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ABSTRACTS OF POSTERS
PRESENTED BY 2007 FUN TRAVEL AWARDEES - SAN DIEGO, CA
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Selective breeding for high novelty-seeking behavior concurrently increases aggression (531.26)
*A. D. ABRAHAM
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S. M. CLINTON, S. J. WATSON, H. AKIL
Award sponsored by the Grass Foundation
Molec Behav Neurosci Inst., Univ. Michigan, Ann Arbor, MI 1. Dept Neurosci 0626, Univ California San Diego, La Jolla, CA, 2. Neurology, VAMC, San Diego, CA.
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We recently began to selectively breed Sprague-Dawley rats according to innate differences in “novelty-seeking”, a trait in rodents which predicts several key facets of emotional reactivity, including anxiety-like behavior, neuroendocrine stress response, and propensity to self-administer drugs of abuse. Our bred High Responder (HR) rats vigorously explore new environments compared to Low Responders (LR), which exhibit very little exploration. HR rats also exhibit less anxiety-like behavior, an exaggerated corticosterone stress response, and increased propensity to self-administer cocaine and amphetamine compared to LRs. In the present experiment we have begun to assess aggressive behavior in HR-LR male rats from the F15 generation of our breeding colony. Males were housed with females for 14 days. On the final mating day, female partners were removed and replaced with an unknown male intruder rat for 10 min. The animals’ interactions were scored to assess aggressive and non-aggressive behaviors, and blood and brain tissue were collected 10 min after the intruder interaction to assess plasma testosterone and corticosterone levels, as well as brain activation patterns via c-fos mRNA expression. HR males were more aggressive towards an intruder entering their home cage compared to LR rats in the same situation. These behavioral differences may be at least partly hormonally driven since HR rats had more than twice as much total testosterone levels compared to LR. HR rats also exhibited higher stress-induced corticosterone levels compared to LRs. In situ hybridization experiments are currently underway to determine the pattern of c-fos mRNA expression in the brains of HR-LR rats to determine whether there are differences in the activation of limbic circuits which may explain their divergent behavioral responses to an intruder. Hyperactivity and aggression frequently coexist psychiatric disorders like Attention Deficit Hyperactivity Disorder (ADHD). Our hyperactive HR rats exhibit several behavioral traits which may be relevant to ADHD-like disorders, thus, this model may be useful for investigating the neural substrates of such illnesses and novel treatment strategies.
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Effects of testicular hormones on spatial memory in male rats
(730.6)
S. E. ALLEN
, E. WHEAT, K. OGREN, L. KLEIN, *J. E. THORNTON
Neurosci Dept, Oberlin Coll, Oberlin, OH
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Previously we reported that castration decreases spatial memory in adult male rats in an object location memory task. In the present studies we determined that testosterone can reinstate maximal levels of spatial memory in male rats and examined whether testosterone’s effects might be mediated by its conversion to estradiol.
Adult male rats were castrated and implanted with physiological levels of gonadal hormones. To test spatial memory, we used a task based on the differential exploration of objects in familiar and novel locations (object location memory task). In Expt 1 adult male rats were castrated and implanted with blank capsules or with capsules that contained testosterone (T). Castrated T-treated males showed clear spatial memory whereas the castrated control males did not. That is, T implanted males spent significantly more time exploring an object that was in a novel than in a familiar location (12.6 ± 3.1 vs 4.8 ± 1.4 sec, p=0.023) whereas castrated males did not (7.1 ± 1.7 vs 6.1 ± 1.3 sec, p>0.05). In Expt 2 castrated males were implanted with either T, estradiol (E2) or a blank capsule and tested for spatial memory. T-treated and E-treated males both showed significantly better spatial memory than controls (T males: 19.0 ± 3.2 vs 11.3 ± 1.7 sec, p=0.02; E males: 19.9 ± 2.1 vs 8.6 ± 2.5 sec, p=0.049; blank males: 14.5 ± 2.3 vs 9.3 ± 1.8 sec, p>0.05). In Expt 3 the intertrial interval between exposure to the objects and test trials was varied to determine that T affects spatial memory retention rather than acquisition or sensory responsivity. Consistent with this, at short intertrial intervals between exposure and testing (2 min) both T-implanted and control males showed good spatial memory and at longer intervals (4h and 24h) neither showed spatial memory retention.
These data indicate that testicular androgens are important for maximal levels of spatial memory in adult male rats and that testosterone may be converted to estradiol to exert its effects.
