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Selected AbstractsExploratory behavior in mice selectively bred for developmental differences in aggressive behaviorDEVELOPMENTAL PSYCHOBIOLOGY, Issue 1 2008Kathryn E. Hood Abstract The development and expression of exploratory behavior was assessed in the Cairns lines of Institute for Cancer Research (ICR) mice that were selectively bred for differences in aggressive behavior, with a high-aggressive 900 line, low-aggressive 100 line, and control 500 line. Four paradigms were employed. Developmental changes were evident in the complex novel arena, with older males faster to contact a novel object, and ambulating more than young males. Within the control 500 line, older males showed longer latency to emerge from the home cage, and shorter latency to contact novel objects. In the 900 line, younger males showed this same pattern. R. B. Cairns proposed that line differences in aggressive behavior arise through alterations in developmental timing [Cairns et al. [1983] Life-span developmental psychology (Vol. 5). New York: Academic Press; Gariépy et al. [2001] Animal Behaviour 61: 933,947]. The early appearance of mature patterns of exploratory behavior in 900 line males supports this interpretation. The 900 line males also appear to be behaviorally inhibited in novel settings such as the light,dark box and the neohypophagia paradigm, compared to the 500 and 100 lines (Experiments 1, 2, and 4). Moreover, in the most complex apparatus, the novel arena, 900 line males were slowest to exit the home cage, and fastest to contact a novel object. The apparent contrast in these parameters of exploratory behavior is discussed in relation to T. C. Schneirla's [1965 Advances in the study of behavior (Vol. 1). New York: PN Academic] approach,withdrawal theory. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 50: 32,47, 2008. [source] PRECLINICAL STUDY: Effect of concurrent saccharin intake on ethanol consumption by high-alcohol-drinking (UChB) ratsADDICTION BIOLOGY, Issue 3 2009Lutske Tampier ABSTRACT This study examined the effect of concurrent presentation of a highly palatable saccharin solution on ethanol consumption during the acquisition or maintenance of ethanol drinking by high-alcohol-drinking (UChB) rats. Rats were exposed to ethanol (10% v/v) and water under a home cage, two-bottle, free-choice regimen with unlimited access for 24 hours/day. After 7 days (acquisition) of ethanol exposure, a third bottle containing saccharin (0.2% w/v) was concomitantly offered for an additional seven consecutive days, and the same process was repeated after 3 months (maintenance) of ethanol exposure. We found that concurrent saccharin intake significantly reduced ethanol intake by UChB rats after 7 days of ethanol exposure indicating that preference for sweet taste tends to override the preference for ethanol. However, the concurrent saccharin presentation to rats after 3 months of stable ethanol consumption did not reduce ethanol intake, whereas their saccharin consumption reached polydipsic-like values. These results support the notion that in UChB rats, a time-dependent sensitization to the rewarding effects of ethanol is developed that may account for the increases in ethanol volition seen following chronic ethanol intake. [source] The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine systemADDICTION BIOLOGY, Issue 3 2005Michael Cowen Acamprosate (Campral ?) is a drug used clinically for the treatment of alcoholism. In order to examine further the time-course and mechanism of action of acamprosate, the effect of acute and repeated acamprosate administration was examined on (i) operant ethanol self-administration and (ii) voluntary home cage ethanol consumption by alcohol-preferring Fawn-Hooded, iP and Alko Alcohol (AA) rats. Acutely, acamprosate was shown to cause a significant decrease in operant ethanol self-administration by Fawn-Hooded and alcohol-preferring iP rats in part by decreasing the motivational relevance of a specific ethanol cue; however, repeated injection of acamprosate led to tolerance to this effect. Voluntary alcohol consumption in the home cage in Fawn-Hooded and AA rats was also reduced by an acute acamprosate injection; however, again tolerance developed to repeated injections. In a separate experiment, the effect of acamprosate on markers of the dopaminergic system was examined. Interestingly, acute acamprosate was also shown to cause increased dopamine transporter density and decreased dopamine D2-like receptor density within the nucleus accumbens but not in the caudate-putamen, suggesting a link between the decreased motivational salience of the ethanol cue and altered dopaminergic signalling within the nucleus accumbens. With repeated injections of acamprosate, markers of the dopaminergic system returned to steady state levels with a similar temporal profile to the development of tolerance in the behavioural studies. Along with previous studies, our findings indicate that acamprosate modulates the mesolimbic dopaminergic system and may thereby decrease ethanol reinforcement processes; however, these effects undergo tolerance in alcohol-preferring rats and may in part explain the fact why some subjects are non-responders to chronic acamprosate treatment. [source] Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cageEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006Bruce T. Hope Abstract Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated cocaine administration to rats in their home cages but rarely after repeated administration outside the home cage, which produces more robust locomotor sensitization. In the present study, we found cocaine-induced