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 PowerPoint PPT Presentation


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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).

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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).

  • 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)


  • Running rats exhibit withdrawal signs (increased aggression) when access to the running wheel is denied.

  • DFos B – up-regulated in reward pathways after addictive drugs and voluntary wheel running.

  • DFos 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.


  • Cross-Tolerance

    • Decreased response to one drug due to exposure to another pharmacologically similar drug.

    • Opioid systems & Morphine


Endogenous opioids

  • Opioids: 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, d, and k ) and the effector pathways for all receptor types are G-protein-mediated.


Neuropeptides

  • Synthesized 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.


Morphine

Hyman et al. (2006) AnnualReviewsNeuroscience 29:565-98


  • 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


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?)


Methods

  • Adult male Sprague-Dawley rats

  • Under reverse 12h light/dark schedule

  • Testing during dark phase


General Procedure

  • Three week access to “activity wheels”

  • Portion of AW rats and SED rats tested for sucrose preference.

  • Day after – CPP to morphine.


  • No differences in sucrose preference between activity groups.

  • AW rats drank more sucrose & water.

    • Exercise did not enhance appetitive properties of sucrose.


Conditioned Place Preference

  • Tested for natural preference first day. (30 min.)

  • Next two days

    • Morning – 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).


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


Locus Coeruleus

  • Noradrenergic neurons.

  • Extensive projections throughout the CNS.

  • Function-attention and arousal, cardiovascular regulation, control of pain, anxiety states and the stress response, etc.

Kandelet al. (2000) Principles of Neural Science 4th ed.


Berridge & Waterhouse (2003) Brain Research Reviews 42: 33-84


  • 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.


Galanin

  • 29-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).


Hokfelt et al., (2000) Neuropeptides — an overview Neuropharmacology 39 1337–1356


Hippocampus is involved in CPP.

Selective induction of BDNF expression in the hippocampus during contextual learning.

Impaired BDNF signaling = impaired spatial learning.

Brain Derived Neurotrophic Factor


Conclusions

  • Exercising 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?


  • 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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