TL neuro

November 10, 2011

SfN Posters (updated 11-14-2011)

Filed under: Uncategorized — mchellemller @ 8:42 am

103.04/XX61: Voluntary wheel running throughout rearing in the rat alters baseline monoamine content and content levels in response to cocaine in brain regions that mediate motivation. Location: Hall A-C; Saturday, Nov 12, 2011, 4:00 PM – 5:00 PM. Authors: *J. C. BASSO, J. W. CALLAHAN, A. M. FARRAR, E. D. ABERCROMBIE, J. I. MORRELL; Rutgers Univ., Newark, NJ

Abstract: Voluntary wheel running (VWR) is a motivated behavior in rodents, suggested by the facts that rats run voluntarily with great vigor, lever press for access to a wheel, and develop a conditioned place preference (CPP) for a place associated with the wheel or the aftereffects of wheel running. VWR decreases anxiety- and depression-like behaviors, improves attention, learning, and memory, and decreases consumption, self-administration, and CPP for drugs of abuse, including cocaine. VWR is reported to alter neurotransmitter content in brain regions that mediate voluntary movement and motivation, but there is limited research on the effects of VWR throughout rearing. We investigated the effects of VWR throughout rearing on monoamine content in regions involved in motivation, voluntary movement, and regulatory functioning. At weaning (p21), one group of female rats was housed with a running wheel, another in standard cages; all groups had food and water ad libitum. At adulthood (p65), rats were injected IP with either saline or 5.0 mg/kg cocaine; 30 minutes later they were decapitated and their brains were removed, frozen, sectioned on a cryostat, and punch dissections were taken from the ventral tegmental area (VTA), nucleus accumbens core (NAc) and shell (NAs), medial prefrontal cortex (mPFC), caudate putamen (CP), and medial preoptic area (mPOA). The tissue samples were processed and analyzed for content of dopamine (DA), serotonin (5HT), norepinephrine (NE), and their metabolites (DOPAC, HVA, 5-HIAA) using high performance liquid chromatography (HPLC). VWR throughout rearing altered monoamine and metabolite content, increasing levels of DA, NE, DOPAC, and HVA in the CP, 5-HIAA in the mPFC, DOPAC in the VTA, and DOPAC in the mPOA while decreasing DA in the mPOA. Cocaine without any wheel running experience had no effect except to decrease DA levels in the mPOA; surprisingly, VWR animals showed a robust cocaine response with decreased levels of NE, DOPAC, and HVA in the VTA and NE, 5HT, and DOPAC in the MPOA, and increased levels of 5HT in the NAs. Since plasma levels of cocaine and its major metabolites at 30 minutes post-injection were similar between rats raised with and without a wheel, differences in peripheral metabolism of cocaine cannot explain any of the differences. Interestingly, these two groups also showed a similar CPP for 5.0 mg/kg cocaine. These data suggest that VWR throughout rearing alters central monoamine content and the central but not peripheral or behavioral response to cocaine at adulthood, which suggests a variety of potential changes, some unexpected, in the neuronal functioning of animals raised with VWR compared to their sedentary counterparts.

Summary: I had the pleasure of meeting Dr. Joan Morrell and she was enthusiastic to hear about our work on exercise and meth SA. She sent me a PDF of the poster, and Julia Colette from her lab will attend Brittani’s poster on Wednesday.  In their study, rats were group housed (3-4 per cage) with toys and an activity wheel available 24-hrs per day from ages 18-21 days. CPP training assessed a range of doses of cocaine from ages 65-85 days. CPP was reduced in wheel-running rats at the 0.5 mg/kg dose, but not at higher doses. They speculate that the early wheel experience plus low initial doses produced reduction in CPP. As dose increased, CPP became more prevalent.

372.19/LL18: Running wheel exercise ameliorates methamphetamine-induced damage to striatal dopamine terminals. Location: Hall A-C. Monday, Nov 14, 2011, 10:00 AM -11:00 AM. Authors: *S. J. O’DELL, A. J. BALL, B. A. GALVEZ, J. F. MARSHALL; Dept Neurobiol & Behav, Univ. of California, Irvine, Irvine, CA.

