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Poster Session III Neurochemical, and Genetic Aspects of Schizophrenia and Psychosis December 8, 2010 5:30PM-7:30 PM Than Current Models Is Highly Desirable

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Poster Session III Neurochemical, and Genetic Aspects of Schizophrenia and Psychosis December 8, 2010 5:30PM-7:30 PM Than Current Models Is Highly Desirable Neuropsychopharmacology (2010) 35, S297–S408 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 www.neuropsychopharmacology.org S297 Poster Session III neurochemical, and genetic aspects of schizophrenia and psychosis December 8, 2010 5:30PM-7:30 PM than current models is highly desirable. Rats chronically treated with low doses of the powerful classical hallucinogenic drug, lysergic acid diethylamide (LSD) represent a new and exciting model to study schizophrenia and psychosis. It is generally regarded that acute LSD in 1. The Role of the 5-HT6 Receptor in Compulsive Responding: humans can reproduce many of the positive symptoms of psychosis, an Investigation Using Viral Mediated Gene Transfer including hallucinations and detachment from reality. We have John Neumaier*, Daniel Eskenazi previously presented behavioral data demonstrating that chronic administration of LSD to rats can produce behaviors highly relevant to University of Washington, Seattle, WA both the positive and negative symptoms of schizophrenia (hyper- Background: The 5-HT6 receptor has been implicated in reward and reactivity, social withdrawal, anhedonia, etc.), appearing after about reinforcement learning, behaviors strongly influenced by striatal six weeks of treatment. Significantly, these behaviors persist for at circuitry. 5-HT6 receptors are abundantly expressed in the dorsal least many months after discontinuing LSD treatment. Furthermore, striatum (caudate-putamen complex), a key brain region for several atypical antipsychotic medications can block these abnormal beha- cognitive and neuropsychiatric-disorders such as obsessive-compul- viors. We also have previously presented data showing that genes for sive disorder (OCD), Tourette Syndrome (TS), and addictive disorders. multiple neurotransmitter systems, including dopamine, serotonin, Our current work investigates the role of the 5-HT6 receptor in and glutamate are persistently altered in prefrontal cortex of these compulsive responding. rats. Here, we present additional data that further validates the use Methods: We over-trained male Long-Evans rats using random of our proposed novel model of psychosis. These data include interval schedules of reinforcement to establish compulsive lever- more comprehensive gene expression results from next generation pressing. We then employed an omission session in which the rat was sequencing, proteomic analysis, and analysis of cytokines. rewarded for not pressing the lever (omitted responses) followed by an Methods: Male Sprague-Dawley rats were treated with 0.16 mg/kg LSD extinction probe test session to measure responsiveness towards the every other day for 90 days. Behavioral analysis was performed 30 days lever. after the last LSD treatment to verify persistent behavioral changes in Results: Rats that received a post-training, pre-omission session the LSD treated group compared to the saline injected control group. infusion of a herpes-simplex viral vector expressing 5-HT6 receptors Brains and blood serum were collected and processed for analysis. demonstrated a decrease in compulsive lever pressing on the Total RNA was isolated from the medial prefrontal cortex of each rat extinction test probe compared to rats receiving the viral vector but and subjected to RNA-seq analysis on an Illumina GAIIx genome that were yoked controls during the omission session. Rats receiving analyzer. QPCR also was performed on select genes form the same an eGFP-only viral vector showed persistent compulsive lever pressing RNA samples. Protein samples isolated from the mPFC of each rat whether they were in the omission or yoked groups. Given that 5-HT6 were analyzed by 2D-DIGE proteomic analysis. Blood serum from each receptors are present on medium spiny neurons (MSNs) of the rat was analyzed by Millipore Milliplex immunoassay to determine direct and indirect pathway (striatonigral and striatopallidal MSNs, cytokine levels. respectively), as a way to distinguish the role of 5-HT6 receptor Results: We found multiple genes relevant to schizophrenia and signaling in distinct cell types, we have developed herpes-simplex psychosis that were altered in expression by chronic LSD. These virus vectors that drive neuronal-subtype specific expression of 5-HT6 include those for dopamine, serotonin, glutamate, and GABA receptor receptors using the prodynorphin promotor and the pre-proenkepha- systems. Expression of additional genes potentially relevant to lin promotor to target direct and and indirect pathway MSNs, schizophrenia, but not directly related to neurotransmitter systems