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).

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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

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


Running as a reinforcer

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)


Dishman et al 2006 neurobiology of exercise obesity vol 14 no 3

  • 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.


Dishman et al 2006 neurobiology of exercise obesity vol 14 no 3

  • Cross-Tolerance

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

    • Opioid systems & Morphine


Endogenous opioids

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

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

Morphine

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


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


Notes on neurogenesis

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

Methods

  • Adult male Sprague-Dawley rats

  • Under reverse 12h light/dark schedule

  • Testing during dark phase


General procedure

General Procedure

  • Three week access to “activity wheels”

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

  • Day after – CPP to morphine.


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.


Conditioned place preference

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

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

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.


Dishman et al 2006 neurobiology of exercise obesity vol 14 no 3

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


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.


Galanin

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).


Dishman et al 2006 neurobiology of exercise obesity vol 14 no 3

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


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.

Brain Derived Neurotrophic Factor


Conclusions

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?


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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