Abstract:Previous research has shown that exercise can promote recovery of motor function and lessen dopamine terminal injury resulting from 6-hydroxydopamine, MPTP, or methamphetamine (mAMPH) administration. An important unresolved issue in this field is whether exercise protects against the initial neurotoxic insult or accelerates recovery from partial dopaminergic damage.
Repeated mAMPH administration to rodents in a single-day “binge” dosing regimen produces long-lasting damage to forebrain dopaminergic nerve terminals that spontaneously recovers over the course of approximately one year. We previously showed that voluntary aerobic exercise in rats could alter the damaging effects of a neurotoxic mAMPH binge. In our initial experiments, adult male Sprague-Dawley rats were allowed to run in 1-meter circumference wheels or kept in home cages for 3 weeks, then given an acute binge regimen of mAMPH (4 mg/kg, sc, at 2 hr intervals for a total of 4 injections) or SAL (4 x 1 ml;/kg, sc). After these injections, the rats were replaced into their original environments (wheels or no wheels) for an additional 3 weeks, then sacrificed for autoradiographic determination of the levels of dopamine transporters (DAT) in the striatum. The data showed that binge mAMPH treatment produced regionally specific decreases in striatal DAT, with the greatest damage occurring in ventral caudate-putamen (CP) and relative sparing of the nucleus accumbens. Exercise significantly blunted the mAMPH-induced CP DAT losses.
To help resolve the issue of whether exercise protected against the mAMPH-induced injury or accelerated recovery from it, rats were allowed to run in wheels for 3 weeks prior to a neurotoxic mAMPH binge (or SAL), then placed into non-wheel cages for an additional 3 weeks post- mAMPH-administration. The resulting autoradiographic data showed a trend towards amelioration of mAMPH-induced induced DAT loss in the CP, relative to sedentary animals given mAMPH. These data suggest that prior running provides some protection against mAMPH-induced neurotoxicity. Although the mechanism of this neuroprotection is still being investigated, we have found that protection is not due to a decrease in mAMPH-induced hyperthermia during the binge injection regimen. Overall, our data show that exercise is an important variable in determining vulnerability to mAMPH-induced neuronal damage; consequently, voluntary exercise may be useful as therapeutic adjunct in the treatment mAMPH addicts.

Summary: In this study, groups of rats had 3 weeks of wheel access or no wheel access (control) followed by a METH neurotox regimen. Then, all rats had no access to a running wheel, and all brains were analyzed for DAT and CERT depletion. They found that rats with running wheel experience had less DAT and CERT depletion, but the results were not significanly significant because they lost a good number of rats during the neurotox regimen. They measured and found no change in hyperthermia (control vs wheel rats) at 22C. Procedural detail: rats running increased steadily across a 21-day period, up to ~7km/day. Looks like running distance would have continued to increase if rats were given the opportunity.

04.01/VV80: The protective effect of exercise against learned helplessness persists after forced cessation of exercise. Location: Hall A-C. Monday, Nov 14, 2011, 1:00 PM – 2:00 PM. Authors: *A. B. LOUGHRIDGE1, B. N. GREENWOOD2, N. C. SADAOUI2, E. R. WOODRUFF2, M. FLESHNER2; 1Integrative Physiol., BOULDER, CO; 2Integrative Physiol., Univ. of Colorado, Boulder, CO.