Fos expression in nucleus accumbens, but not caudate-putamen, was enhanced 1 and 6 months after repeated drug administration in locomotor activity chambers. Double-labelling of Fos protein and enkephalin mRNA indicated that Fos expression in nucleus accumbens was enhanced in enkephalin-positive, but not enkephalin-negative, medium spiny neurons. In contrast, cocaine-induced Fos expression was absent altogether in nucleus accumbens and unaltered in caudate-putamen 1 month after repeated cocaine administration in the home cage. As cocaine-induced locomotor activity was also enhanced 1 and 6 months after repeated cocaine administration in locomotor activity chambers, we wanted to confirm that neuronal activity in nucleus accumbens mediates cocaine-induced locomotor activity using our particular treatment regimen. Bilateral infusions of the GABA agonists baclofen and muscimol (1 µg/side) into nucleus accumbens of sensitized rats blocked cocaine-induced Fos expression and locomotor activity. Thus, while neuronal activity in both D1- and D2-type neurons in nucleus accumbens can mediate acute cocaine-induced locomotor activity, the enhanced activation of enkephalinergic D2-type neurons suggests that these latter neurons mediate the enhancement of cocaine-induced locomotor activity for up to 6 months after repeated drug administration outside the home cage. [source] Context-dependent behavioural and neuronal sensitization in striatum to MDMA (ecstasy) administration in ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2006Kevin T. Ball Abstract To investigate the neuronal mechanisms underlying the behavioural alterations that accompany repeated exposure to MDMA (ecstasy), we recorded the activity of >,200 striatal units in response to multiple, intermittent, locomotor-activating doses (5.0 mg/kg) of MDMA. Rats were treated with once-daily injections of either saline or MDMA for 5 days when housed in their home cage, followed by a challenge injection 3,5 days later when housed in a recording chamber. Because contextual drug associations might be particularly important to the expression of behavioural sensitization to chronic MDMA, a separate group of rats received repeated injections of MDMA alternately in the recording chamber or home cage, according to the above timeline. A sensitized locomotor response was observed only in rats that had previously experienced MDMA in the context of the recording chamber, and only on the challenge day. These sensitized animals also showed a decreased basal firing rate in neurons that were subsequently excited by MDMA when compared with the same category of neurons earlier in the treatment regimen. This resulted in a greater percentage increase from the baseline firing rate on the challenge day compared with the first and fifth days of treatment, even though this trend was not evident with an analysis of absolute firing rate. These results strongly support a role for context in the expression of MDMA-induced locomotor sensitization, and implicate striatal involvement in the neurobehavioural changes associated with the repeated use of MDMA. [source] Hyperactivity, startle reactivity and cell-proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1frc/frc miceGENES, BRAIN AND BEHAVIOR, Issue 7 2010B. K. Y. Wong The NR2E1 region on Chromosome 6q21-22 has been repeatedly linked to bipolar disorder (BP) and NR2E1 has been associated with BP, and more specifically bipolar I disorder (BPI). In addition, patient sequencing has shown an enrichment of rare candidate-regulatory variants. Interestingly, mice carrying either spontaneous (Nr2e1frc) or targeted (Tlx,) deletions of Nr2e1 (here collectively known as Nr2e1 -null) show similar neurological and behavioral anomalies, including hypoplasia of the cerebrum, reduced neural stem cell proliferation, extreme aggression and deficits in fear conditioning; these are the traits that have been observed in some patients with BP. Thus, NR2E1 is a positional and functional candidate for a role in BP. However, no Nr2e1 -null mice have been fully evaluated for behaviors used to model BP in rodents or pharmacological responses to drugs effective in treating BP symptoms. In this study we examine Nr2e1frc/frc mice, homozygous for the spontaneous deletion, for abnormalities in activity, learning and information processing, and cell proliferation; these are the phenotypes that are either affected in patients with BP or commonly assessed in rodent models of BP. The effect of lithium, a drug used to treat BP, was also evaluated for its ability to attenuate Nr2e1frc/frc behavioral and neural stem cell-proliferation phenotypes. We show for the first time that Nr2e1 -null mice exhibit extreme hyperactivity in the open field as early as postnatal day 18 and in the home cage, deficits in open-field habituation and passive avoidance, and surprisingly, an absence of acoustic startle. We observed a reduction in neural stem/progenitor cell proliferation in Nr2e1frc/frc mice, similar to that seen in other Nr2e1 -null strains. These behavioral and cell-proliferation phenotypes were resistant to chronic-adult-lithium treatment. Thus, Nr2e1frc/frc mice exhibit behavioral traits used to model BP in rodents, but our results do not support Nr2e1frc/frc mice as pharmacological models for BP. [source] Mouse inbred strain differences in ethanol drinking to intoxicationGENES, BRAIN AND BEHAVIOR, Issue 1 2007J. S. Rhodes Recently, we described a simple procedure, Drinking in the Dark (DID), in which C57BL/6J mice self-administer ethanol to a blood ethanol concentration (BEC) above 1 mg/ml. The test consists of replacing the water with 20% ethanol in the home cage for 4 h early during the dark