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Adult, bone-marrow-derived stem cells that are genetically engineered to over-express brain derived neurotrophic factor and nerve growth factor reduce behavioral deficits in the yeast artificial chromosome transgenic mouse model of Huntington’s disease. (51.13)
M. C. BOMBARD1,
N. D. DEY1, B. P. ROLAND1, M. LU1, M. I. SANDSTROM1, D. A. SHEAR2, L. LESCAUDRON3, *G. L. DUNBAR1
Award sponsored by Kinder Scientific
1Dept Psychol, Central Michigan Univ., Mt Pleasant, MI; 2Field Neurosciences Inst., Saginaw, MI; 32Institute de Transplantation et de Recherche en Transplantation, Univ. de Nantes, Nantes, France
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Huntington’s disease (HD) is a genetic disorder leading to cognitive, motor, and psychiatric disturbances. Our previous work indicated that transplants of bone-marrow-derived stem cells (BMSC) provide modest reductions in behavioral deficits in the quinolate rat model of HD via a putative increase in neurotrophic support. The aim of the present study was to test whether BMSC that are genetically engineered to over-express brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), or a combination of these, can potentiate the effects of BMSC and reduce behavioral deficits in the yeast artificial chromosome (YAC) mouse model of HD. Bone marrow was extracted from the femurs of mice transgenic for green fluorescent protein (GFP). The cells were cultured in complete isolation medium. After 2 passages with a complete expansion medium, the cells were transfected via Murine Stem Cell Virus vectors containing genes that constitutively express BDNF or NGF. The engineered stem cells were further isolated via magnetic cell sorting using anti-mouse Ly-6A/E (Sca-1). Transfection was confirmed via polymerase chain reaction and enzyme-linked immunosorbent assay. Following 12 passages in culture, approximately 300,000 suspended BMSC or NGF/BMSC or BDNF/BMSC or 150,000 of each type of transfected BMSC or equivalent amounts of vehicle (Delbeccos’s Modified Eagle Medium) were injected bilaterally into the neostriatum of YAC mice. Control, wild-type mice received injections of vehicle. All mice were assessed for 14 months on rotarod, clasping, open-field, pre-pulse inhibition (PPI), and a two-choice swim tasks. Results indicated that all YAC mice showed some behavioral deficits, relative to wild-type mice, but of the YAC mice, those given BDNF/BMSC transplants had the fewest behavioral deficits, followed by those given NGF/BMSC transplants, whereas those given the combined BDNF/NGF/BMSC transplants and those given transplants of only BMSC showed modest reductions in deficits relative to vehicle-treated YAC mice. Immunohistolochemical analyses and measures of GFP fluorescence indicated approximately equivalent survival of transplanted cells in all groups. These findings indicate that BMSC are viable vectors for delivering therapeutically significant levels of trophic factors and could provide a potentially efficacious treatment strategy for HD.
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Effects of neonatal isolation on amygdalo-hippocampal synaptic efficacy in freely behaving rats (46.18)
U. CHOW,
K. E. HAINES,
J. L. KORANDA, *J. BLAISE
Award sponsored by Simbiotic Software
Dept Engin., Trinity Col., Hartford, CT
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To assess whether neonatal isolation, a known emotional stressor, had any persisting effects on bidirectional synaptic plasticity of the basolateral amygdala-dentate gyrus (BLA-DG) synapse, changes in field evoked potential amplitude were recorded in the DG following tetanization of the BLA in non-handled (NH) and neonatally isolated (ISO) freely behaving rats. Our isolation protocol consisted of separation of neonates from their mother and each other for 1 hour daily from postnatal days 2-9. Those neonates were then allowed to mature until 70-120 days of age at which time they were chronically implanted with electrodes in the BLA and DG. Another group of neonates were not handled and thus served as the control treatment group. LTP was induced in naïve subjects of both treatment groups via application of a 100-pulse, 5-Hz theta-burst stimulation (TBS) and LTD was induced by application of a sustained 900-pulse, 1-Hz low frequency stimulation (LFS) to the basolateral amygdala in freely behaving animals. Results indicate significantly increased levels of both LTP and LTD in the BLA-DG synapse of isolated rats compared to their non-handled counterparts. These neonatal isolation induced alterations in the bidirectional synaptic plasticity profile of this pathway may help to explain neural mechanisms relating stressful and emotional responses in the amygdala with long-term memory consolidation and information processing in the hippocampus.
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Chronic administration of the typical and atypical antipsychotics, haloperidol and risperidone, impair functional outcome after experimental brain trauma. (381.1)
A. N. HOFFMAN,
H. A. ASLAM, J. P. CHENG, P. LUTHRA, C. N. SOZDA, A. S. OLSEN, R. D. ZAFONTE, *A. E. KLINE
Award sponsored by Lafayette Instruments
Phys Med. & Rehab, Psych, Safar Ctr. Resuscitation Res., Univ. Pittsburgh, Pittsburgh, PA
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Agitation and aggression are common behavioral sequelae of clinical traumatic brain injury (TBI) and management of these symptoms is necessary for successful caring of patients who may resist treatment, become disruptive, and pose a physical risk to themselves and/or medical personnel, which ultimately impedes rehabilitation. As such, antipsychotics are routinely provided to TBI patients albeit the benefits vs. risks of this approach on functional recovery remain unclear. Previous studies have shown that haloperidol (HAL) impairs motor recovery after TBI when given singly or cognitive performance when provided chronically. A recent study from our laboratory showed that chronic, but not single, administration of either HAL or risperidone (RIS) provided prior to training in a spatial learning paradigm impaired acquisition relative to vehicle controls. One possible explanation for the observed effect was that both HAL and RIS induced sedation, as evidenced by slower swim speed, which may have confounded the behavioral outcome. Hence, the aim of the current study was to evaluate the effects of chronic HAL or RIS on functional outcome when treatments were provided after daily testing, thus circumventing the potential sedative effect. Fifty-three isoflurane-anesthetized male rats received either a controlled cortical impact or sham injury and then were randomly assigned to three TBI (HAL 0.5 mg/kg, RIS 0.45 mg/kg, or VEH 1 mL/kg) or three sham (HAL 0.5, RIS 0.45, or VEH) groups. Treatments began 24 hr after surgery and were administered (i.p.) every day thereafter for 19 days. Function was assessed by established motor (beam balance/walk) and cognitive (spatial learning/memory) tests on days 1-5 and 14-19, respectively. Only RIS delayed beam balance recovery, but both HAL and RIS impaired spatial learning relative to VEH (p’s < 0.05). No differences were revealed between HAL and RIS in any task. These data indicate that chronic administration of HAL and RIS hinder functional outcome after experimental brain trauma in rats. The deleterious effect cannot be attributed to drug-induced sedation as there were no differences in swim speed among the TBI groups, regardless of treatment. The results have important implications for physicians and rehabilitation specialists who are faced with the decision of whether to administer antipsychotics to attenuate TBI-induced aggression/agitation so that patient care can resume, but at the risk of compromising behavioral recovery.