Abstract: Exposure of rats to an uncontrollable stressor produces behavioral consequences that resemble symptoms of human anxiety and depression. These behaviors are known as learned helplessness and include exaggerated freezing, deficits in shuttle box escape, and reductions in social exploration. Learned helplessness behaviors are dependent upon hyperactivation and sensitization of serotonin neurons in the dorsal raphe nucleus (DRN). Six weeks of voluntary wheel running constrains activation of serotonin neurons in the DRN and protects against learned helplessness behaviors. It is unknown, however, how long the protective effect persists after cessation of physical activity. Voluntary wheel running produces neural plasticity within the DRN itself, at DRN afferent sites, and at DRN projection sites. Exercise-induced adaptations within these sites may confer ongoing protection against the behavioral consequences of exposure to an uncontrollable stressor, regardless of the exercise status of the rat. The aim of the current study was to determine the duration of the protective effect of exercise against learned helplessness behaviors after forced cessation of voluntary wheel running. Male Fisher 344 rats (n=9-20/grp) remained sedentary or were allowed voluntary access to running wheels for six weeks. At six weeks, wheels remained mobile or were locked. Rats in the locked group had wheels rendered immobile for five, ten, or fifteen days before behavioral testing. Behavioral testing occurred 24 hours after exposure to stress or uncontrollable tail shock. Social exploration of a juvenile, freezing, and shuttle box escape behaviors were measured. Studies are ongoing, but preliminary data indicate that the protective effect of wheel running against learned helplessness behaviors persists for at least five days after forced exercise cessation. A partial protection against learned helplessness behaviors was observed ten days following exercise cessation. These data suggest that six weeks of wheel running produces changes in stress responsive neurocircuitry that persist and endure following forced cessation of exercise.

Summary: missed this one.

#: 412.08/AAA17 Chronic exercise exerts anxiolytic-like effects and promotes active defensive  behaviors despite repeated pharmacological stress. Hall A-C. Monday, Nov 14, 2011, 11:00 AM -12:00 PM  Authors: *N. R. SCIOLINO1,3, R. K. DISHMAN3,2, P. V. HOLMES1,3;1Psychology, Univ. of Georgia, ATHENS, GA; 2Kinesiology, Univ. of Georgia, Athens, GA;   3Neurosci. Program, Biomed. and Hlth. Sci. Inst., Athens, GA.

Abstract: Exercise reduces anxiety in humans. However, it is uncertain whether exercise is anxiolytic in animal models because it also enhances some defensive behaviors. It is also unclear how stress influences the anxiolytic profile of exercise. We tested the hypothesis that exercise would enhance adaptive responding in behavioral tests of acute anxiety and mitigate the effects of chronic pharmacological stress. Rats were housed in the presence or absence of a running wheel for 21 d and concomitantly received either no injections or repeated intraperitoneal injections of vehicle or the benzodiazepine receptor inverse agonist FG7142 (7.5 mg/kg per d on last 10 d of running). Anxiety-like and defensive behaviors were assessed in the defensive withdrawal (DW), shock probe defensive burying (SPDB), and elevated plus maze (EPM) test the day following the last injection. Injections did not alter voluntary wheel running, as all rats similarly increased running distance across the first 7-10 days and ran ~6 km/d thereafter. Consistent with anxiolytic effects of exercise, rats allowed to run spent less time burying in the SPDB and exhibited increased open arm time and entries in the EPM compared to sedentary rats. Similarly, exercise facilitated locomotor habituation in the DW test; exercise rats were not initially (first 5 min of test) different in distance traveled in the DW test, but later (last 10 min of the test) exhibited reduced distance traveled relative to sedentary rats. Consistent with exercise enhancing active defensive responding, rats allowed to run exhibited a faster onset of burying and greater frequency of probe returns and bites in the SPDB. Chronic treatment with FG7142 did not alter behavior in the DW compared to vehicle. However, chronic FG7142 treatment increased open arm time and entries in the EPM and decreased immobility time in the SPDB relative to vehicle. The “stress” of injection did not reliably affect these measures, as rats not receiving injections were similar to those injected with vehicle. The results suggest alterations in emotion rather than locomotion or pain sensitivity, as neither exercise nor FG7142 altered the initial distance traveled in the DW, number of closed arm entries in the EPM, or onset of initial probe contact and shock reactivity in the SPDB. The data caution against interpreting exercise-induced increases in defensive behavior as anxiogenic, and they further support the conclusion that a chronic exercise regimen produces beneficial effects on anxiety.

