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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. Running as a Reinforcer. Rodents that run have increased DA release in nucleus accumbens (natural and drug reward). - PowerPoint PPT Presentation
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Page 1: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3
Page 2: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

Dishman et al. (2006) Neurobiology of Exercise OBESITY Vol. 14 No. 3

Page 3: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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.

Page 5: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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

Page 10: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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

Page 11: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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?)

Page 12: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

Methods Adult male Sprague-

Dawley rats

Under reverse 12h light/dark schedule

Testing during dark phase

Page 13: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

General ProcedureThree week access

to “activity wheels”Portion of AW rats

and SED rats tested for sucrose preference.

Day after – CPP to morphine.

Page 14: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

No differences in sucrose preference between activity groups.

AW rats drank more sucrose & water.

Exercise did not enhance appetitive properties of sucrose.

Page 15: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3
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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).

Page 18: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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

Page 24: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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.

Page 25: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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?

Page 35: Dishman et al. (2006) Neurobiology of Exercise  OBESITY  Vol. 14 No. 3

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.


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