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Anatomic analysis of corticostriatal projection neurons during development
. (129.14)
*I. KOTCHETKOV,
U. S. SOHUR, J. D. MACKLIS
Award sponsored by Brandeis University
MGH-HMS Ctr. Nervous Syst. Repair, Depts Neurosurgery, Neurol., Program in Neurosci., Mass Gen. Hosp/ Harvard Med. School, Harvard Stem Cell Inst., Harvard Univ., Boston, MA
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Understanding how neurons develop normally is a critical step toward repairing or supporting those that degenerate or are damaged in disease. Corticostriatal projection neurons (CStrPN) are the cortical efferent neurons of the cortico-basal ganglia circuitry, loss of which are implicated in Huntington's disease (HD), cerebral palsy (CP), and Parkinson's disease (PD), among others. Thus, increased knowledge regarding the anatomic development of CStrPN may be critical, both in understanding the development and organization of this critical circuitry, and toward potential therapeutics.
We are investigating the anatomic development of CStrPN at distinct stages of mouse development by retrograde labeling from the striatum and other structures. Our current data suggest that there is a period of exuberance in projection pattern of the CStrPN, during early development, followed by pruning of axons, and maturation of their dendritic organization. Multiple approaches are being used to more fully investigate the cellular anatomy of CStrPN. The study of the stage-specific anatomy of CStrPN may enable identification of critical mechanisms that define, specify, and control differentiation and maturation of cortico-basal ganglia circuitry.
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Importance of the intracellular domain of beta 3 in Nav1.2 modulation
. (466.31)
*E. C. MERRICK
, M. K. PATEL
Award sponsored by the Grass Foundation
Anesthesiol., Univ. of Virginia, Charlottesville, VA
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Sodium channels contribute to the control of cellular excitability due to their vital role in generating and propagating action potentials. They are composed of an a subunit and are modulated by at least four ß subunits (ß1- 4). ß1 and ß3 have both been found to modulate the gating of sodium channels. The extracellular domain of the ß subunit is thought to interact with the a subunit, modulating channel gating. Recent studies, however, have implicated a role for the intracellular domain as well. ß1 and ß3 are only 50% homologous with each other and the subunits have distinct expression profiles in the brain, especially in the hippocampus. These differences may be important in differential modulation of sodium channel activity. One specific difference between ß1 and ß3 is a serine residue (S161) that is represented by an alanine in ß1. To determine the importance of S161, we have generated a S161A ß3 mutant to represent a non-phosphorylatable residue. Co-expression of wild type (WT) ß3 caused a depolarizing shift in steady-state activation and inactivation and also enhanced the development of inactivation. S161A co-expression attenuated the WT ß3 shift in activation and abolished the shift in inactivation and development of inactivation. To determine if these effects are a result of differences in membrane expression, confocal microscopy was performed using GFP-tagged constructs. In contrast to WT ß3, there was a significant amount of intracellular labeling of the S161A mutant, suggesting a disruption in subunit trafficking either to or from the membrane. These studies suggest an important role for the intracellular domain of ß3 in not only channel modulation, but also membrane expression. The attenuation of the WT shifts in activation and inactivation parameters by the non-phosphorylatable S161A mutant suggests that ß3 modulation of channel gating could be mediated by phosphorylation of the serine residue, perhaps by protein kinase C.
