The neutral endopeptidase-24.11 inhibitor SCH 34826 does not change opioid binding but reduces D1 dopamine receptors in rat brain.

The effect of repeated administration of the neutral endopeptidase-24.11 (NEP) inhibitor SCH 34826 on the kinetic properties of opioid and dopamine binding in the rat cerebral cortex and striatum was investigated. SCH 34826, given at 100 and 300 mg/kg orally twice a day for 14 days, did not alter either Bmax or Kd for the mu, delta, or kappa opioid receptor type in the cortex, as measured by studying binding parameters for the mu-selective ligand [3H][D-Ala2, Me-Phe4,Gly(ol)5]enkephalin (DAGO), the delta-selective ligand [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) and the kappa ligand [3H]ethylketazocine (EKC). SCH 34826 reduced significantly the number of D1 dopamine receptors labeled with [3H]SCH 23390 in the striatum (Bmax was 90 and 84% of controls at 100 and 300 mg/kg, respectively). The number of D2 receptors, measured by [3H]spiperone binding was unaltered. The Kd values for both receptor types were not affected. The data demonstrate that chronic inhibition of enkephalin degradation by SCH 34826 does not alter opioid receptors, whereas it reduces the number of D1 receptors. These findings provide further support for the role of opioids in modulating central dopaminergic systems. As a reduction in the number of D1 receptors is an effect common to antidepressant treatments, the antidepressant potential of NEP inhibitors should be investigated.