2004 — 2007 |
Richtand, Neil Mark |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of D3 Dopamine Receptor in Behavioral Sensitization @ University of Cincinnati
DESCRIPTION (provided by applicant): Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, augments rodent locomotion in a long-standing fashion. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. The role of individual dopamine receptor subtypes in sensitization, however, has not been clearly identified. D3 dopamine receptor stimulation inhibits rodent locomotion. D3 receptor activity may be regulated through expression of an alternatively spliced, truncated receptor isoform (termed "D3nf") altering receptor localization and function via dimerization with the full-length subunit. The central hypotheses for our research are that 1.) repetitive D3 receptor stimulation contributes to development of sensitization through decreased responsivity of D3 receptor-mediated locomotor inhibition; and 2.) increased D3nf expression directs altered receptor localization and subsequent release of D3-receptor mediated inhibition, contributing to expression of sensitization. We will test these hypotheses with the following Specific Aims. In Specific Aim 1,we identify the role of D3 receptors in behavioral sensitization to amphetamine. We test the hypothesis that a homeostatic, compensatory response to D3 receptor stimulation contributes to altered D3 receptor splicing and the development of sensitization by determining the effect of dopamine receptor agonists and antagonists on development of sensitization and D3 receptor isoform expression. In Specific Aim 2, we will evaluate behavioral response to D3 receptor antagonists following chronic drug administration. We will measure the behavioral response to D3 receptor blockade, using D3-selective drugs as a tool to measure D3 receptor function. This aim tests the hypothesis that expression of sensitization results in part from release of D3-mediated inhibition, therefore resulting in decreased response to D3 receptor antagonist. In Specific Aim 3, we will determine the consequences of chronic amphetamine administration on D3 dopamine receptor expression. We will measure expression of both full-length D3 receptor and D3nf mRNA, and also measure D3 receptor internalization. This aim tests the hypothesis that chronic amphetamine administration increases D3nf expression, thereby inhibiting full-length D3 receptor function by internalizing the full-length receptor. We expect to demonstrate increased D3nf expression, and increased D3 receptor internalization, following sensitization. This finding would suggest alternative splicing pathways as a novel intervention to prevent sensitization, as well as restore D3-mediated inhibitory function, and would also suggest a biological function for D3nf. Collectively; these studies provide a multi-faceted test of a novel hypothesis of the mechanism underlying long-standing changes in limbic-mediated behaviors. These outcomes may suggest new interventions for neuropsychiatric conditions in which dopamine is known to play an important role, including psychosis and drug dependence. Significantly, these studies may also elucidate a previously unrecognized mechanism regulating receptor desensitization and trafficking relevant to other receptor systems and pathological conditions.
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2008 — 2009 |
Richtand, Neil Mark |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Antipsychotics, Hypoglycemia, Glutamate and Cognition @ University of Cincinnati
[unreadable] DESCRIPTION (provided by applicant): Severe hypoglycemic episodes are a common occurrence among diabetic patients. An important interaction between hypoglycemia and antipsychotic medications, however, has gone largely unnoticed. The risk for diabetes is doubled in schizophrenia, and hypoglycemic episodes are a common side effect of treatment for both type 1 and type 2 diabetes. Preclinical studies demonstrate cognitive impairment mediated by elevated glutamate following insulin-induced hypoglycemia. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate through antagonist effects on dopamine D2 and serotonin 5HT1A receptors, while serotonin 5HT2A receptor antagonists inhibit glutamate release. Glutamate is excitotoxic through effects on ionotropic receptor channels and synergistic effects with other neurotoxic pathways activated by hypoglycemia. Haloperidol could worsen the cognitive dysfunction of insulin-induced hypoglycemia by elevating extracellular glutamate. In contrast, alternative atypical antipsychotic medications including quetiapine and aripiprazole have pharmacological properties limiting extracellular glutamate and may be neuroprotective in this setting. The objective of this application is to determine the relative effects of haloperidol, quetiapine and aripiprazole on extracellular glutamate and cognitive outcome following insulin-induced hypoglycemia. We hypothesize quetiapine and aripiprazole's more limited D2 antagonism, increased 5HT2A affinity, and 5HT1A partial agonism decrease extracellular glutamate and improve cognitive outcome compared to haloperidol. We will test this hypothesis in