To study the role of dopamine D1 receptors in enhanced oral activity effects of SKF 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) in neonatal 6-hydroxydopamine-lesioned rats, SKF 38393 was compared to the full agonist, A77636 ((1R,3S)-3-(1′-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran). At 3 days after birth rats were treated with 6-hydroxydopamine HBr (200 μg, salt form, i.c.v.; desipramine (20 mg/kg i.p.), 1 h) or vehicle. At 6-8 months a 0.01 mg/kg dose of A77636 HCl increased oral activity in 6-hydroxydopamine vs. control rats (P < 0.01). A77636 and SKF 38393 produced identical maximal responses of 35-36 oral movements at 0.1 and 1.0 mg/kg, respectively. SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) HCl (0.3 mg/kg i.p.) attenuated the response to A77636. Neither A77636 HCl (0.01-1.0 mg/kg i.p.) nor SKF 38393 HCl (0.03-3.0 mg/kg i.p.) induced oral activity in intact rats. The findings demonstrate that A77636 is more potent than SKF 38393, and that supersensitized dopamine D1 receptors are involved in the induction of oral behavior in neonatal 6-hydroxydopamine-lesioned rats.

Phosducin (Pdc) is a 28 kDa binding partner for the G protein beta gamma subunit dimer (G-beta-gamma) found abundantly in the photoreceptor cells of the retina and pineal gland. In the retina, light-dependent changes in cAMP and Ca2+ control the phosphorylation of Pdc at serine 73 and 54, respectively, which in turn controls the binding of Pdc to G protein beta gamma subunit dimer . G protein beta gamma subunit dimer binding has been proposed to facilitate light-driven transport of G protein beta gamma subunit dimer from the site of phototransduction in the outer segment of the photoreceptor cell to the inner segment, thereby decreasing light sensitivity and contributing to the process of light adaptation. Dopamine and melatonin are neuromodulators whose concentrations in the retina vary reciprocally during the circadian cycle, with dopamine high during the day and melatonin high during the night. Together, they control numerous aspects of light and dark adaptation in the retina. In this study, we have investigated the possible roles of dopamine and melatonin in regulating Pdc phosphorylation. Using phosphorylation-site specific antibodies to serines 54 and 73, we show that dopamine decreases the phosphorylation of both sites. This decrease is blocked by D4 receptor antagonists and pertussis toxin, indicating that dopamine causes a decrease in photoreceptor cell cAMP and Ca2+ concentration via the D4 receptor coupled to the Gi protein. Conversely, melatonin increases the phosphorylation of both S54 and S73, most likely via the inhibition of dopamine synthesis. These results demonstrate that dopamine and melatonin control the phosphorylation state of phosducin by changing the concentration of cAMP and Ca2+ in photoreceptor cells, and they suggest that dopamine and melatonin may contribute to the light-induced movement of the photoreceptor G protein by regulating Pdc phosphorylation.

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published_or_final_version / Zoology / Master / Master of Philosophy

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