Wheel running as a predictor of cocaine self-administration and reinstatement in female rats

1. Wheel running as a predictor of cocaine self-administration and reinstatement in female rats Larson and Carroll (2005) Presented by Amanda Jonas

2. High-Responders • Palatable tastes • Novelty-seeking • Impulsivity • Stress reactivity

3. High-Responders vs. Low- Responders • More sensitive to the locomotor effects of drugs of abuse • More likely to self-administer drugs

4. Wheel Running • Nondrug behavior actively engaged in by rats • Reinforcing effects similar to drugs • Rats will lever press for access • Show conditioned place preference • Escalate wheel running when given unlimited access

5. Wheel Running and Vulnerability to drugs • Wheel running experience produced cross-tolerance to the rewarding effects of morphine • Access during ethanol withdrawal potentiated subsequent ethanol intake

6. Objective 1 of the current study • Determine whether individual differences in voluntary wheel running predicted the subsequent sensitivity to the locomotor-activating effects of cocaine • Hypothesis: High-Responder (HiR) rats will show greater locomotor activity in response to an acute injection of cocaine compared to Low-Responder (LoR) rats

7. Objective 2 • Compare HiR and LoR rats on the cocaine self-administration behavior during maintenance • Hypthesis: HiR rats will self-administer more cocaine than LoR rats

8. Objective 3 • Compare HiR and LoR rats on their cocaine-seeking behavior during extinction and reinforcement • Determine whether HiR rats are more motivated than LoR rats to seek cocaine under extended abstinence conditions

9. Animals • 14 sexually mature female Wistar rats • 250-340 g • Females more active in running wheels than males • Estrous cycles were allowed to vary randomly and were not monitored or analyzed

10. Food • Food and water were available as libitum until surgery • After surgery it was reduced to 16 g/day and remained that amount for the rest of the experiment • Food restriction used to accelerate training and to control potential difference in food intake between groups

11. Other conditions • All rooms on 12/12 light/dark cycle • Lights on at 0600 h • Acclimated for 3 days priors to surgery • Housed in experimental chambers

12. Apparatus • Stainess steel locomotor tracks • Used to measure novelty-induced locomotor activity, baseline locomotor activity, and locomotor activity after acute exposure to either saline or cocaine • Tracks had inner and outer diameters of 46 and 71 cm

13. Apparatus continues • Walls were 25 cm high • Tracks covered with Plexiglas sheet during testing • Four infrared sensors mounted above the floor of the track on the outer wall at 0º, 90º, 180º, and 270º • Two successive sensor interruptions were measured as one activity count and counts were totaled and recorded in 5-min increments

14. Wheel Running and i.v. cocaine self-administration • Octagonal operant chamber enclosed w/ a fan for white noise and ventilation • Eight walls alternated with stainless steel or Plexiglas • Two response levers on two of the steel panels • Stimulus light located above each lever and illuminated for 20-s after each lever press

15. SA chamber • Chambers also contained a ceiling house light, a food hopper, and a panel for the water bottle • Chamber had guillotine-style door which allowed access to a running wheel • Four sensors located along the wheel • Every 4 sensor breaks were counted as one wheel revolution

16. Cocaine • Dissolved in 0.9% NaCl solution along with heparin • Rats received cocaine (0.4 mg/kg/inf) at a rate of 0.025 ml/s and a duration of 1 s/100g body weight

17. Figure 1: Wheel running

18. Assessment of locomotor response activity • Prior to running wheel access, tested in the circular track for 45 min for 2 days • Locomotor activity was significantly lower on day 2 than day 1 • Day 1 reflects the locomotor response to novelty • Day 2 reflects baseline activity levels

19. Figure 2 : Day 1

20. Figure 2: Day 2

21. Wheel Running and locomotor response to cocaine • Allowed access to wheel for 21 days, 6 h/day • Wheel access was then discontinued • Median split used to divide rats into HiR and LoR groups • The two groups were retested on the circular track for 2 days, 7 days after no wheel access • First day-i.p. injection of saline prior to track • Second day- 10 mg/kg cocaine i.p. injection

22. Figure 3

23. Figure 4: Mean activity

24. Figure 4: Mean overall activity

25. Surgery • Rats were implanted with jugular catheters for i.v. cocaine self-administration • 3 days of recovery

26. Figure 1: SA

27. SA training • Trained to self-administer cocaine in 2 h daily sessions • When active or inactive lever pressed, stimulus lights lit for 20 s • Active lever resulted in cocaine infusion • Active lever initially baited with peanut butter and rats given 2 cocaine priming injections at the beginning of each session • PB and priming discontinued after rats administered greater than 20 infusions for 3 days

28. Maintenance • If lever pressing maintained, rats tested in reinstatement procedure • Rats allowed to lever press for 14 days during 2-h sessions

29. Figure 5

30. Extinction • Saline was substituted for cocaine and behavior extinguished over the next 21 days • All other stimulus conditions remained the same • Drug pumps and stimulus lights were unplugged for 3 days • After 3 days of extinction without cues, reinstatement testing commenced

31. Figure 6

32. Reinstatement • Testing consisted of 6 days of alternating saline and cocaine priming injections • One injection (either cocaine or saline) was given at the beginning of each 2-h session

33. Figure 7

34. Discussion • HiR rats had greater cocaine SA during maintenance and cocaine-induced reinstatement of lever responding • Rats did not differ in their locomotor response (novel and baseline) • Results indicated that individual differences in wheel running predicted the subsequent vulnerability for cocaine SA and reinstatement

35. Discussion continued • Suggests that HiR rats more motivated for cocaine-seeking during ongoing SA as well as during reinstatement • HiR were not more sensitive than LoR rats to the locomotor-activating effects of cocaine • HiR had an enhanced response to locomotor activating effects of cocaine and cocaine SA during maintenance

36. Discussion continued • HiR’s for nondrug rewards are motivated to self-administer psychostimulant drugs • Escalation: a key feature of drug addiction, increased performance may reflect attempt to compensate for tolerance to the rewarding aspects of these behaviors and may occur with other nondrug rewards such as wheel running • HiR rats may SA more cocaine in maintenance to compensate for higher levels of deprivation of the wheel reward

37. Discussion continued • No group differences in extinction • Study shows that wheel running predicts vulnerability to the reinstatement of drug-seeking behavior after an extended abstinence period • May lead to screening methods for identifying at-risk drug users and may aid in developing prevention strategies based on specific vulnerabilities

38. Thank You!