Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

12-1993

Abstract

To test whether SKF 38393 could ontogenetically sensitize dopamine (DA) D$\sb1$ receptors and whether this sensitization would be associated with biochemical changes, intact and neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats (200 $\mu$g i.c.v.) were treated daily from birth with SKF 38393 (3.0 mg/kg i.p. x 28 days) or its vehicle. In DA D$\sb1$ neonatally sensitized 6-OHDA rats, enhanced locomotor responses were observed with the first SKF 38393 challenge dose (3.0 mg/kg i.p.) at 6 weeks. This response increased further with weekly SKF 38393 treatments. Enhanced stereotyped behaviors were seen in both lesioned and sensitized rats at 8 weeks. There was no change in the percentage of high affinity D$\sb1$ sites in these groups of rats. Striatal mRNA levels for D$\sb1$ receptors were reduced in the lesioned rats, but restored to control level after treatments with SKF 38393 in adulthood. Basal, DA-, NaF- and forskolin-stimulated adenylate cyclase activities were similar among treatment groups. Striatal DA content was reduced ($>$99%), whereas serotonin (5-HT) content was elevated ($>$50%) in the 6-OHDA groups. To study possible interaction between DA and 5-HT systems, the effects of a series of 5-HT agents on the induction of oral activity were determined. The 5-HT$\sb{\rm 1C}$ receptor agonist, m-chlorophenylpiperazine (m-CPP), produced a marked increase in oral activity in 6-OHDA-lesioned rats. The respective 5-HT$\sb{\rm 1A}$ and 5-HT$\sb{\rm 1B}$ agonists, 8-OH-DPAT and CGS-12066B did not increase oral activity. The m-CPP-induced oral response in the lesioned rats was attenuated by mianserin, a 5-HT$\sb{\rm 1C}$ antagonist, but not by ketanserin or MDL-72222, 5-HT$\sb2$ and 5-HT$\sb3$ antagonists, respectively. Although the supersensitized oral response of lesioned rats to m-CPP was not attenuated by SCH 23390, the enhanced response of SKF 38393 was attenuated by mianserin. Additionally, mRNA levels for 5-HT$\sb{\rm 1C}$ receptor were not altered in both intact and lesioned rats. These findings demonstrate that ontogenetic treatments of neonatal 6-OHDA-lesioned rats with a D$\sb1$ agonist produce partial sensitization of DA D$\sb1$ receptors in adulthood without altered biochemical markers, and that this neonatal lesion is associated with both supersensitized DA D$\sb1$ and 5-HT$\sb{\rm 1C}$ receptors. Moreover, induction of oral activity by DA agonists is mediated via a serotonergic system.

Document Type

Dissertation - unrestricted

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