phase of the light/dark cycle. Three experiments were conducted to explore this high ethanol drinking model further. In experiment 1, a microanalysis of C57BL/6J behavior showed that the pattern of ethanol drinking was different from routine water intake. In experiment 2, drinking impaired performance of C57BL/6J on the accelerating rotarod and balance beam. In experiment 3, 12 inbred strains were screened to estimate genetic influences on DID and correlations with other traits. Large, reliable differences in intake and BEC were detected among the strains, with C57BL/6J showing the highest values. Strain means were positively correlated with intake and BEC in the standard (24 h) and a limited (4 h) two-bottle ethanol vs. water test, but BECs reached higher levels for DID. Strain mean correlations with other traits in the Mouse Phenome Project database supported previously reported genetic relationships of high ethanol drinking with low chronic ethanol withdrawal severity and low ethanol-conditioned taste aversion. We extend these findings by showing that the correlation estimates remain relatively unchanged even after correcting for phylogenetic relatedness among the strains, thus relaxing the assumption that the strain means are statistically independent. We discuss applications of the model for finding genes that predispose pharmacologically significant drinking in mice. [source] Common variations in the pretest environment influence genotypic comparisons in models of anxietyGENES, BRAIN AND BEHAVIOR, Issue 7 2005G. S. Izídio The behavioral characterization of rodent strains in different studies and laboratories can provide unreplicable results even when genotypes are kept constant and environmental control is maximized. In the present study, the influence of common laboratory environmental variables and their interaction with genotype on the results of behavioral tests of anxiety/emotionality were investigated. To this end, the inbred rat strains Lewis (LEW) and spontaneously hypertensive rats (SHR), which are known to differ for numerous emotionality-related behaviors, were tested in the open field (OF), elevated plus maze (EPM) and black/white box (BWB), while three environmental factors were systematically controlled and analyzed: (1) the experimenter handling the animal (familiar or unfamiliar); (2) the position of the home cage (top or bottom shelf of the rack) and (3) the behavioral state of the animal immediately before the test (arousal or rest). Experimenter familiarity did not alter the behavior of rats in the OF. Cage position, on the other hand, influenced the behavior in the OF and BWB, with rats housed in top cages appearing less anxious like than those housed in the bottom. In the BWB (but not in the OF), these effects were genotype dependent. Finally, the behavioral state of the animals prior to testing altered the results of the EPM in a strain-dependent manner, with some anxiety-related genotypic differences being found only among rats that were aroused in their home cages. This study showed that common variations in the laboratory environment interact with genotype in behavioral tests of anxiety/emotionality. Recognizing and understanding such variations can help in the design of more effective experiments. [source] Long-term treadmill exposure protects against age-related neurodegenerative change in the rat hippocampusHIPPOCAMPUS, Issue 10 2009Rachel M. O'Callaghan Abstract The potential of exercise or environmental enrichment to prevent or reverse age-related cognitive decline in rats has been widely investigated. The data suggest that the efficacy of these interventions as neuroprotectants may depend upon the duration and nature of the protocols and age of onset. Investigations of the mechanisms underlying these neuroprotective strategies indicate a potential role for the neurotrophin family of proteins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). In this study, we have assessed the effects of 8 months of forced exercise, begun in middle-age, on the expression of long-term potentiation (LTP) and on spatial learning in the Morris water maze in aged Wistar rats. We also assessed these measures in a cage control group and in a group of rats exposed to the stationary treadmill for the same duration as the exercised rats. Our data confirm an age-related decline in expression of LTP and in spatial learning concomitant with decreased expression of NGF and BDNF mRNA in dentate gyrus (DG). The age-related impairments in both plasticity and growth factor expression were prevented in the long-term exercised group and, surprisingly, the treadmill control group. Given the extensive handling that the treadmill control group received and their regular exposure to an environment outside the home cage, this group can be considered to have experienced environmentally enriched conditions when compared with the cage control group. Significant correlations were observed between both learning and LTP and the expression of NGF and BDNF mRNA in the dentate gyrus. We conclude that decreased expression of NGF and BDNF in the dentate gyrus of aged rats is associated with impaired LTP and spatial learning. We suggest that the reversal of these age-related impairments by enrichment and exercise may be linked with prevention of the age-related decline in expression of these growth factors and, furthermore, that enrichment is as efficacious as exercise in preventing this age-related decline. © 2009 Wiley-Liss, Inc. [source] Impairment and recovery on a food foraging task following unilateral vestibular deafferentation in ratsHIPPOCAMPUS, Issue 4 2006Yiwen Zheng Abstract It has been suggested that the vestibular system may