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

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

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)

4. 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.

5. Cross-Tolerance • Decreased response to one drug due to exposure to another pharmacologically similar drug. • Opioid systems & Morphine

6. 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.

7. 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.

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

10. 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

11. 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?)

12. Methods • Adult male Sprague-Dawley rats • Under reverse 12h light/dark schedule • Testing during dark phase

13. General Procedure • Three week access to “activity wheels” • Portion of AW rats and SED rats tested for sucrose preference. • Day after – CPP to morphine.

14. No differences in sucrose preference between activity groups. • AW rats drank more sucrose & water. • Exercise did not enhance appetitive properties of sucrose.

17. 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).

18. 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

22. 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.

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

24. 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.

25. 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).

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

31. 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

34. 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?

35. 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.