Dishman et al. (2006) Neurobiology of Exercise OBESITY Vol. 14 No. 3
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Transcript of Dishman et al. (2006) Neurobiology of Exercise OBESITY Vol. 14 No. 3
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Dishman et al. (2006) Neurobiology of Exercise OBESITY Vol. 14 No. 3
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Running as a Reinforcer
Rodents that run have increased DA release in nucleus accumbens (natural and drug reward).
Drug addiction prone rodent strains ( Lewis,
C57BL/6) develop high running activity, (10km/day v. 2 km/day) This study: SD rats, 1.2-2.8 Km over three weeks (four week peak?)
No absolute correlation.
Rodents can be trained to lever press for access to running wheels (Self administration).
Long access to wheel running- shift from low to high activity. Not seen with shorter access (as in drug self-administration)
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Running rats exhibit withdrawal signs (increased
aggression) when access to the running wheel is denied.
Fos B – up-regulated in reward pathways after addictive drugs and voluntary wheel running.
Fos B over-expression increases running activity and increases sensitivity to rewarding effects of morphine.
Rodents display conditioned preference to an environment associated with running “after-effects”Attenuated by naloxone.
Repeated activation of opioid systems by running could possibly change sensitivity to morphine.
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Cross-ToleranceDecreased response to one drug due to
exposure to another pharmacologically similar drug.
Opioid systems & Morphine
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Endogenous opioidsOpioids: Naturally occurring peptides having opiate-like
pharmacological effects.
3 distinct genes : preproopiomelanocortin (POMC), preproenkephalin A (PENK), preproenkephalin B/ preprodynorphin (PDYN) produce precursors of 3 major groups: 1) enkephalins 2) dynorphin 3) endorphins.
They possess some affinity for any or all of the opioid receptor subtypes ( µ, , and ) and the effector pathways for all receptor types are G-protein-mediated.
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NeuropeptidesSynthesized in soma
and stored in dense-core vesicles in neurons which also contain a classical fast-acting transmitter (i.e. glutamate)
Act as co-transmitters serving to modulate the actions of the primary transmitter.
Released at high neuronal firing frequency or burst firing pattern
Levitan and Kaczmarek (1997) “The Neuron” 2nd ed.
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Morphine
Hyman et al. (2006) Annual Reviews Neuroscience 29:565-98
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Exercise slows down aging .Returns levels of hippocampal
neurogenesis and learning (MWM).
Exercise enhances contextual learning
and memory.Radial arm maze, etc.
Therefore, exercise possibly will increase motivational / associative learning, i.e. CPP
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Notes on Neurogenesis
Voluntary running increases hippocampal neurogenesis and enhances hippocampal dependant learning.
Hippocampal dependant learning increases hippocampal neurogenesis.
Conditioned Place Preference – Contextual / spatial learning
However, Chronic opiate self-administration decreases hippocampal neurogenesis. (timing? Procedure?)
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Methods Adult male Sprague-
Dawley rats
Under reverse 12h light/dark schedule
Testing during dark phase
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General ProcedureThree week access
to “activity wheels”Portion of AW rats
and SED rats tested for sucrose preference.
Day after – CPP to morphine.
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No differences in sucrose preference between activity groups.
AW rats drank more sucrose & water.
Exercise did not enhance appetitive properties of sucrose.
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Conditioned Place Preference
Tested for natural preference first day. (30 min.)
Next two daysMorning – injected sc. saline & 5 minutes later
enclosed in the non-conditioned chamber (prefered in natural preference, 45 min.)
Afternoon- injected sc. Saline or morphine & 5 minutes later placed in chamber not prefered in natural preference test (45 min).
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Conditioned Place Preference (Cont’d)
After conditioning – Test as on first day. 30 min.Time in and entries into chambers recorded
CPP score = time in conditioning chamber on test day – time spent on initial day
24 hours after test decapitated for In situ Hybidization
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Locus CoeruleusNoradrenergic
neurons.
Extensive projections throughout the CNS.
Function-attention and arousal, cardiovascular regulation, control of pain, anxiety states and the stress response, etc.
Kandel et al. (2000) Principles of Neural Science 4th ed.
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Berridge & Waterhouse (2003) Brain Research Reviews 42: 33-84
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Neurochemical and behavioral effects of opiate withdrawal mediated by LC hyperactivity.Opiate withdrawal syndrome
Hyperactivity Rearing Teeth chattering Wet dog shakes Piloerection Ptosis
Transgenic mice overexpressing Galanin – decreased morphine withdrawal signs.
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Galanin29-AA peptide neurotransmitter.In CNS, expressed in regions implicated in
mood and anxiety – hypothalamus, amygdala, LC, dRN, VTA.
Coexists with NE ~80% LC neurons.Voluntary exercise increases preproGAL
mRNA in the LC. -Chronic social stress & Chronic Fluoxetine
increases GAL in LC (& GALR2).
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Hokfelt et al., (2000) Neuropeptides — an overview Neuropharmacology 39 1337–1356
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Brain Derived Neurotrophic Factor
Hippocampus is involved in CPP.
Selective induction of BDNF expression in the hippocampus during contextual learning.
Impaired BDNF signaling = impaired spatial learning.
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ConclusionsExercising and sedentary rats did not display
significantly different degrees of CPP to morphine.
CPP to morphine occurred in a dose-dependent manner in exercising and sedentary rats.
Exercising rats displayed greater CPP when presented as time spent per entry – overcoming of cross-tolerance effect?
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Dose dependant increase in LC preprogalanin mRNA in Exercising rats. Not related to CPP to morphine
Increase of hippocampal BDNF mRNA in exercising rats that also displayed CPP to morphine.