contribute to the development of higher cognitive function, especially spatial learning and memory that uses idiothetic cues (e.g., dead reckoning). However, few studies have been done using behavioral tasks that could potentially separate the animals' ability for dead reckoning from piloting. The food foraging task requires the animal to continuously monitor and integrate self-movement cues and generate an accurate return path. It has been shown that bilateral vestibular-lesioned rats were impaired on this task. The present study used the same task to further examine the contribution of vestibular information to spatial navigation by comparing unilateral and bilateral lesions and by testing the animals at different time points following the lesion. The results demonstrated that animals with unilateral vestibular deafferentation were impaired in performing the task in the dark at 3 months after the lesion, and this impairment disappeared at 6 months after the lesion. This supports the notion that vestibular information contributes to dead reckoning and suggests possible recovery of function over time after the lesion. Animals with bilateral vestibular deafferentation were not able to be tested on the foraging task because they exhibited behavior distinct from the unilateral-lesioned animals, with significant hesitation in leaving their home cage for as long as 6 months after the lesion. © 2005 Wiley-Liss, Inc. [source] Intensity and Duration of Chronic Ethanol Exposure Is Critical for Subsequent Escalation of Voluntary Ethanol Drinking in MiceALCOHOLISM, Issue 11 2009William C. Griffin III Background:, Excessive alcohol drinking continues to be an important health problem. Recent studies from our laboratory and others have demonstrated that animal models of ethanol dependence and relapse can contribute to understanding factors that contribute to excessive drinking. In this study, we tested the hypothesis that the amount and duration of ethanol exposure is critical for promoting the escalation in drinking by mice given access to ethanol in a limited access paradigm. Methods:, We used several methods of chronic intermittent ethanol exposure in male C57BL/6J mice that would vary in the amount and duration of exposure to ethanol as indicated by blood ethanol concentrations (BEC). After establishing baseline drinking in the mice using a 2 hours, 2 bottle choice drinking paradigm, each study involved alternating between periods of ethanol exposure and periods of limited access to ethanol (1 cycle) for a total of 3 cycles. In Study 1, mice were allowed extended access (16 hours) to ethanol for oral consumption or remained in the home cage. In Study 2, the ethanol exposure consisted of intragastric gavage of increasing doses of ethanol or isocaloric sucrose as the control. Study 3 compared intragastric gavage combined with pyrazole, an alcohol dehydrogenase inhibitor, with vapor inhalation of ethanol using procedures known to lead to increased drinking in mice. Finally, Study 4 was a retrospective review of several studies conducted in our laboratory using inhalation procedures. The retrospective review encompassed a range of postvapor chamber BEC values and ethanol intakes that would allow a relationship between increased drinking and BEC to be examined. Results:, Allowing mice to drink for longer periods of time did not cause increased drinking in subsequent limited access sessions. Likewise, gastric intubation of ethanol which produced high BEC (>300 mg/dl) with or without pyrazole did not increase drinking. Only the vapor inhalation procedure, which was associated with sustained BEC above 175 mg/dl for the entire exposure period resulted in increased drinking. The retrospective study provided further evidence that sustained BEC levels above 175 mg/dl was critical to the escalation in drinking. Conclusions:, We found that the intensity (amount) and duration of ethanol exposure, indexed by BEC, is critical to produce increased drinking in mice. Specifically, BEC must regularly exceed 175 mg/dl for the escalation in drinking to occur. Future studies will examine neurobiological adaptations that may underlie the increased drinking behavior caused by chronic intermittent ethanol exposure. [source] Differential Effects of Chronic Ethanol Consumption and Withdrawal on Homer/Glutamate Receptor Expression in Subregions of the Accumbens and Amygdala of P RatsALCOHOLISM, Issue 11 2009Ilona Obara Background:, Homer proteins are constituents of scaffolding complexes that regulate the trafficking and function of central Group1 metabotropic glutamate receptors (mGluRs) and N -methyl- d -aspartate (NMDA) receptors. Research supports the involvement of these proteins in ethanol-induced neuroplasticity in mouse. In this study, we examined the effects of short versus long-term withdrawal from chronic ethanol consumption on Homer and glutamate receptor protein expression within striatal and amygdala subregions of selectively bred, alcohol-preferring P rats. Methods:, For 6 months, male P rats had concurrent access to 15% and 30% ethanol solutions under intermittent (IA: 4 d/wk) or continuous (CA: 7 d/wk) access conditions in their home cage. Rats were killed 24 hours (short withdrawal: SW) or 4 weeks (long withdrawal: LW) after termination of ethanol access, subregions of interest were micropunched and tissue processed for detection of Group1 mGluRs, NR2 subunits of the NMDA receptor and Homer protein expression. Results:, Within the nucleus accumbens (NAC), limited changes in NR2a and NR2b expression were detected in the shell (NACsh), whereas substantial changes were observed for Homer2a/b, mGluRs as well as NR2a and NR2b subunits in the core (NACc). Within the amygdala, no changes were detected in the basolateral subregion, whereas substantial changes, many paralleling those observed in the NACc, were detected in the central nucleus (CeA) subregion. In addition, most of the changes observed in the CeA, but not NACc, were present in both SW and LW rats. Conclusions:, Overall, these subregion specific, ethanol-induced increases in mGluR/Homer2/NR2 expression within the NAC and amygdala suggest changes in glutamatergic plasticity had taken place. This may be a result of learning and subsequent memory formation of ethanol's rewarding effects in these brain structures, which may, in part, mediate the chronic relapsing nature of alcohol abuse. [source] The Dopamine Response in the Nucleus Accumbens Core,Shell Border Differs From That in the Core and Shell During Operant Ethanol Self-AdministrationALCOHOLISM, Issue 8 2009Elaina C. Howard Background:, Ethanol self-administration has been shown to increase dopamine in the nucleus accumbens; however, dopamine levels in the accumbal subregions (core, shell, and core,shell border) have not yet been measured separately in this paradigm. This study was designed to determine if dopamine responses during operant ethanol self-administration are similar in the core, core,shell border, and shell, particularly during transfer from the home cage to the operant chamber and during consumption of the drinking solution. Methods:, Six groups of male Long,Evans rats were trained to lever-press for either 10% sucrose (10S) or 10% sucrose + 10% ethanol (10S10E) (with a guide cannula above the core, core,shell border, or shell of the accumbens). On experiment day, 5-minute microdialysis samples were collected from the core, core,shell border, or shell before, during, and after drinking. Dopamine and ethanol concentrations were analyzed in these samples. Results:, A significant increase in dopamine occurred during transfer of the rats from the home cage into the operant chamber in all 6 groups, with those trained to drink 10S10E exhibiting a significantly higher increase than those trained to drink 10S in the core and shell. No significant increases were observed during drinking of either solution in the core or shell. A significant increase in dopamine was observed during consumption of ethanol in the core,shell border. Conclusions:, We conclude that dopamine responses to operant ethanol self-administration are subregion specific. After operant training, accumbal dopamine responses in the core and shell occur when cues that predict ethanol availability are presented and not when the reinforcer is consumed. However, core,shell border dopamine responses occur at the time of the cue and consumption of the reinforcer. [source] Early Social Isolation in Male Long-Evans Rats Alters Both Appetitive and Consummatory Behaviors Expressed During Operant Ethanol Self-AdministrationALCOHOLISM, Issue 2 2009Brian A. McCool Background:, Postweaning social isolation in rats produces profound and long-lasting cognitive and behavioral deficits in adult animals. Importantly, this housing manipulation alters sensitivity to a number of drugs of abuse including ethanol. However, most studies with ethanol have utilized continuous or limited home-cage access to examine interactions between juvenile social experience and drinking. More recently, social isolation was shown to increased ethanol responding in a "dipper" model of self-administration (Deehan et al., 2007). In the current study, we utilize a "sipper" operant self-administration model to distinguish the effects of isolation rearing on ethanol seeking- and drinking-related behaviors. Methods:, Postweaning juvenile male Long-Evans rats were placed into 2 housing groups for 6 weeks: one group consisted of individually housed animals; the second group was housed 4 animals per cage. Following the isolation period, anxiety-like behavior was assessed to confirm the efficacy of the isolation procedure. In some animals, ethanol drinking in the home cage was assessed using a continuous access, 2-bottle choice paradigm. All animals were then individually housed and trained to lever-press for a sipper tube containing either an ethanol solution or a sucrose solution. Results:, Postweaning social isolation increased the expression of anxiety-like behavior in the elevated plus maze but not the light-dark box. Ethanol consumption was also increased during continuous home-cage access with the 2-bottle choice paradigm. During operant self-administration, isolation housing increased the response rate and increased ethanol consumption but did not alter responding for or consumption of sucrose. The housing manipulation did not change the total number of lever responses during extinction sessions. Paired-pulse inhibition deficits that are characteristic of juvenile isolation remained intact after prolonged experience with sucrose self-administration. Discussion:, The effects of postweaning social isolation on ethanol drinking in the home cage are also manifest during operant self-administration. Importantly, these alterations in adult operant self-administration are ethanol-specific. [source] Dopamine-dependent motor learning: Insight into levodopa's long-duration responseANNALS OF NEUROLOGY, Issue 5 2010Jeff A. Beeler PhD Objective Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. Methods To examine this question, we took advantage of PITx3-deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3-deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. Results We show that the deficiency in motor skill learning in PITx3(,/,) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. Interpretation This observation resembles the