Dopamine-deficient (DD) mice cannot synthesize dopamine (DA) in dopaminergic neurons due to selective inactivation of the tyrosine hydroxylase gene in those neurons. These mice become hypoactive and hypophagic and die of starvation by 4 weeks of age. We used gene therapy to ascertain where DA replacement in the brain restores feeding and other behaviors in DD mice. Restoration of DA production within the caudate putamen restores feeding on regular chow and nest-building behavior, whereas restoration of DA production in the nucleus accumbens restores exploratory behavior. Replacement of DA to either region restores preference for sucrose or a palatable diet without fully rescuing coordination or initiation of movement. These data suggest that a fundamental difference exists between feeding for sustenance and the ability to prefer rewarding substances.

from animal and human studies suggests that eropeptide Y (NPY) may be a potent endogenous .my tie. The anatomic structures mediating this action �fht peptide remain unknown. Furthermore, in addition �iIs anxiolytic-like effects, intracerebroventricular ""istration of NPY induces food intake through IIJpothalamic me chanisms, making the anxiolytic-like • of the peptide more difficult to interpret. The JI1JIOSi of this study was to examine the anatomic _rate for the effects of NPY on anxiety, and to _ferize the NPY receptors mediating these effects. lItrIctrebroventricular injection of NPY produced irrmse d food intake in free-feeding animals, and dose Itpmdent anticonflictlanxiolytic-like effects in an IIIbI ished animal model of anxiety, the Geller-Seifter Mlished by Elsevier Science Publishing Co., Inc.• Avenue of the Americas, New York, NY 10010 punished responding test. In contrast, microinjection of NPY into the central nucleus of the amygdala did not increase food intake in free-feeding animals, did not affect unpunished lever pressing for food, but did reproduce the anticonflictlanxiolytic-like effect with high potency. The selective NPY-YI agonist, p[Leu 31 ,Pro 3 4]NPY was approximately equipotent with native NPY in the conflict paradigm, and markedly more potent than the Y2 agonist, NPY 13 -3 6. Intrastriatal injections had no effect on conflict behavior. Thus, activation of YI receptors in the central nucleus of the amygdala produces effects similar to established anxiolytics without affecting food intake, suggesting that YI-receptors in the amygdala may be a substrate for anxiolytic actions of NPY.

We have hypothesized that the midbrain dopamine (DA) neurons are a target for insulin action in the central nervous system (CNS). In support of this hypothesis, we have previously demonstrated that direct intracerebroventricular infusion of insulin results in an increase in mRNA levels for the DA reuptake transporter (DAT). In this study, 24- to 36-hour food deprivation was used as a model of decreased CNS insulin levels, to test whether DAT mRNA levels, DAT protein concentration or DAT functional activity would be decreased. DAT mRNA levels, assessed by in situ hybridization, were significantly decreased in the ventral tegmental area/substantia nigra pars compacta (VTA/SNc) (77 ± 7% of controls, p < 0.05) of food-deprived (hypoinsulinemic) rats. Binding of a specific high-affinity DAT ligand (¹²⁵I-RTI-121) to membranes from brain regions of fasted or free-feeding rats provided an estimate of DAT protein, which was unchanged in both of the major terminal projection fields, the striatum and nucleus accumbens (NAc). In addition, we utilized the rotating disk electrode voltametry technique to assess possible changes in the function of the DAT in fasting (hypoinsulinemic) rats. The V_max of DA uptake was significantly decreased (87 ± 7% of control, p < 0.05), without a change in the K_m of uptake, in striatum from fasted rats. In vitro incubation with a physiological concentration (1 nM) of insulin resulted in an increase of striatal DA uptake to control levels. We conclude that striatal DAT function can be modulated by fasting and nutritional status, with a contribution by insulin.

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