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Poster Session II the Effects of Targeted NMDA Receptor Interventions on Sociability December 7, 2010 5:30PM-7:30 PM in a Standardized Paradigm

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Poster Session II the Effects of Targeted NMDA Receptor Interventions on Sociability December 7, 2010 5:30PM-7:30 PM in a Standardized Paradigm Neuropsychopharmacology (2010) 35, S188–S296 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 S188 www.neuropsychopharmacology.org Poster Session II the effects of targeted NMDA receptor interventions on sociability December 7, 2010 5:30PM-7:30 PM in a standardized paradigm. Disclosure: S. Deutsch: None. J. Burket: None. L. Jacome: None. W. Cannon: None. A. Herndon: None. 1. D-cycloserine Improves the Impaired Sociability of the Balb/c Mouse Stephen Deutsch*, Jessica A. Burket, Luis Jacome, William R. Cannon, 2. Serotonin Systems and Modulation in Dopamine Transporter Amy L. Herndon (DAT)-Deficient Mice Meredith A. Fox*, Micaella G. Panessiti, F. Scott Hall, George Uhl, Eastern Virginia Medical School, Norfolk, VA Dennis Murphy Background: The genetically-inbred Balb/c mouse strain shows NIMH/NIH, Bethesda, MD evidence of impaired sociability in a standard paradigm and is hypersensitive to behavioral effects of MK-801 (dizocilpine), a Background: Serotonergic compounds, serotonin transporter noncompetitive NMDA receptor antagonist. Specifically, relative to depletion and serotonin receptor alterations alter baseline and/or 8 week-old male outbred Swiss-Webster mice, 8 week-old male Balb/c drug-induced phenotypes expressed by dopamine transporter (DAT)- mice show diminished locomotor activity and spend less time in the deficient mice, adding to abundant evidence for interactions between vicinity of an enclosed 4 week-old male ICR stimulus mouse in a serotonergic and dopaminergic systems. 5-minute period and, when allowed to interact freely with the stimulus Methods: We now report studies that confirm and extend evidence for mouse for 5 minutes, make fewer discrete episodes of social approach selective influences of pharmacological alterations in the serotonin system and show suppression of its locomotor activity. Additionally, MK-801 in DAT wildtype ( + / + ), heterozygous ( + /-) and knockout (-/-) mice. elicits more irregular episodes of intense jumping behavior, referred Results: As previously reported, DAT -/- mice were hyperactive in the B to as ‘‘popping,’’ and more intense mouse circling behavior, and open field, traveling 3x as far as DAT + / + mice; intermediate antagonizes electrically-precipitated seizures more potently, on a phenotypes were displayed by DAT + /- mice. DAT -/- mice traveled mg/kg basis, in the Balb/c strain, relative to other genetically-inbred at higher velocities and displayed different locomotor patterns and outbred mouse strains. Importantly, a mutant mouse strain with when assessed for features that included meandering and turn angles. diminished expression of the NR1 subunit of the NMDA receptor In the marble burying test, DAT -/- mice buried significantly (approximately 5-10% of normal levels) is impaired on standardized fewer marbles than DAT + / + or + /- mice. The 5-HT1A agonist measures of mouse sociability; thus, diminished endogenous tone 8-OH-DPAT induced its distinctive serotonin syndrome in wildtype of NMDA receptor-mediated neurotransmission is associated with mice, but overall serotonin syndrome scores were greater in DAT -/- impaired sociability of the mouse. Because the Balb/c mouse strain is mice. Several individual behaviors that contribute to this syndrome, impaired in its sociability and has an altered endogenous tone of including head weaving and forepaw treading, were also significantly NMDA receptor-mediated neurotransmission, we explored the effect increased, perhaps suggesting increased postsynaptic 5-HT1A receptor of D-cycloserine (320 mg/kg, ip), a partial glycine agonist that binds function. Although previous work showed that the 5-HT2A antagonist to the obligatory co-agonist glycine binding site on the NMDA M100907 reversed several behavioral deficits in DAT -/- mice, receptor, on the sociability of this strain in a standard paradigm. DOI-induced head twitches were unchanged in DAT -/- mice, Methods: D-Cycloserine (320 mg/kg or saline vehicle) was injected ip suggesting at least some intact 5-HT2A receptor function. HPLC 20 minutes prior to testing sociability. The locomotor activity and analyses of monoamines and metabolites in brain regions revealed discrete episodes of social approach in a 5-minute period of 8-week-old decreased dopamine, increased dopamine/DOPAC ratios, small ‘‘test’’ mice (i.e., Balb/c or Swiss-Webster) in the presence of an enclosed differences in tissue levels of serotonin and no genotypic differences 4-week-old male stimulus mouse (ICR) were measured. Thereafter, in levels of 5-HIAA or norepinephrine in DAT -/- mice. measures of social approach and