long-duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long-duration response to chronic levodopa treatment is a manifestation of rescued motor learning. ANN NEUROL 2010;67:639,647 [source] Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbensEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2009Marcelo T. Marin Abstract Learned associations are hypothesized to develop between drug effects and contextual stimuli during repeated drug administration to produce context-specific sensitization that is expressed only in the drug-associated environment and not in a non-drug-paired environment. The neuroadaptations that mediate such context-specific behavior are largely unknown. We investigated context-specific modulation of cAMP-response element-binding protein (CREB) phosphorylation and that of four upstream kinases in the nucleus accumbens that phosphorylate CREB, including extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase, calcium/calmodulin-dependent kinase (CaMK) II and CaMKIV. Rats received seven once-daily injections of cocaine or saline in one of two distinct environments outside their home cages. Seven days later, test injections of cocaine or saline were administered in either the paired or the non-paired environment. CREB and ERK phosphorylation were assessed with immunohistochemistry, and phosphorylation of the remaining kinases, as well as of CREB and ERK, was assessed by western blotting. Repeated cocaine administration produced context-specific sensitized locomotor responses accompanied by context-specific enhancement of the number of cocaine-induced phosphoCREB-immunoreactive and phosphoERK-immunoreactive nuclei in a minority of neurons. In contrast, CREB and CaMKIV phosphorylation in nucleus accumbens homogenates were decreased by cocaine test injections. We have recently shown that a small number of cocaine-activated accumbens neurons mediate the learned association between cocaine effects and the drug administration environment to produce context-specific sensitization. Context-specific phosphorylation of ERK and CREB in the present study suggests that this signal transduction pathway is selectively activated in the same set of cocaine-activated accumbens neurons that mediate this learned association. [source] Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cageEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006Bruce T. Hope Abstract Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated cocaine administration to rats in their home cages but rarely after repeated administration outside the home cage, which produces more robust locomotor sensitization. In the present study, we found cocaine-induced Fos expression in nucleus accumbens, but not caudate-putamen, was enhanced 1 and 6 months after repeated drug administration in locomotor activity chambers. Double-labelling of Fos protein and enkephalin mRNA indicated that Fos expression in nucleus accumbens was enhanced in enkephalin-positive, but not enkephalin-negative, medium spiny neurons. In contrast, cocaine-induced Fos expression was absent altogether in nucleus accumbens and unaltered in caudate-putamen 1 month after repeated cocaine administration in the home cage. As cocaine-induced locomotor activity was also enhanced 1 and 6 months after repeated cocaine administration in locomotor activity chambers, we wanted to confirm that neuronal activity in nucleus accumbens mediates cocaine-induced locomotor activity using our particular treatment regimen. Bilateral infusions of the GABA agonists baclofen and muscimol (1 µg/side) into nucleus accumbens of sensitized rats blocked cocaine-induced Fos expression and locomotor activity. Thus, while neuronal activity in both D1- and D2-type neurons in nucleus accumbens can mediate acute cocaine-induced locomotor activity, the enhanced activation of enkephalinergic D2-type neurons suggests that these latter neurons mediate the enhancement of cocaine-induced locomotor activity for up to 6 months after repeated drug administration outside the home cage. [source] Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposureEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2001Gregory Hotsenpiller Abstract To study the role of glutamate in cocaine-conditioned responses, we developed a rat model in which conditioned locomotion is produced by repeated pairing of cocaine with discrete stimuli (flashing light and metronome). ,Paired' subjects received cocaine (15 mg/kg) prior to six exposures to stimuli for 30 min in the test environment. ,Unpaired' subjects received equivalent presentations of the stimuli yet received cocaine in home cages. Tests with the stimuli alone demonstrated that the conditioned locomotion displayed by Paired subjects was evident at 3 or 10 days post-training and resistant to two sessions of testing. The degree of conditioned locomotion was not correlated with the subjects' response to novelty or cocaine. Administration of the noncompetitive AMPA receptor antagonist GYKI 52466 (2.5 mg/kg, a dose without effect on spontaneous activity) attenuated the expression of conditioned activity. In vivo microdialysis revealed that Paired subjects had significantly lower basal glutamate levels in the nucleus accumbens (NAc) than did Unpaired subjects when no stimuli were presented. Presentation of the conditioned stimuli resulted in significant increases in glutamate levels in the NAc in the Paired group whilst glutamate levels in the Unpaired group remained unchanged. The associative control of glutamate levels in the NAc by stimuli formerly paired with a drug of abuse is an unprecedented finding. It is likely to reflect the convergence of excitatory inputs that the NAc receives from limbic