The positive symptoms of schizophrenia primarily result from an excess of high affinity D2-like receptors (i.e. D2High receptors). First-generation antipsychotics, such as haloperidol, are D2-like antagonists that can cause severe extrapyramidal effects. Aripiprazole, a dopamine and serotonin partial agonist, has fewer side effects, making it tolerable for adults and children. Extrapyramidal effects (e.g. Parkinsonism, dystonia, and akathisia) are among the most problematic side effects produced by antipsychotic compounds, which likely result from an excess of D2-like receptors in the dorsal striatum. In order to examine the effects of repeated antipsychotic treatment on dopamine system functioning, this thesis compared the molecular effects of repeated haloperidol and aripiprazole administration on D2High receptors, as well as various indices of dopamine second messenger system functioning. Preadolescent and adult rats were pretreated with haloperidol or aripiprazole for 11 consecutive days. After either a 4- or 8-day drug abstinence period dorsal striatal tissue was extracted. [35S]GTPγS binding assays were conducted to assess the effects of repeated haloperidol and aripiprazole treatment on the efficacy and potency of D2-like receptors. PKA subunits and components of the Akt pathway were measured using Western Blots. Results showed that repeated treatment with haloperidol or aripiprazole did not significantly affect D2-like receptor efficacy or potency in young or adult rats. In both age groups, haloperidol significantly increased the expression of PKA-Cα, PKA-Cβ, and PKA-RII, but not p-PKA. Haloperidol also significantly increased PKA-Cβ and PKA-RII levels relative to aripiprazole. Repeated administration of haloperidol significantly increased p-GSK-3β levels in young and adult rats, but neither haloperidol nor aripiprazole significantly affected GSK-3β, Akt, or p-Akt levels. Overall, the results of this thesis indicate that repeated aripiprazole and haloperidol treatment differentially affects D2 signaling pathways in the dorsal striatum. Aripiprazole has less extreme or prolonged effects on D2 receptor signaling pathways than haloperidol, as evidenced by the lack of post-treatment upregulation in the cAMP and Akt pathways. Upregulation of D2-like receptors and, in turn, upregulation of proteins in the cAMP and Akt pathways may be partially responsible for the side effects induced by long-term antipsychotic treatment.
| Identifer | oai:union.ndltd.org:csusb.edu/oai:scholarworks.lib.csusb.edu:etd-1470 |
| Date | 01 December 2016 |
| Creators | Becker, Megan Leigh |
| Publisher | CSUSB ScholarWorks |
| Source Sets | California State University San Bernardino |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses, Projects, and Dissertations |
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