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Structural relationships affect the antioxidant and neuroprotective efficacies of flavonoids and ginkgolide diterpenes from Ginkgo biloba leaf extracts against induced neurotoxicity in rat hippocampal explants in vitro. (702.22)
*B. O'KEEFE,
A. BETTICA,
M. SKRELJA
Award sponsored by Simbiotic Software
Biol., Manhattanville Col., Purchase, NY
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Flavonoid constituents of the Ginkgo biloba extract EGb 761, such as quercetin and kaempferol, have been shown to be potent antioxidants, anti-inflammatory, and antihypoxic agents. Enhanced flavonol mechanisms, such as metal chelation to scavenge free radicals, altering membrane permeability, enzyme interactions and transcription activation, may depend on hydroxylation of its phenolic ring structure. The ginkgolide diterpenes, such as Gin A, B, and C, also differ in the number and position of hydroxyl substituents, which may determine their effectiveness to attenuate damage from reactive oxygen species (ROS), to stabilize cell membranes, and to protect neurons from ischemic trauma. Both Gin A and B have been shown to reduce focal ischemia, but only Gin B protected neurons against glutamate and apoptotic damage, while Gin A had no apparent anti-apoptotic capacity. Both Gin B and C may affect the inhibitory mechanisms of synaptic transmission by inhibiting glycine and GABAa receptors in the central nervous system. In order to determine the antioxidant and neuroprotective efficacies of these flavonol and diterpene constituents, with relationship to the number and position of hydroxyl groups, pretreatments of hippocampal explants to individual and combination agents against a neurotoxic insult by verapamil, a calcium channel blocker or sodium nitroprusside (SNP), a nitric oxide generator, were undertaken. Explants from excised 1mm coronal brain slices from 7-9 day old Sprague-Dawley rats were placed on Millicell inserts in 6-well plates for 24 hours and exposed to either Gin A, B, C, quercetin, kaempferol, or isorhamnetin (20-160µg/ml) for 24 hours and subsequently to verapamil (5mM) or SNP (100µM) for 24 hours. Morphometric data from cresyl violet-stained frozen sections were analyzed using Motic Images Plus 2.0. A dose-response comparison revealed that ginkgolide B and C protected the neurons against damage caused by verapamil as determined by morphometric analysis (p < 0.05), while Gin A showed little attenuation of neurodegeneration. Preliminary studies suggested that Gin B demonstrates significant protection against SNP-induced toxicity. At lower doses of 20µg/ml, quercetin and kaempferol ameliorated the negative effects of verapamil, while doses of isorhamnetin needed to be significantly higher to have the same effect.
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Escalation and reinstatement of morphine self-administration in periadolescent vs. adult male rats
. (387.2)
*Y. E. OGBONMWAN,
B. F. WILLIAMS, C. LI, N. H. WALDRON, A. MOFFETT, K. J. FRANTZ
Award sponsored by MedAssociates
Biol. Dept., Georgia State Univ., Atlanta, GA
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Despite high rates of opiate drug abuse among human adolescents, few laboratory experiments address adolescent vulnerability to opiates using animal models. To examine potential differences in the transition from recreational, controlled drug use to compulsive, escalated drug abuse during adolescence vs. adulthood, we used the escalation model of intravenous (i.v.) drug self-administration, comparing conditions of long vs. short daily access to morphine. After catheterization and recovery, periadolescent (PND 35 at start) and adult (PND 91 at start) male Sprague-Dawley rats acquired lever-pressing maintained by i.v. morphine (0.6 mg/kg/infusion) on a fixed ratio 1 schedule of reinforcement during daily 1 hr sessions over six days. They were then assigned to either short (1-hr/day)- or long (8-hr/day)-access conditions for 18 days of escalation testing at the same dose. Subsequent 1-hr extinction sessions were followed by tests of cue- or drug-induced reinstatement of lever-pressing. During training and throughout short-access conditions, periadolescent rats self-administered less morphine than adults, confirming previous results from this laboratory. Under long-access conditions, daily drug intake escalated gradually in both periadolescents and adults, but escalation was attenuated in the younger age group. Moreover, preliminary results suggest that despite similar rates of extinction, younger rats exhibited less cue-induced reinstatement than older rats. However, access conditions did not affect reinstatement of drug-seeking behavior, and i.p. morphine injections (10 mg/kg) did not reinstate drug-seeking behavior in any group. One interpretation of these findings is that in some cases developmental changes may protect adolescent subjects from long-term drug effects, such as escalation and cue-induced reinstatement of drug-seeking behavior.
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Juvenile cognitive training effectively ameliorates the deficient pre-pulse inhibition seen in male rats subjected to prenatal repeated variable stressors (606.22)
C. M. RAMSEY,
*M. T. KERCHNER
Award sponsored by Sinauer Associates
Dept Psychol, Washington Col., Chestertown, MD
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Research has shown that schizophrenic patients who are able to achieve a higher level of education have a better prognosis than those who have a lower education level. Using a repeated variable prenatal stress model of schizophrenia [Koenig, et al. 2005; Behav. Brain Res., 156, 251-261], we investigated the effects of cognitive training during the juvenile stage on adult behaviors in male Sprague-Dawley rats. Rats in the prenatal stress condition and those in the control condition were given daily cognitive training utilizing a radial arm maze and non-delay non-match to sample operant sessions, beginning on postnatal day (PD) 28 and continuing through PD56. Because decreased pre-pulse inhibition (PPI) to acoustic startle stimuli and working memory deficiencies are characteristic of schizophrenia, acoustic startle response and performance in the Morris water maze were measured in adulthood, beginning on PD57. No significant group differences in performance were observed in the water maze paradigm. Stressed rats exhibited a startle response despite the presentation of a pre-pulse stimulus, while non-stressed rats showed the expected PPI. Additionally, stressed rats that received cognitive training showed comparable PPI to that observed in the non-stressed groups. These findings provide yet another indication that the repeated variable stress paradigm may be of further utility as an animal model of schizophrenia