structures. [source] Common variations in the pretest environment influence genotypic comparisons in models of anxietyGENES, BRAIN AND BEHAVIOR, Issue 7 2005G. S. Izídio The behavioral characterization of rodent strains in different studies and laboratories can provide unreplicable results even when genotypes are kept constant and environmental control is maximized. In the present study, the influence of common laboratory environmental variables and their interaction with genotype on the results of behavioral tests of anxiety/emotionality were investigated. To this end, the inbred rat strains Lewis (LEW) and spontaneously hypertensive rats (SHR), which are known to differ for numerous emotionality-related behaviors, were tested in the open field (OF), elevated plus maze (EPM) and black/white box (BWB), while three environmental factors were systematically controlled and analyzed: (1) the experimenter handling the animal (familiar or unfamiliar); (2) the position of the home cage (top or bottom shelf of the rack) and (3) the behavioral state of the animal immediately before the test (arousal or rest). Experimenter familiarity did not alter the behavior of rats in the OF. Cage position, on the other hand, influenced the behavior in the OF and BWB, with rats housed in top cages appearing less anxious like than those housed in the bottom. In the BWB (but not in the OF), these effects were genotype dependent. Finally, the behavioral state of the animals prior to testing altered the results of the EPM in a strain-dependent manner, with some anxiety-related genotypic differences being found only among rats that were aroused in their home cages. This study showed that common variations in the laboratory environment interact with genotype in behavioral tests of anxiety/emotionality. Recognizing and understanding such variations can help in the design of more effective experiments. [source] Transfer from "edible" categorization training to feeding behavior in pigeons (Columba livia)1JAPANESE PSYCHOLOGICAL RESEARCH, Issue 1 2006SHUNJI AWAZU Abstract:, We investigated a transfer from an operant experimental situation to a feeding situation in pigeons using real objects as stimuli. Four pigeons were trained in an operant box to categorize familiar edible items as positives and inedible items as negatives with a go/no-go procedure. Next, two pairs of unfamiliar edible items were added as stimuli. One of the paired stimuli was arbitrarily assigned as positive and the other as negative. We tested the subjects in their home cages to see whether they would feed on the items they were trained to categorize as positives. In three of the six cases in which categorization training was successful, they continued to peck the positive items. This result suggests that the pigeons transfer what they learned in the operant training situation to the feeding situation. [source] Corticosterone Facilitates Saccharin Intake in Adrenalectomized Rats: Does Corticosterone Increase Stimulus Salience?JOURNAL OF NEUROENDOCRINOLOGY, Issue 5 2000Bhatnagar1 Unlike normal rats, adrenalectomized rats do not voluntarily drink sweet saccharin solutions. To test whether this is a function of corticosterone in the circulation, and if corticosterone also increases the impetus for drinking saccharin after a period of withdrawal, we performed the following experiments. Young male rats were sham adrenalectomized (sham) or adrenalectomized (ADX); the ADX rats were provided with subcutaneous pellets containing (percent replacement of corticosterone, %B) 0%B, 15%B, 30%B or 100%B. Sham and ADX rats were immediately provided with saline (0.5%) and saccharin (2 mM) bottles in their home cages. Saccharin was allowed for 4 days on, 3 days off, 4 days on, 3 days off and a final day on, over the 15 days experiment. The dose of corticosterone determined both how much saccharin was voluntarily drunk by the ADX rats and the degree of overshoot after days off. Corticosterone also determined energy balance of the groups of ADX rats. The 30%B pellets restored food intake, body weight gain, insulin and caloric efficiency to the normal levels observed in sham rats. White fat depot weights and uncoupling protein concentration in brown adipose tissue were restored to sham levels by 100%B, suggesting that these variables which depend on activity in the sympathetic nervous system require considerable glucocorticoid receptor occupancy. We conclude that corticosterone increases the willingness to ingest sweetened water in a unimodal, dose-related manner, while moderate doses of corticosterone restore energy balance. [source] Genetic and Other Contributions to Alcohol Intake in Rhesus Macaques (Macaca mulatta)ALCOHOLISM, Issue 3 2006Joseph G. Lorenz Background: The etiology of alcoholism and alcohol abuse, like many other complex diseases, is heterogeneous and multifactorial. Numerous studies demonstrate a genetic contribution to variation in the expression of alcohol-related disorders in humans. Over the past decade, nonhuman primates have emerged as a valuable model for some aspects of human alcohol abuse because of their phylogenetic proximity to humans. Long-term, longitudinal studies of rhesus macaques (Macaca mulatta) have provided much insight into environmental influences, especially early life experiences, on alcohol consumption and behavior patterns that characterize alcohol intake later in life. It is not known, however, whether there is a genetic component as well to the variation seen in alcohol consumption in rhesus macaques. A significant genetic component to variation in alcohol consumption in rhesus macaques would show for the first time that like humans, for nonhuman primates additive