Summary: Rats were given 24-hr access to running wheel for 21 days (daily running distance increased steadily across this time period up to ~5 km/day) followed by an injection stress paradigm (acute or chronic injections FG7142). They assessed defensive withdrawal & burying, maze behavior, and shock probes. They found that exercise combined with stress produced anxiolytic-like behaviors and increased defensive behaviors. These were male SD rats; 2 months old.

504.02/VV81: The role of exercise controllability in exercise-induced stress resistance Location: Hall A-C. Monday, Nov 14, 2011, 2:00 PM – 3:00 PM. Authors: *K. SPENCE, B. N. GREENWOOD, D. M. CREVLING, J. M. RIGALI, M. FLESHNER; Fleshner Lab., Boulder, CO.

Abstract: Exercise increases stress resistance and reduces the incidence of stress-related mood disorders, such as depression and anxiety. In rats, voluntary access to a running wheel for 6 wk produces similar protection against the behavioral consequences of inescapable stress; which resemble depression and anxiety. Although voluntary, or controllable, exercise clearly increases stress resistance, whether or not forced, or uncontrollable, exercise confers similar stress-buffering effects is unknown. Results of prior rodent studies employing forced treadmill training or swimming suggest that forced exercise does not increase stress resistance, and is itself anxiogenic. These studies, however, are difficult to interpret because these types of forced exercise introduce additional stressors, such as foot shock or water exposure. To determine if the protective effects of exercise against the depression- and anxiety-like behavioral consequences of inescapable stress are dependent upon the controllability of exercise, young adult, male F344 rats were divided into the following groups (n=9/grp): sedentary, treadmill training (TT), controllable wheel running (CW), and uncontrollable wheel running (UW). Rats in the TT group were forced to run on a progressive schedule (up to 1 hr/day) known to produce fitness benefits and were motivated by foot shock. Rats in the CW group were allowed voluntary access to running wheels. Rats in the UW group were placed into motorized wheels that were forced to rotate on a schedule closely matching the pattern (speed, duration, distance, and frequency) of voluntary activity. Rats in the UW group were forced to exercise, but additional stressors were not necessary to motivate the animals to run. All rats exercised 5 days / wk for 6 weeks during the active cycle. Running distance, food intake, and body weight were measured throughout the study. Following 6 wk of these exercise conditions, rats either remained in their home cages or were exposed to inescapable stress. Social exploration, fear conditioning, and shuttle box escape learning were assessed the following day. Although CW prevents stress-induced behaviors, preliminary data indicate that TT does not prevent the behavioral consequences of uncontrollable stress. The effect of UW on behavior is currently being investigated. The results of these studies will provide insight into the mechanism by which the experience of exercise is communicated to the brain, and can inform the design of exercise programs designed to maximize stress resistance.

Summary: In addition to the above, they did another study: they created a simulated “forced” exercise regimen based on naturalistic running patterns of rats given unlimited access to a running wheel, which shows bouts of running interespersed with periods of non-running. The rats were “forced” to run according to this schedule (by locking and unlocking the running wheel): both voluntary and forced regimen blocked behavioral deficits. They also lesioned the mPFC; similar effects in both groups. 

89.10/KK1: 96-hour methamphetamine self-administration in rats: A novel model of human drug addiction. Location: Hall A-C. Tuesday, Nov 15, 2011, 2:00 PM – 3:00 PM. Authors: *E. M. CORNETT, C. D. SCHMOUTZ, G. F. GUERIN, N. E. GOEDERS; Pharmacology, Toxicology, Neurosci., Louisiana State Univ. Hlth. Sci. Ctr., Shreveport, LA.