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A comparison of serotonin, dopamine, and norepinephrine in the medial pre-frontal cortex of male and female adolescent rats
(37.9)
A. M. STAITI1,
D. C. BASS1, P. J. MORGANE1,2, J. R. GALLER2, *D. J. MOKLER1,2
Award sponsored by Plexon
1Dept Pharmacol., Univ. New England, Biddeford, ME; 2Ctr. for Behavioral Develop. and Mental Retardation, Boston Univ. Sch. of Med., Boston, MA
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We have initiated studies investigating how juvenile male brains compared to juvenile female brains when comparing the neurotransmitter levels in the medial prefrontal cortex (mPFC) of the rat. Recent evidence has shown that the medial prefrontal cortex is an important brain area in the control of impulsivity, decision-making and executive function (Morgane et al., Prog.Neurobiol.,2005). The neurotransmitters serotonin (5-HT), dopamine (DA), and norepinephrine (NE) are integral to the function of the mPFC and are increased by the drugs used to treat attentional deficit disorder, i.e. methylphenidate and methamphetamine. The purpose of our investigation was to determine the extracellular concentrations of DA, 5-HT, and NE in the mPFC of adolescent male and female rats. Because some studies have shown differences between the left and right mPFC in terms of extracellular 5-HT and DA we have used dual probes to examine both left and right mPFC. The overlying hypothesis is the juvenile male brain of the rat has a decreased extracellular dopamine and norepinephrine and an increased serotonin. This would be in keeping with findings that low dopamine or norepinephrine and/or high serotonin lead to impulsive behavior and inattention. Dual microdialysis probes (2 mm) were placed into the left and right ventral mPFC of adolescent (postnatal day 40-45) rats. Following collection of baseline samples, 100 microM methamphatamine was perfused through the probes for 1 hr. Microdialysate was analyzed for DA, 5-HT and NE via HPLC. Our preliminary findings show that basal extracellular levels of DA are decreased in the left and right ventral mPFC in adolecent male rats when compared to adolescent female rats. There was also a modest decrease in 5-HT in the mPFC of male adolescent rats compared to female adolescent rats. These data suggest that there are differences between adolescent male and female rats in the basal extracellular concentrations of serotonin, dopamine, and norepinephrine in the ventral mPFC, which may relate to the impulsivity and attentional differences between male and female adolescents. This may relate to behavioral differences between male and female adolescent rats. This also adds to our previous work showing differences in basal 5-HT and DA in the ventral mPFC of adolescent male rats and adult male rats (Staiti et al.,Soc.Neurosci.Abstracts, 2006).
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Stimulation of kappa-opioid receptors elicits nicotine withdrawal in adult but not adolescent rats (843.20)
*H. A. TEJEDA,
L. A. NATIVIDAD, O. V. TORRES, L. E. O'DELL
Award sponsored by Coulbourn Instruments
Dept Psychol, Univ. Texas-El Paso, El Paso, TX
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Previous research in our laboratory has demonstrated that the affective properties of nicotine withdrawal are lower during the adolescent period of development. However, the underlying mechanisms mediating this developmental difference are not known. Thus, this study assessed the role of kappa-opioid receptors in mediating nicotine withdrawal in adolescent and adult rats. The ability of the kappa receptor agonist, U50,488H, to induce the negative affective properties of nicotine withdrawal was assessed using conditioned place aversion (CPA) and elevated plus maze (EPM) procedures. In the CPA study, rats were first tested for their preference for 1 of 2 distinct compartments of our conditioning apparatus. The following day, rats were prepared with subcutaneous mini-pumps that delivered saline or an equivalent dose of nicotine (adolescents=4.7 and adults=3.2 mg/kg/day; base) for 14 days. Six days later, rats received U50,488H (5 mg/kg; sc) and were immediately placed into their initially preferred side for 30 min. On alternating days, rats received saline and were placed into their initially non-preferred side for 30 min. This 2-day procedure was repeated over 8 consecutive days for 4 conditioning trials. Control rats received saline on both sides. Following conditioning, rats were re-tested for their preference. The results revealed that kappa receptor stimulation produced CPA in nicotine-dependent adult, but not adolescent rats. Also, stimulation of these receptors did not produce an aversion in saline control rats. In the EPM study, rats were prepared with mini-pumps containing the same nicotine doses that were used in the CPA study. Six days later, rats received 4 injections of U50,488H (5 mg/kg; sc) every other day to mimic the treatment regimen used in the CPA study. On the test day, rats received U50,488H or saline and the amount of time spent in the open and closed arms was recorded for 5 min. The results revealed that kappa receptor stimulation produced anxiety-like behavior (increased time spent in closed arm) in nicotine-dependent adult but not adolescent rats. Collectively, our results suggest that stimulation of kappa receptors elicits the negative affective properties of nicotine withdrawal in adult rats; however, adolescent rats appear to be less sensitive to the modulatory role of kappa receptors in mediating nicotine withdrawal.