Specific Aim 1 by measuring extracellular glutamate in rats treated with haloperidol, quetiapine, aripiprazole or vehicle during insulin-induced hypoglycemia. We expect to observe decreased extracellular glutamate with quetiapine and aripiprazole treatment compared to haloperidol, demonstrating a neurochemically relevant but unappreciated measure distinguishing quetiapine and aripiprazole from typical psychotics. In Specific Aim 2, we will measure cognitive outcome in rat treated with haloperidol, quetiapine, aripiprazole or vehicle during insulin-induced hypoglycemia. We expect to identify improved cognition in rats treated with quetiapine and aripiprazole compared to haloperidol, demonstrating a functional improvement resulting from alternative treatment. The proposed studies are innovative in that while there is widespread recognition of each individual step comprising the risk of interaction between haloperidol and insulin-induced hypoglycemia, awareness of the resulting medical significance is limited. The clinical implication of this study is that it could immediately lead to improved safety for 35 million diabetic patients worldwide taking antipsychotic medications. [unreadable] [unreadable] PUBLI HEALTH RELEVANCE: We propose to determine the effect of the antipsychotic medications haloperidol, quetiapine, and aripiprazole on extracellular glutamate, and cognitive outcome, following insulin-induced hypoglycemia. We expect to observe decreased extracellular glutamate, and improved cognitive outcome, in rats treated with quetiapine and aripiprazole compared to haloperidol. These outcomes are important because they will demonstrate a neurochemically relevant measure distinguishing quetiapine and aripiprazole from typical antipsychotic medications which may lead to improved safety for diabetic patients taking antipsychotic medications. [unreadable] [unreadable] [unreadable]
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2012 — 2013 |
Richtand, Neil Mark |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Conditioned Place Preference to Amphetamine Following Prenatal Immune Activation @ University of Cincinnati
DESCRIPTION (provided by applicant): Addiction has been described as a disease of learning and memory, as the learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play a central role in human addictions. Our knowledge of specific environmental factors influencing drug-associated learning and memory is incomplete. A well-studied mechanism in other fields is prenatal infection, which stimulates maternal cytokines, soluble polypeptides mediating the innate inflammatory response. Consequences to the offspring of maternal cytokine elevation have been studied in an animal model termed prenatal immune activation using the synthetic nucleic acid poly I:C, which stimulates maternal cytokine expression. Injecting poly I:C during pregnancy alters function in the offspring of neuronal systems involved in response to drugs of abuse. Estimates from studies of other disorders suggest as many as 1/3 of drug dependent patients may have had in utero exposure to conditions stimulating maternal cytokine expression. The objective of this application is to characterize the effect of poly I:C injection on acquisition, extinction, and reinstatement of conditioned place preference to amphetamine. We will also identify neurochemical indices of relevance to these behaviors. Our overarching hypothesis is that prenatal immune activation alters glutamate and dopamine transmission in prefrontal cortex and nucleus accumbens, elements of the final common pathway mediating drug relapse, thereby impairing extinction and facilitating reinstatement of conditioned preference for drugs of abuse. We will test this hypothesis in Specific Aim 1 by determining the consequence of prenatal immune activation on acquisition, extinction, and drug- and stress-induced reinstatement of conditioned place preference to amphetamine. In Specific Aim 2, we will determine extracellular glutamate and dopamine in prefrontal cortex and nucleus accumbens preceding conditioning, and during drug-induced reinstatement following prenatal immune activation using microdialysis. Upon completion of these studies, we expect to demonstrate behavioral and neurochemical alterations following prenatal immune activation of direct relevance to the risk for drug relapse. Our expected findings may therefore suggest opportunities to detect a population at elevated risk for drug relapse, and simultaneously identify novel targets for intervention in this group. PUBLIC HEALTH RELEVANCE: We propose to determine the effect of prenatal immune activation on learning and memory associated with drug use. We also expect to identify neurochemical mechanisms contributing to the observed behavioral effects. Our expected outcomes are important because they will elucidate the effect of a common environmental exposure, prenatal immune activation, on a key outcome measure of relevance to drug dependence: learning and memory associated with drug use. The expected findings may advance the understanding of prevention, treatment, and prognosis for drug dependence.
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