Abstract: In 2009, the economic cost to society of methamphetamine use was estimated at $16.2-$48.3 billion. Additionally, methamphetamine addiction is associated with crime, violence and deviant and risky sexual behavior. In the laboratory, methamphetamine addiction is typically modeled using non-contingent drug injections and/or 2 hr or 6 hr access self-administration sessions. While these models have increased our understanding of both the molecular and behavioral intricacies of methamphetamine addiction, they can be improved by more closely modeling human drug usage, which was the goal of these experiments. Human methamphetamine users typically follow a binge-pattern of 3-15 days of continual drug use, followed by a 1-3 day “crash” period of continuous sleep, and then they repeat the cycle. Of additional importance are potential gender differences associated with methamphetamine use since there are few reports of the effects of methamphetamine on female rats, especially using a binge paradigm. Male and female adult Wistar rats were implanted with jugular catheters and allowed to recover from surgery. The rats were placed in self-administration chambers and trained to self-administer methamphetamine with free access to water and fed 1x per day for 96 consecutive hours. Blood samples were drawn before, during and after the 96-hour session to monitor corticosterone, ACTH and testosterone. Estrous cycle fluctuations were also monitored in the female rats. Both male and female rats displayed shifts in their circadian rhythms (more drug intake during their normally inactive periods compared to their active periods), and interestingly, significantly decreased corticosterone and ACTH levels during the first 96-hour session relative to baseline that then increased back to baseline during the second 96-hour session. Additionally, female rats displayed estrous cycle disruption by the second 96-hour methamphetamine session, consistent with human female menstrual cycle disruption reported with methamphetamine use. Finally, both male and female rats displayed violent, aggressive and self-harmful behaviors, all consistent with human methamphetamine users. These data suggest that our 96-hour binge model of methamphetamine exposure may be useful as a novel model to more closely mimic human drug-taking behavior and perhaps further contribute to elucidating gender differences in methamphetamine use and addiction.

688.03/JJ3: Sex differences in the effects of exercise on subsequent cocaine craving in rats. Location: Hall A-C. Tuesday, Nov 15, 2011, 3:00 PM – 4:00 PM. Authors: *A. PETERSON, W. LYNCH; Psychiatry and Neurobehavioral Sci., Univ. of Virginia, Charlottesville, VA .

Abstract: Currently there are no approved pharmacotherapies for treating cocaine addiction. Recent studies using animal models of cocaine addiction demonstrate that concurrent access to a running wheel can decrease the reinforcing effects of cocaine during a maintenance phase. Consistent with this idea, our lab has recently shown in males that 2-hrs/day of exercise during abstinence not only prevents an increase in cocaine-seeking that develops over an abstinence period, but also prevents an increase in neuronal signaling in the prefrontal cortex (PFC). Thus, the objective of this study was to extend our previous findings to females and determine whether there are sex differences in the effects of exercise, during an abstinence period, on subsequent cocaine-seeking in an animal model of cocaine relapse. Intact adult male and female rats were trained to self-administer (SA) cocaine (1.5 mg/kg/infusion) under a fixed ratio 1 schedule of reinforcement with a maximum of 20 infusions per session. Once rats acquired cocaine SA, they were given 24/hr extended access to cocaine (1.5 mg/kg/infusion) under a discrete trial procedure (4 infusions/hr) for a total of 10 days. Following extended access rats began a 14 day abstinence period in which they either had 2-hr/day access to a running-wheel (exercise group, n=9 for males and n=9 for females) or 2-hr/day access to a locked running wheel (environmentally enriched sedentary group, n=10 for males and n=10 for females). As an additional control for environmental enrichment, following the same extended access self-administration protocol, an additional group of female rats (n= 3-6) were placed in isolated living conditions (without any running-wheel attachment). Cocaine-seeking, assessed under a cued-induced reinstatement paradigm, were examined after the 14day abstinence period when cocaine seeking is known to be high. Results showed that in males wheel running significantly reduced cocaine-seeking in response to the cues formerly associated with cocaine. In females, both groups that had access to the wheel (locked and unlocked) had similar low levels of reinstatement responding, and these levels were significantly lower than those observed in the isolated group. This finding suggests that exercise and environmental enrichment had equal effects on cocaine-seeking in females. Taken together, these results suggest that exercise blocks incubation of cocaine-seeking in males and has equal effects as environmental enrichment in females.


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