locomotion while the ‘‘test’’ and Discussion: These findings extend the behavioral and biochemical ‘‘stimulus’’ mice were allowed to interact freely were recorded. phenotypes of DAT-deficient mice, confirm hyperactivity and stereo- Results: Locomotor activity/5 min of the Balb/c strain was significantly typy in these mice, support alterations in the phenotypes of reduced when the stimulus mouse was enclosed and when ‘‘test’’ and DAT -/- mice by serotonergic compounds, but indicate relatively ‘‘stimulus’’ mice were allowed to interact freely, relative to the intact serotonin levels and functions of several serotonin receptors - Swiss-Webster strain. Relative to the vehicle only condition, treatment of the one notable exception may be postsynaptic 5-HT1A receptors - in Balb/c mice with D-cycloserine (320 mg/kg, ip) 20 minutes before testing in these interesting mice. All studies were performed in accordance with the sociability apparatus significantly increased their locomotor activity in the Guide for the Care and Use of Laboratory Animals (NIH). thepresenceofanenclosedICRsocialstimulusmouse(po0.001) and Disclosure: M. Fox: None. M. Panessiti: None. F. Hall: None. G. Uhl: when allowed to interact freely with ICR social stimulus mice (po0.001); None. D. Murphy: None. locomotor activity of Balb/c mice treated with D-cycloserine did not differ from saline-treated Swiss-Webster mice in these two conditions. Similarly, D-cycloserine (320 mg/kg, ip) restored the number of discrete episodes of 3. The Puzzle Box as Simple and Efficient Behavioral Test for social approach/5 min of the Balb/c strain when allowed to interact freely Impairments of General Cognition and Executive Functions in Mouse with social stimulus mice (po0.001), raising the number of social Models of Schizophrenia approaches to those shown by saline-treated Swiss-Webster mice. Peter Gass*, Nada Ben Abdallah, Johannes Fuss, Mike Galsworthy, Discussion: The current results complement the clinical trial data Robert Deacon, Marco Riva, Christoph Kellendonk, Andreas of Posey and colleagues (2004), supporting continued exploration Meyer-Lindenberg, Hans-Peter Lipp of targeted NMDA receptor agonist interventions for psychiatric Central Institute of Mental Health Mannheim, Mannheim, Germany disorders manifesting impaired sociability, such as schizophrenia and autism spectrum disorders. Further, the current data replicate Background: In the light of the current breakthroughs that are and extend earlier work on the impaired sociability of the Balb/c unraveling molecular and genetic underpinnings of schizophrenia, it mouse strain. In fact, because this genetically-inbred mouse strain is becomes indispensable to establish and/or refine new or currently hypersensitive to behavioral effects of MK-801, a noncompetitive available analytical tools in animal models. Cognitive symptoms of NMDA receptor antagonist, it may be an ideal strain in which to study schizophrenia that primarily depend on the prefrontal cortex, and to ACNP 49th Annual Conference S189 some extent also on the hippocampus, i.e. attention deficits, working changes. Phenytoin (PHE) is an anticonvulsant that stabilizes excitable memory and executive function impairments, are important features membrane activity and has some efficacy in treating PTSD (Bremner of chronic manifestation of schizophrenia. Various behavioral rodent et al. 2005), possibly via effects on glutamatergic transmission. We models have therefore been used when attempting to find animal utilized a validated animal model of PTSD - single prolonged stress correlates of cognitive symptoms, most of which require extensive (SPS, Liberzon et al. 1997; 1999) - to study the impact of stress/trauma labor and time, to name only few of their limitations. We tried here to on fear renewal and reinstatement and the effects of chronic PHE on establish a simple but informative test on executive functions in mice these phenomena. in different schizophrenia models. Methods: Thirty-two male Sprague Dawley rats were subjected to SPS Methods: The puzzle box is a behavioral test developed in rodents, in or a control procedure. SPS rats were restrained for two hours, which subjects are presented with different problems of increasing followed by 20 minutes of forced swimming. After 15 minutes of difficulties, and are expected to solve the problems during a limited recuperation they were exposed to ether until anaesthetized. Rats were lapse of time. The arena consists of a white Plexiglas box divided by a then administered PHE (subcutaneous injection, 40 mg/kg) or saline, removable barrier into two separate compartments: a big and brightly- once a day for seven days. All rats underwent fear conditioning, fear lit start zone (58 cm long, 28 cm wide), and a smaller protected goal extinction, and renewal testing followed by a reminder shock and a test zone (15 cm long, 28 cm wide) containing sawdust and cardboards. of reinstatement.
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