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Oxytocin and cortisol changes after kissing in adult human heterosexual pairs (938.7)
C. A. WILSON,
*W. L. HILL
Award sponsored by Smith College
Dept Psych, Lafayette Col., Easton, PA
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The present study examined the roles of oxytocin (OT) and cortisol in the physiological response to kissing. We hypothesized that kissing originated from breastfeeding and predicted that similar hormone changes observed following nursing in human infants would occur in adults after kissing. The participants were thirty undergraduate students (fifteen females; fifteen males; age 18-22) who were currently in a sexual relationship with a member of the opposite sex. The couples had relationship lengths ranging from 30 to 1087 days. Couples were randomly assigned to either a control (C) or an experimental (E) group. The (C) participants were asked to hold hands and talk with their partner for sixteen minutes while listening to music on a CD, while the (E) participants were asked to open-mouth kiss their partner while listening to the same music. Cortisol and OT levels were measured before and after the test session via saliva and blood plasma samples, respectively. The plasma samples were prepared for analysis through solid phase extraction techniques. Hormone specific enzyme immunoassay procedures were then used to measure pre- and post-session hormone levels on a tissue plate reader. Four questionnaires to determine levels of intimacy, stress, and personality, as well as to provide personal information concerning relationship length, kissing frequency, and oral contraceptive use were completed. Females scored significantly higher on the intimacy and the stress scales. Female OT levels were significantly higher than males at baseline. Female OT levels significantly decreased following the test session, regardless of experimental group, whereas male OT levels increased. There were no significant differences for hormone levels between the (E) and (C) groups. Females using contraceptive pills exhibited significantly higher baseline OT levels than those not using pills. Mean cortisol levels decreased from pre- to post-session, which may indicate either decreases in stress levels or habituation to the environment. Finally, the gender effect on changes in OT suggests that females may require a more intimate atmosphere than males in order to respond positively to a kiss. A future study could further examine how birth control pills affect OT levels and subsequent behavior in females. Other studies could explore the observed gender specific response to social and sexual stimuli in terms of hormone changes.
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Activation of alpha-2A adrenergic receptors inhibits CA3 network activity in the rat hippocampus: Functional characterization of adrenergic receptor agonists
. (166.4)
K. XU,
B. NELSON, B. GOLDENSTEIN, K. DAVIS, J. PRIBULA, J. O'BRIEN, K. GREEN, S. BOESE, J. LICHTER, C. JURGENS, J. PORTER, *V. A. DOZE
Award sponsored by MBF Bioscience
Dept Pharmacol Physiol & Ther, Univ. N Dakota Sch. Med. & Hlth. Sci., Grand Forks, ND
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The potent antiepileptic effect of the endogenous neurotransmitter norepinephrine (NE) is well-documented, but the mechanism of action is largely unknown. Under inhibitory GABAergic blockade, NE has been shown to reduce rat hippocampal CA3 epileptiform burst activity through activation of a2 adrenergic receptors (AR). In this study, we used various AR agonists and antagonists to delineate which a2 (2A, 2B, and/or 2C) AR subtype(s) mediate the antiepileptic effect of NE. Hippocampal CA3 epileptiform burst activities were monitored using field potential recordings from rat hippocampal slices. First, we characterized the efficacy and potency of several AR agonists. Concentration-dependent dose response curves of each AR agonist were analyzed for their effects on reducing the frequency of hippocampal CA3 epileptiform burst discharges. The potency and efficacy of the three chemical classes (catecholamines, imidazolines, and guanidines) of AR agonists indicated that the endogenous catecholamines and their derivatives were all full agonists (relative efficacy =80% of NE), but were less potent than imidazolines and guanidines. In contrast, only one non-catecholamine imidazoline compound, UK-14304, appeared to be a full agonist, while all others were partial agonists. Experimental efficacy and potency values of each agonist were then compared to previously determined functional values for the human a2 AR subtypes, as no rat data were available. The correlation coefficient and slope for the a2A AR subtype were 0.89 and 1.0 for potency, and 0.86 and 1.0 for efficacy, respectively. However, no significant correlations were found for the other human a2 AR subtypes, suggesting that the a2A AR is mediating the effect of NE. Next, equilibrium dissociation constants (Kb) of various AR antagonists were functionally determined using epinephrine, an analogue of NE, and compared to previously established binding values (Ki) for the rat a1A, a1B, a1D, a2A, a2B, a2C, 5-HT1A, and D2 receptor subtypes. A correlation coefficient of 1.0 and a slope of 1.0 for the a2A AR subtype, and an absence of significant positive correlation for the other rat receptor subtypes tested were found. These antagonist results are in agreement with the previous AR agonist correlations, and indicate that the a2A AR mediates the antiepileptic effect of NE under conditions of GABAergic impairment in the rat hippocampal CA3 region. These findings will not only increase our understanding of the role of NE in attenuating epileptogenesis, but may aid the future development of subtype selective a2 AR agonist-based pharmaceutical agents for treating epilepsy.
