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State-dependent dopamine system regulation using current and novel antipsychotic drug mechanisms: developmental implications in a schizophrenia model

Sonnenschein, Susan (2020) State-dependent dopamine system regulation using current and novel antipsychotic drug mechanisms: developmental implications in a schizophrenia model. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Current antipsychotic drugs act on dopamine (DA) D2 receptors for their therapeutic effects, but their limitations have driven a search for novel treatments. Pharmaceutical research is generally performed in normal rats, whereas models that account for variables including disease-relevant pathophysiology may improve predictive validity. D2 antagonists have been shown to reduce DA neuron activity via D2 autoreceptors to produce over-excitation induced cessation of cell firing (depolarization block). Aripiprazole is a D2 partial agonist shown to normalize hypodopaminergic and hyperdopaminergic states, but through unclear mechanisms. The methylazoxymethanol acetate (MAM) model was used to observe aripiprazole’s effects on hyperdopaminergic activity, compared to control (SAL) rats, using in vivo, anesthetized, electrophysiological recordings. Aripiprazole had no effect in controls, but reduced hyperdopaminergic activity in MAM rats, which was not reversed by apomorphine, suggesting a mechanism other than depolarization block. Furthermore, aripiprazole removed D2 antagonist-induced depolarization block in MAM rats, consistent with autoreceptor agonism, potentially explaining its downregulation of hyperdopaminenrgic activity. These results demonstrate state-dependent neuropharmacological effects. Group II metabotropic glutamate receptors (mGluR2/3) showed promise as a novel target in preclinical research, but the mGluR2/3 agonist, pomaglumetad methionil (POM), showed insufficient efficacy in clinical trials. Although previous studies have shown that mGluR2/3 agonists have no effect on DA in normal rats, MAM rats were used to determine whether POM normalizes a hyperdopaminergic state. POM dose-dependently reduced DA neuron activity of MAM rats, not observed in SAL rats. Intra-ventral hippocampal (vHPC) infusion of POM was sufficient to reduce dopaminergic activity in MAM rats. POM also increased novel object recognition in MAM rats and blocked stress-induced increases in dopaminergic activity in normal rats. To examine developmental effects of POM on MAM, MAM and SAL rats were treated peripubertally and DA neuron activity and vHPC pyramidal neuron activity were recorded in early or late adulthood. POM-treated MAM rats demonstrated normalized DA neuron activity and vHPC pyramidal neuron activity at both timepoints. Thus, POM indirectly regulates DA neuron activity by reducing increased vHPC activity and can prevent DA system hyperactivity in adult MAM rats following peripubertal administration.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sonnenschein, Susansfs29@pitt.edusfs290000-0003-4486-3206
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGrace,
Committee MemberSesack,
Committee MemberLuna,
Committee MemberTurner,
Committee MemberVolk,
Committee MemberAbi-Dargham,
Date: 8 June 2020
Date Type: Publication
Defense Date: 19 December 2019
Approval Date: 8 June 2020
Submission Date: 30 January 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 144
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: schizophrenia, antipsychotic, dopamine, VTA, hippocampus
Date Deposited: 08 Jun 2020 17:02
Last Modified: 08 Jun 2020 17:02


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