1. Prior cocaine exposure disrupts extinction of fear conditioning
Authors:
Kathryn A. Burke, Theresa M. Franz, Nishan Gugsa, and Geoffrey Schoenbaum

2. Addiction Compulsive behavior
Excessive seeking/taking of drugs in face of aversive consequences
Drugs = long-lasting consequences
Prefrontal cortex
Medial prefrontal cortex (MPFC)

3. Role of Medial Prefrontal Cortex
Not studied for effects w/ drugs but altered by them
Suppresses inappropriate behavior
Behavioral flexibility
Needed to change behavior in response to uncertain/ambiguous events
Not needed for initial learning
Lesions (to the MPFC)
Alters Attentional set-shifting
Alters Extinction of fear conditioning

4. Hypothesis
If psychostimulant-induced neuroadaptations in MPFC are functionally significant, then should observe changes in performance in these tasks in drug-experienced rats

5. Methods & Materials 23 3 mo old male Long-Evans rats
Testing in behavioral boxes (12x10x12 inches) and recorded activity levels w/ photocell monitors
For all training (except inflation) boxes were enclosed in sound and light-resistant shells
Boxes configured with cues, food cups, response levers
During conditioning & extinction, bar pressing rates calculated for pre-CS & CS periods for each trial & a suppression ratio was calculated from data for each at on each trial (bar pressingpre-tone – tone) / (bar pressingpre-tone + tone)

6. Methods & Materials (cont)
Freezing scored manually (scored 1 sec increments using timed pulses) & averaged during pre-CS & CS periods
Rats were deprived of food (85% baseline) then trained to bar press for sucrose pellets on a VI60 schedule until response of ~20 respones/min
Saline-treated rats n=11, cocaine-treated rats n=12
14 days of 30 mg/kg, i.p. of cocaine for cocaine-treated rats & similar volume of saline for saline-treated rats
After injection, each rat put into operant box to record activity for 1 hr

7. Methods & Materials (cont)
3 wks after cocaine sensitization retrained to bar press for food & then tested for FC and extinction
Habituation 4 tones (conditioned stimulus) alone
Then given 6 tones (CS) w/ mild footshock (unconditioned stimulus)
After FC, divided into 4 groups: cocaine inflated (new environment; 3 US 6 X Intensity of previous FS; 4 min intervals and no tones), cocaine noninflated (no FS), saline inflated, saline noninflated
24 h after inflation began extinction training (2 sessions w/ 16 presentations of tone alone w/ no FS over 2 days)

8. Experimental Procedure
Inflations procedure used to increase the incentive value of the shock stimulus and increases subsequent conditioned responding dependent on the basolateral amygdala (BLA).

9. Fig. 1 Effect of cocaine on locomotor activity
Cocaine-treated rats exhibited sig. increase in locomotor activity after 14 day sensitization period (Fig. 1 left side). Cocaine-treated rats exhibited greater sensitivity to cocaine in the challenge test shown by increased activity to lower doses (30-45 and min into the session) (Fig. 1 right side).

10. Fig. 2 Effect of cocaine on conditioned freezing & suppression at the end of habituation/during fear conditioning
Freezing - % time during tone (CS) spent freezing
Suppression - ratio comparing bar pressing during CS w/ bar pressing during pre-CS period

11. Results (Fig. 2)
Cocaine- & saline-treated rats showed similar conditioning of both measures to the tone
ANOVA’s indicated sig. main effects of trial for both freezing & conditioned suppression
No sig. main effects or interactions involving treatment on either freezing or suppression behavior

12. Fig. 3 Effect of cocaine on extinction of conditioned freezing & suppression
Cocaine-treated rats were sig. slower to extinguish both conditioned freezing and suppression and continued to show higher conditioned suppression on a 2nd day of extinction training.

13. Fig. 4 Effect of inflation of conditioned freezing in saline-treated (A) and cocaine-treated (C) rats
Inflated rats in both groups froze sig. more than non-inflated rats (beginning of extinction); there was no effect of cocaine. Inflation affects previously acquired learning.

14. Fig. 4 Effect of inflation of conditioned suppression in saline-treated (B) and cocaine-treated (D) rats
No effect of inflation on suppression in either group. The effect of cocaine treatment on extinction of conditioned freezing & suppression (shown in Fig. 2) was evident here in both inflated &non-inflated rats.

15. Discussion
Associations b/w conditioned stimuli & fear-producing events are thought to be formed in the basolateral complex of the amygdala (BLA)  then expressed though excitatory output to central nucleus (CeA)
CeA operates in parallel to encode motivating aspects of fear-producing conditioned stimuli
Results may reflect effects of cocaine w/i BLA & CeA or downstream regions  make such learning resistant to extinction
Difficult to separate effects of cocaine on locomotor activity from effects on conditioned behavior

16. Discussion
Processing of fear associations w/in amygdala is largely intact after cocaine exposure
Impaired extinction in amygdala would be selective
More likely candidate for this process is the mPFC
Due to alterations in mPFC or alterations in how mPFC interacts w/ amygdala
Cocaine does cause alterations in MPFC structure and function
Expression of fear memories in subcortical regions is modulated by output from the mPFC
mPFC modulates encoding in the amygdala (BLA)
Enhanced responding to fear-associated cues during extinction learning

17. Conclusion
No effects of inflation on conditioned suppression in saline- or cocaine-treated rats
Transfer of aversive properties of fear-producing US to the instrumental bar pressing response is insensitive to the value of the US predicted by the Pavlovian cue
Similar to what has been reported for appetitive Pavlovian-to-instrumental transfer
Dissociation of the effects of US conditioned suppression (remained unchanged) is consistent w/ the proposal that the properties of Pavlovian CS are mediated by different circuits in the amygdala