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

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

Larson and Carroll (2005)Presented byAmanda Jonas

High-RespondersPalatable tastesNovelty-seeking ImpulsivityStress reactivity

High-Responders vs. Low- RespondersMore sensitive to the locomotor effects

of drugs of abuseMore likely to self-administer drugs

Wheel RunningNondrug behavior actively engaged in

by ratsReinforcing effects similar to drugsRats will lever press for access Show conditioned place preferenceEscalate wheel running when given

unlimited access

Wheel Running and Vulnerability to drugsWheel running experience produced

cross-tolerance to the rewarding effects of morphine

Access during ethanol withdrawal potentiated subsequent ethanol intake

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

Objective 2Compare HiR and LoR rats on the

cocaine self-administration behavior during maintenance

Hypthesis: HiR rats will self-administer more cocaine than LoR rats

Objective 3Compare 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

Animals14 sexually mature female Wistar rats250-340 gFemales more active in running wheels

than malesEstrous cycles were allowed to vary

randomly and were not monitored or analyzed

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

Other conditionsAll rooms on 12/12 light/dark cycle Lights on at 0600 hAcclimated for 3 days priors to surgeryHoused in experimental chambers

ApparatusStainess 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

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

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

SA chamberChambers 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 wheelEvery 4 sensor breaks were counted as

one wheel revolution

CocaineDissolved in 0.9% NaCl solution along

with heparinRats received cocaine (0.4 mg/kg/inf) at

a rate of 0.025 ml/s and a duration of 1 s/100g body weight

Figure 1: Wheel running

Assessment of locomotor response activityPrior to running wheel access, tested in

the circular track for 45 min for 2 daysLocomotor activity was significantly

lower on day 2 than day 1Day 1 reflects the locomotor response

to noveltyDay 2 reflects baseline activity levels

Figure 2 : Day 1

Figure 2: Day 2

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

Figure 3

Figure 4: Mean activity

Figure 4: Mean overall activity

SurgeryRats were implanted with jugular

catheters for i.v. cocaine self-administration

3 days of recovery

Figure 1: SA

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

Maintenance If lever pressing maintained, rats tested

in reinstatement procedureRats allowed to lever press for 14 days

during 2-h sessions

Figure 5

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

Figure 6

ReinstatementTesting 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

Figure 7

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

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

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

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

Thank You!