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Steroid receptor coactivator-2 (SRC-2) from hypothalamus and hippocampus interacts differently with the progestin receptor isoforms. (295.9)
M. A. YORE1
, D. IM2, J. G. CHADWICK2, *M. J. TETEL2
Award sponsored by Wellesley College
1Biochem. Program, 2Neurosci. Program, Wellesley Col., Wellesley, MA
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The ovarian steroid hormone, progesterone, acts in the brain to profoundly influence a variety of events, including development, cognition and reproductive physiology and behavior. Progesterone elicits many of these biological effects by binding to intracellular progestin receptors (PR). PR are expressed as two structurally distinct isoforms, full length PR-B and the truncated PR-A. A variety of in vitro studies suggest that PR-B is a stronger transcriptional activator than PR-A. In addition, in vitro studies reveal that steroid receptor coactivator-2 (SRC-2), and other members of the p160 nuclear receptor coactivator family, physically interact with PR and estrogen receptors to enhance their transcriptional activity. Previous work from our lab has shown that nuclear receptor coactivator action in the ventromedial nucleus of the hypothalamus is important in modulating PR-dependent aspects of female sexual behavior in rats. In the present study, GST pull-down assays were done to determine if SRC-2 from brain physically associates with PR-A and PR-B. Human PR-A and PR-B, expressed with a GST tag in insect baculovirus cells, were incubated in the presence or absence of a PR agonist (R5020) or in the presence of a PR antagonist (RU486). We found that SRC-2 from female rat hypothalamus (Hyp) or hippocampus/cortex (Hipp/Ctx) interacts efficiently with PR-B in the presence of R5020, but not in the absence of ligand or in the presence of RU486. These data suggest that SRC-2 from Hyp and Hipp/Ctx physically associates with PR-B in a ligand-dependent manner. While SRC-2 from these two brain regions did interact with PR-A to some extent, these interactions were not ligand-dependent. These differential interactions of SRC-2 with the two PR forms provide a possible mechanism by which PR-B is a stronger transcriptional activator than PR-A and support the idea that these two receptors have distinct functions in brain.
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Impairment of hippocampal neurogenesis in diabetic rats
. (896.13)
*W. ZHANG1
, Y.-F. TAN1, J. T. Y. YUE2, M. VRANIC2, J. M. WOJTOWICZ1
Award sponsored by Campden Instruments
1Physiology Rm 3214, 2Physiology Rm 3363, Univ. Toronto, Toronto, ON, Canada
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Adult neurogenesis in dentate gyrus is an evolutionarily preserved trait in most mammals examined thus far. Neuronal proliferation and subsequent integration of new neurons into the hippocampal circuit are regulated processes that can have profound effects on an animal’s behaviour. A streptozotocin model of type I diabetes, characterized by low insulin and high plasma glucose levels, affects not only body’s overall metabolism but also brain activity. We report here that seven weeks after the onset of uncontrolled diabetes, neuronal production is dramatically reduced. Neurogenesis was measured within the dentate gyrus of the hippocampus using standard immunohistochemical markers Ki67, Doublecortin, Calbindin and BrdU. Cell proliferation was reduced by 46 % and neuronal maturation was reduced by 53 % for a combined reduction of neuronal production of 75 %. Such reduction is expected to cause a significant functional impairment of learning and memory in the diabetic animals. These results may shed light not only on causes of diabetic neuropathy but also provide an explanation for the proposed beneficial therapeutic effects of exogenous insulin on memory functions.
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UCH-L1 functions in neocortical development
(673.24)
*A. A. CHANDAWARKAR,
P. H. OZDINLER, P. J. CODD, N. KISHI, J. D. MACKLIS
Award sponsored by AD Instruments
MGH-HMS Ctr. Nervous Syst. Repair, Depts Neurosurgery, Neurol., Program in Neurosci., Mass Gen. Hosp/ Harvard Med. School, Harvard Stem Cell Inst., Harvard Univ., Boston, MA
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UCH-L1 (ubiquitin carboxy-terminal hydrolase L1) is abundantly expressed in the brain, but its functions in the central nervous system are not yet well understood. Covalent conjugation of ubiquitin to proteins plays an important role in selective protein degradation, and this process is very specifically regulated. Likewise, removal and recycling of ubiquitin from proteins is precisely controlled via specific proteolytic enzymes, such as UCH-L1. UCH-L1 is an important component of the ubiquitin system, and is suggested to be involved both in Parkinson's disease and several forms of cancer. Its control over cell cycle regulation, and its presence in neurons suggest a possible role in neuronal birth and development. Using both in vitro and in vivo approaches, we investigated the role of UCH-L1 in neocortical neuronal development during embryonic corticogenesis. Immunocytochemical analysis indicates that UCH-L1 is specifically expressed in a subset of neurons. We further find that UCH-L1 expression is developmentally regulated; UCH-L1 is not present in neural progenitors, but is expressed at increasing levels as neuroblasts differentiate into mature neurons. We investigated the effects of loss of UCH-L1 function by in vitro application of function-blocking reagents in E13.5 neural progenitor cell cultures. In addition, we examined the effects of over-expression of UCH-L1, both in vitro via viral infection of neural progenitor cells with a UCH-L1 expressing construct, and in vivo via introduction of the construct into E13.5 neural progenitors by ultrasound-guided in utero microinjection and electroporation. Our ongoing studies suggest that correct temporal expression of UCH-L1 is important for proper development and maturation of specific neuronal populations of the developing neocortex.
