits in both food and water intake. Although these similarities could be coincidental, it seems more likely that they reflect a functional interaction between these two groups of cells. Anatomical data suggest a number of ways in which the hypothalamus and tegmental dopamine cells could be interconnected, and a number of workers have speculated on the presence of various relationships, but the available functional data are extremely limited. We here propose five sets of experiments aimed at investigating the relation between the LH and ascending dopamine systems with respect to the control of ingestive behavior. The first study will attempt to provide direct evidence for a functional relation between the LH and the ascending dopamine system by comparing the effects on feeding and drinking produced by combined unilateral excitotoxic lesions of the LH and .unilateral 6-OHDA lesions of the dopamine cell bodies made on either the same, or the opposite sides of the brain. If the LH and the dopamine cells form parts of a functionally interconnected circuit, one would expect that larger effects would be produced with """"""""crossed"""""""" lesions, than when the lesions were made on the same side of the brain. The remaining experiments examine various possible mechanisms which might underlie LH/dopamine interactions. Experiment 2 examines whether chemical stimulation of cells in the LH is able to alter dopamine release, as measured by in vivo microdialysis, in the nucleus accumbens or the dorsal striatum, the main termini of dopamine projections arising in the ventral tegmental area (VTA) and substantia nigra (SN) respectively. Experiment 3 examines whether injections of 2-deoxyglucose a treatment which induces feeding is able to promote expression of the immediate-early gene c-fos in LH cells projecting to the VTA or SN. Experiment 4 examines whether unilateral 6-OHDA lesions alter the ability of cells in the LH to respond to injections of 2-deoxyglucose. The final .experiment examines whether excitotoxic lesions of the LH are able to attenuate the ability of low doses of amphetamine to induce feeding behavior. Relevance: These studies should help to clarify the neural mechanisms controlling ingestive behavior and the way in which these circuits may be influenced by certain drugs of abuse. Gaining an understanding of these systems is a prerequisite for the rational development of novel treatments for disturbances of ingestion, such as occur in obesity, bulemia and cahchexia. ? ? ?
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