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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 selfadministration)
 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
Levitan and Kaczmarek (1997) “The Neuron” 2nd ed.
firing frequency or burst
firing pattern
Morphine
Hyman et al. (2006) Annual Reviews Neuroscience 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 Kandel et al. (2000) Principles of Neural Science 4th ed.
the stress response,
etc.
Berridge & Waterhouse (2003) Brain Research Reviews 42: 33-84
 Neurochemical and behavioral effects of opiate
withdrawal mediated by LC hyperactivity.
 Opiate withdrawal syndrome





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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
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.
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 crosstolerance 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.