genetic influences are important. Moreover, their use as a model for alcohol-related disorders in humans would have even greater relevance and utility for designing experiments incorporating the expanding molecular genetics field, and allow researchers to investigate the interaction among the known environmental influences and various genotypes. Methods: In this study, we investigate factors contributing to variation in alcohol consumption of 156 rhesus macaques collected over 10 years when subjects were adolescent in age, belonging to a single extended pedigree, with each cohort receiving identical early rearing backgrounds and subsequent treatments. To measure alcohol consumption each animal was provided unfettered simultaneous access both to an aspartame-sweetened 8.4% (v/v) alcohol-water solution, the aspartame-sweetened vehicle, and to water for 1 hour each day during the early afternoon between 13:00 and 15:00 in their home cages for a period of 5 to 7 weeks. We use multiple regression to identify factors that significantly affect alcohol consumption among these animals and a maximum likelihood program (ASReml) that, controlling for the significant factors, estimates the genetic contribution to the variance in alcohol consumption. Results: Multiple regression analysis identified test cohort and rearing environment as contributing to 57 and 2%, respectively, of the total variance in alcohol consumption. Of the remaining 41% of the variance about half (19.8%) was attributable to additive genetic effects using a maximum likelihood program. Conclusion: This study demonstrates that, as in humans, there are additive genetic factors that contribute to variation in alcohol consumption in rhesus macaques, with other nongenetic factors accounting for substantial portions of the variance in alcohol consumption, Our findings show the presence of an additive genetic component and suggest the potential utility of the nonhuman primate as a molecular genetics tool for understanding alcohol abuse and alcoholism. [source] Evidence That the Lore-1 Region Specifies Ethanol-Induced Activation in Addition to Sedative/Hypnotic Sensitivity to EthanolALCOHOLISM, Issue 11 2001Jeremy C. Owens Background: Low-dose ethanol-induced activation (LDA) and initial sensitivity to alcohol are both predictors of alcohol abuse in human populations. Our hypothesis is that one or more genes specifying hypnotic sensitivity also specify LDA. We tested this hypothesis by using congenic mice derived from the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, which carry an ILS region introgressed onto an ISS background. Methods: LDA was assessed by assigning mice randomly to receive one of five doses of ethanol ranging from 1.2 to 2.4 g/kg. On day 1, animals were injected with saline and placed in a brightly lit activity monitor for 30 min, after which they were returned to their home cages. On day 2, mice were injected with ethanol (20% w/v), their activity was monitored for a 30-min period, and LDA was determined by subtracting day 1 activity. The blood ethanol concentration of each animal was then assessed at 30 min by retro-orbital collection of 25 ,l of blood. Results: Ethanol had a significant effect on the activity of ISS mice, but ILS mice showed no activation at any dose, similar to the activities of the outbred lines. All three congenic strains were activated at several doses. Lore-2 and Lore-5 were not ILS-like (less active than ISS) at any dose. In contrast, ISS.ILS- Lore-1 congenics (carrying an ILS-derived Lore-1 allele on the ISS background) were significantly less activated than the ISS controls at 1.8 and 2.4 g/kg of ethanol. Conclusions: The Lore-2 and Lore-5 congenic regions do not affect LDA. In contrast, the Lore-1 congenic region carries one or more genes specifying both initial hypnotic sensitivity to ethanol and LDA. [source] Functional significance of genetic variation underlying limb bone diaphyseal structureAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 1 2010Ian J. Wallace Abstract Limb bone diaphyseal structure is frequently used to infer hominin activity levels from skeletal remains, an approach based on the well-documented ability of bone to adjust to its loading environment during life. However, diaphyseal structure is also determined in part by genetic factors. This study investigates the possibility that genetic variation underlying diaphyseal structure is influenced by the activity levels of ancestral populations and might also have functional significance in an evolutionary context. We adopted an experimental evolution approach and tested for differences in femoral diaphyseal structure in 1-week-old mice from a line that had been artificially selected (45 generations) for high voluntary wheel running and non-selected controls. As adults, selected mice are significantly more active on wheels and in home cages, and have thicker diaphyses. Structural differences at 1 week can be assumed to primarily reflect the effects of selective breeding rather than direct mechanical stimuli, given that the onset of locomotion in mice is shortly after Day 7. We hypothesized that if genetically determined diaphyseal structure reflects the activity patterns of members of a lineage, then selected animals will have relatively larger diaphyseal dimensions at 1 week compared to controls. The results provide strong support for this hypothesis and suggest that limb bone cross sections may not always only reflect the activity levels of particular fossil individuals, but also convey an evolutionary signal providing information about hominin activity in the past. Am J Phys Anthropol 143:21,30, 2010. © 2010 Wiley-Liss, Inc. [source] | ||||||||||||||||