respectively. also were found to be influenced. Analysis of inflammatory related Discussion: Our hypothesis is that given the opposite signaling cytokines revealed that circulating levels of cytokines relevant to between 5-HT6 receptors and dopamine D2 receptors in striatopallidal psychosis (e.g. IL-4, IL-6) were elevated by chronic LSD. Proteomic MSNs, selective over-expression of 5-HT6 receptors in these neurons analysis has identified a small collection of proteins that also are will be sufficient to replicate our previous finding. We plan to further altered by chronic LSD. our investigations into the role of the 5-HT6 receptor in compulsive Discussion: Rats chronically treated with low doses of LSD develop responding using these newly developed tools. behavioral changes potentially relevant to both the positive and Disclosure: J. Neumaier: None. D. Eskenazi: None. negative symptoms of schizophrenia, which persist for many months after the last dose of LSD. Unlike other models of psychosis, where single or short term treatment with a drug leads to acute behaviors that 2. A New Animal Model of Psychosis: Chronic Treatment with are primarily mediated through acute neurotransmitter modulation, Lysergic Acid Diethylamide (LSD) chronic LSD may more closely model the neuroadaptive processes in Charles Nichols*, David Martin, Zach Daniels, Danuta Marona- humans that lead to abnormal brain function and psychosis. In other Lewicka, David Nichols words, chronic LSD may model the development of schizophrenia, as well as the pathological endpoint. The persistence of abnormal LSU Health Sciences Center, New Orleans, LA behaviors induced by chronic LSD are not a direct result of LSD Background: Schizophrenia is a severe neuropsychiatric disease that at because they are present in the absence of drug. Rather, it is the present has no cure. Schizophrenia is a believed to be a complex gradual neuroadaptive change in gene and protein expression multifactorial disorder involving genetic, environmental, and devel- facilitated by LSD that together lead to the abnormal persistent opmental mechanisms. Current animal models to study this disorder behaviors. Significantly, we also have found evidence for a chronic are problematic because they employ, for example, blockade of the inflammatory state in our model that is similar to what has been behavioral effects of dopaminergic agonists such as apomorphine or observed in patients with schizophrenia. How inflammation is related amphetamine, as well as acute administration of drugs whose effects to schizophrenia is presently unknown, but our model may help to are thought to resemble psychosis, such as phencyclidine (PCP), and address this issue in the future. do not, in fact, represent what occurs with the onset of psychosis. Disclosure: C. Nichols: None. D. Martin: None. Z. Daniels: None. Therefore, an animal model that more closely mimics the behavioral, D. Marona-Lewicka: None. D. Nichols: None. ACNP 49th Annual Conference S298 3. The Role of CaMKIIb Upregulation in Schizophrenia: A New Drug (GCV) to toxic nucleotide analogues which induces Target for Schizophrenia Treatment cell death. As adult neural stem cells are derived from astrocytes Gabriela Novak*, Philip Seeman expressing GFAP, administration of GCV to these mice produces a conditional ablation of neurogenesis in the adult brain. At least 14 days University of Toronto and CAMH, Toronto, ON, Canada of GCV treatment are necessary to achieve significant reductions in Background: The cerebral frontal cortex of schizophrenia patients adult neurogenesis (Bush et al., 1998). Following implantation of mice shows elevated levels of mRNA for calcium/calmodulin-dependent with jugular vein catheters and osmotic minipumps (Alzet model 1004, protein kinase II beta (CaMKIIb), but not CaMKIIa. In parallel, animal flow rate 0.11 ul/hr) containing either saline or GCV (10 mg/kg/day), models of schizophrenia consistently show both an increase in mice were allowed to spontaneously acquire heroin self-administration CaMKIIb mRNA levels and an elevation in levels of dopamine 2 (0.03 mg/kg/infusion, 20 ul over 1 sec) on an FR1 schedule of receptors in their high-affinity state (D2High), the major target of reinforcement in 3 hr daily sessions. Self-administration chambers antipsychotic medication. In the present study we examined whether (Med Associates) were equipped with an active and inactive lever as an elevation in the levels of CaMKIIb could lead to an increase in levels well as a stimulus light that was illuminated during each drug infusion. of D2High. Each heroin infusion was followed by a 20 sec timeout during which Methods: We used quantitative real-time PCR to measure CaMKIIa additional active lever presses were recorded but did not result in drug and CaMKIIb mRNA levels in the frontal cortices and striata of infusion. Following 12 days of heroin self-administration, mice heterozygous and wild type CaMKIIa knock-out
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