Modification of brain function regulating metabolism by antisense oligodeoxynucleotides

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In the ventromedial nucleus of the hypothalamus (VMH), gamma-aminobutyric acid (GABA) plays an important role in regulating metabolism. The GABA synthetic enzyme, glutamic acid decarboxylase (GAD) consists of two isozymes, GAD65 and GAD67. In the present study, the effect of injection of antisense oligodeoxynucleotides (ODNs) to each GAD isozyme into the VMH of the male rat on food intake, body weight and locomotor activity was examined. Phosphorothioated antisense ODNs were incorporated in the water-absorbent polymer (WAP) and injected into bilateral VMH,and the day of injection was designated as day 0. Antisense ODNs to GAD65 and GAD67 tended to reduce food intake on day 1, though not significant. Simultaneous injection of antisense ODNs to both GAD isozymes significantly decreased food intake on only day 1, but body weight remained suppressed by this treatment for 5 days. On the other hand, simultaneous administration of antisense ODNs to GAD65 and GAD67 significantly increased loco … More motor activity between days 3-5, whcreas other treatments did not. This increase in daily locomotor activity was mainly due to the increase in locomotor activity during the light, but not dark, phase. Neither vehicle (WAP) nor control ODN affected food intake, body weight and locomotor activity. Histological studies indicated that, 24 h after the injection, antisense ODN distributed within about 800 mum from the edge of area where WAP was located and then gradually disappeared with days, but still remained within 300 mum distance even 7 days after the injection. Antisense ODN was effectively incorporated by all the cell types examined, i.e.neurons, astrocytes and microglias. Further, HPLC analysis revealed that antisense ODN to either GAD isozyme decreased the content of GABA,but not other amino acids, in the VMH by 24 h. These results suggest that either GAD isozyme is synergistically involved in enhancing food intake and suppressing locomotor activity in rat VMH.This study also indicates that central injection of antisense oligodeoxynucleotides is useful means to regulate animal metabolism. Less