Overeating after midbrain 6-hydroxydopamine: prevention by central injection of selective catecholamine reuptake...

Earlier research from this laboratory showed that 6-hydroxydopamine (6-OHDA) injected into the ventral midbrain of rats causes overeating and the gradual development of obesity in association with extensive depletion of forebrain norepinephrine. It was proposed that depletion of norepinephrine or epinephrine was the cause of the behavioral abnormality. This was questioned on the basis of experiments showing that 6-OHDA can cause non-selective lesions and also that non-selective neurotoxins can cause hyperphagia. To help resolve this question, the present experiments used 191 rats in 28 groups to test 3 doses of 6-OHDA and 3 different pretreatments with reuptake blockers, amphetamine, desmethylimipramine and benztropine. The result of midbrain 6-OHDA alone was hyperphagia that was highly correlated with the dose. Pretreatment with intraperitoneal desmethylimipramine (DMI) caused gastric distress, and systemic amphetamine caused delayed overeating, but these unwanted side effects were avoided by injecting the drugs directly into the midbrain 15 min before the 6-OHDA. DMI and amphetamine partially prevented catecholamine depletion in the forebrain and totally prevented subsequent hyperphagia and obesity. Benztropine prevented dopamine depletion, but had no effect on hyperphagia. We conclude that some of the neurons protected by local injection of amphetamine and DMI are probably norepinephrine or epinephrine fibers that ascend through the ventral midbrain and have as one of their functions the inhibition of food intake. These neurons could also play a role in the control of body weight.