Attenuation of Antagonist-induced Impairment of Dopamine Receptors by L-prolyl - L-leucyl-glycinamide

ATTENUATION OF ANTAGONIST-INDUCED IMPAIRMENT IN DOPAMINE RECEPTOR ONTOGENY BY L-PROLYL-L-LEUCYL-GLYCINAMIDE by Mohamad Iqbal Saleh, M.D. It has been shown by others that the prenatal treatment of rats with haloperidol, a dopamine D2 receptor antagonist, leads to a permanent reduction in the number of striatal dopamine D2 receptors in adulthood. Conversely, postnatal treatment of lactating dams with haloperidol from birth for 21 days, leads to an increase in the number of striatal dopamine D2 receptors in the litters, when assessed as adults. The present study was undertaken in order to determine whether chronic, long-term postnatal challenge of rat pups per se, with specific dopamine D1 and D2 receptor antagonists, would modify the ontogeny of the respective receptor types. Since the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) attenuates the effect of haloperidol on dopamine D2 receptors in adult rats, it was of interest to determine whether PLG would modulate antagonist-induced alterations in the ontogeny of striatal dopamine D1 and D2 receptors. Half of the rats were treated daily for 32 cjlays from birth with SCH-23390 (0.30 mg/kg/d i.p.), a selective dopamine D1 antagonist; or spiroperidol (1.0 mg/kg/d i.p.), a selective dopamine D2 antagonist; or both SCH-23390 and spiroperidol; or saline. The other half of the litters were treated with PLG (1.0 mg/kg/d, i.p.), in combination with the other treatments. Animals were decapitated at 5,8, and 12 weeks from birth for neurochemical analysis of the striatum. Chronic SCH-23390 treatment produced a 70-80% decrease in the binding of [3H] SCH-23390 (300 pM) to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for [3H] SCH-23390 binding, and no change in the K^. Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of [3H] spiroperidol (300pM) to striatal homogenates by 70-80%. The alteration at 5 weeks was associated with a 74% decrease in the Bmax for [3H] spiroperidol binding, and no change in Kq . Furthermore, PLG attenuated these respective changes in dopamine D1 and D2 binding, when assessed at 5 and 8 weeks. These findings demonstrate that the postnatal period is a sensitive and critical time in the development of striatal dopamine Dl and D2 receptors and that PLG is able to attenuate the alterations in ontogeny that are produced by dopamine Dl and D2 receptor antagonists. iii