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Synaptotagmin and FMRFamide immunofluorescence and video microscopy reveal myogenic nature of the ventral diaphragm muscle in the moth, Manduca sexta
(924.17)
S. R. PUNZELL,
*R. J. BAYLINE
Award sponsored by AD Instruments
Dept Biol, Washington and Jefferson Coll, Washington, PA
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The objective of this study was to determine the anatomy and physiology of the ventral diaphragm muscle (VDM) in Manduca sexta. The VDM is located abdomen of the adult moth and consists of 2 bundles of laterally projecting fibers in each body segment of abdominal segments 3-6 (A3-A6). The fibers connect to the dorsal pad and contract antagonistically in a rhythmic manner to aid in hemolymph circulation in conjunction with the dorsal vessel, or heart. The dorsal vessel is a myogenic muscle, yet it also receives neural inputs. Glutamatergic neurons innervate the dorsal vessel and influence its contractile properties, and it also responds to neuromodulatory signaling (ie., FMRFamide and serotonin). Since the dorsal vessel and VDM both carry out similar functions, we hypothesized that the VDM would exhibit similar neuroanatomical and physiological features. To observe the pattern of innervation of the VDM, immunofluorescent detection of both synaptotagmin and FMRF-amide was employed. Video analysis of live preparations following denervation was conducted to determine if the muscle was myogenic. When a portion of muscle was removed from all neural input it was able to contract on its own completely suggesting that the VDM contractions are myogenic in origin. Synaptotagmin immunofluorescence revealed that the most posterior region of the VDM in segment A6 was densely innervated, the anterior region in segment A3 was innervated but to a lesser extent and the middle regions in segments A4-A5 had no innervation. This staining pattern is similar to the pattern of synaptotagmin staining in the dorsal vessel. FMRFamide immunofluorescence showed labeled neurons following two long tracts on both sides of an antagonistic pair of muscles. However, this pattern was only seen in segment A6. Thus, the innervation of the VDM is similar to the innervation of the dorsal vessel in both its function and its anatomical structure. We hypothesize that the regulation of both circulatory structures is likewise correlated.
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Morris water maze performance of adult rats appears insensitive to lifetime acrylamide treatment
(95.3)
*M. E. SMITH,
M. G. PAULE, J. D. GAREY, S. A. FERGUSON
Award sponsored by Noldus
Neurotoxicology, Natl. Ctr. Toxicological Res/FDA, Jefferson, AR
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The neurotoxicant acrylamide (AA) is found in many fried or baked carbohydrate-containing foods common in Western diets. AA treatment has been shown to cause peripheral neuropathy in laboratory animals (reviewed in Shipp et al., 2006); however, the effects of AA treatment on cognitive behaviors such as spatial learning and memory have not been widely investigated. Here, pregnant Fischer 344 rats (n=9-11/dose) were gavaged with 0 (water), 0.1, 0.3, 1.0, or 5.0 mg/kg AA from gestational day 6 to 21. On the day after parturition, offspring (4/sex/litter) were gavaged with the same dose as the dam until weaning at postnatal (PND) 22. Post-weaning treatment continued via the drinking water at doses which approximated the prior gavage doses. On PNDs 165-169 and again at PNDs 347-351, one male and female/litter were assessed in the standard Morris water maze (same subjects were tested at both ages). Subjects were allowed 3 trials/day for 5 consecutive days. At both ages, the platform remained in the same location. Swimming speed of the 1.0 mg/kg females at both ages was somewhat faster than that of the other treatment groups (8-21% faster). Latency to locate the platform and path length were not affected by AA treatment at either test age. Relative to the younger age, older rats exhibited improved performance as demonstrated by decreased latencies and path lengths. This effect may have been an aging effect, memory of the test requirements, and/or memory of the platform location. These data extend previous data (Garey et al., 2006) and demonstrate that in the water maze as used here, there were no systematic effects of AA treatment at these doses on spatial learning and memory. AA treatment and additional assessments of these subjects are ongoing (see also Garey et al. and Paule et al. at this meeting for additional AA results). (Supported by NTP #224-93-001 and ORISE.)
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Effects of selective hippocampal lesion on alcohol consumption and alcohol preference: Does brain damage caused by drinking make it more difficult to quit?
(553.5)
T. A. YAGER,
J. A. PECH, J. M. HALL, *K. CHAN
Award sponsored by Noldus
Dept Psych, Hartwick Coll, Oneonta, NY
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Animal studies have shown that chronic alcohol use causes anatomical and physiological damage to the hippocampus. Rats with hippocampal lesions can learn to associate a neutral stimulus (CS) with food (US) and approach a food cup in the presence of the CS, but are impaired in learning to suppress the response during extinction when the CS is no longer followed by food. This observation led to the hypothesis that hippocampal damage caused by chronic alcohol use may lead to impairments in learning to suppress alcohol use even when the cues associated with alcohol are no longer followed by rewarding consequences. This experiment tested the hypothesis by comparing the amount of 10% ethanol consumed by hippocampal-lesioned rats, alcohol-exposed rats, and sham controls. The hippocampal lesion group received NMDA lesions of the complete hippocampus. The alcohol-exposed group received a 10% ethanol solution as the only source of fluid for fifteen weeks. The control group received sham lesions but did not receive any exposure to alcohol prior to the test phase. During the first test phase, a 10% ethanol solution was the only fluid available. On each of the three test days, both the alcohol-exposed and the hippocampal-lesioned rats consumed significantly more 10% ethanol than controls, but the alcohol-exposed and the hippocampal-lesioned rats consumed comparable amounts. When there was a choice between water and 10% ethanol in the second test, hippocampal-lesioned rats showed a significantly higher preference for 10% ethanol than did the controls; and the alcohol-exposed rats showed a significantly higher preference for the 10% ethanol than both the hippocampal-lesioned rats and the controls. These findings are consistent with the hypothesis that hippocampal damage can lead to impaired ability to suppress alcohol consumption.
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