CP-154,526, a CRF type-1 receptor antagonist, attenuates the cue-and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior in rats

Moffett and Goeders (2007)

Presented by

Amanda Jonas

Acquisition of psychostimulant self-administration Repeated tail pinch Social Stress Social Isolation Electric Footshock

Ketoconazole Corticosterone synthesis inhibitor

Inhibits 11β-hydroxylase Decrease low-dose cocaine self-administration Also used to treat fungal infections Shown to partially attenuate increases in plasma

corticosterone Reinstatement of cocaine-seeking behavior Exposure to electric footshock Cocaine pretreatment

CP-154,526 Corticotropin-releasing hormone (CRF) type 1

receptor antagonist Decreases cocaine intake across several doses of

cocaine Centrally acting antagonist at CRF1 receptors Has been shown to attenuate the airpuff startle-

induced rise in plasma corticosterone and adrenocorticotropic hormone (ACTH)

Extinction/Reinstatement Model Often used as an animal model of relapse Rats trained to self-administer a drug until

stable behavior maintained Rats exposed to extinction Drug-seeking behavior reinstated by

presentation of specific stimuli

Specific Stimuli Acute exposure to a stressor Stimuli previously paired with the drug Acute exposure to the self-administered

drug

Hypothalamo-pituitary-adrenal (HPA) axis Role in acquisition and maintenance of

psychostimulant self-administration Potential role in relapse

Purpose Investigate the potential role for the HPA

axis in the ability of environmental stimuli and priming infusions of methamphetamine to stimulate extinguished methamphetamine seeking by using two drugs that act on different levels of the HPA axis

Hypothesis CP-154,526 and Ketoconazole will

attenuate the cue- and methamphetamine-induced reinstatement of methamphetamine-seeking behavior in a manner similar to cocaine-trained rats

Subjects 85 male Wistar rats 80-100 days old Housed individually Reversed 12-h ligh-dark cycle Maintained at 85 to 90% of free-feeding

body weights by presentation of food pellets during behavioral sessions

Water access was ad libitum

Venous Catheterization and Drug Delivery Implanted with chronic indwelling jugular

catheters 22-gauge cannula guide

i.c.v CP-154,526 infusions Implanted with a 22-gauge guide cannula

Into the right or left lateral cerebral ventricle

Apparatus Sound-attenuating chambers Equipped with two retractable response

levers on either side Stimulus light about each lever House light mounted on wall opposite

levers with tone source wired directly to the light

Self-Administration Training Trained to self-administer methamphetamine by

pressing a lever under a continuous schedule of reinforcement 2-h daily sessions 5 days a week

Two levers Methamphetamine (Active)

Stimulus light illuminated when methamphetamine available

Inactive

Extinction Daily 2-h sessions The stimulus light was on for the active

lever Brief (0.6 s) darkening of the lever light

when pressed No methamphetamine was delivered

Extinction continued Session continued until the total number of

responses were equal to or lower than 20% of the mean number of responses to the active lever during self-administration

After extinction, tested for reinstatement of methamphetamine seeking using the cues

Cue-induced reinstatement Conditions were similar to self-administration

except for methamphetamine was not delivered Ketoconazole or vehicle was injected 30 min

before the start of the test session in the home cage

After a single response to the active lever, the house light was illuminated and tone sounded for 5.6 s

After reinstatement training, rats returned to self-administration training

Cue-induced for i.c.v CP-154,526 Rats implanted with i.c.v. underwent cue-induced

reinstatement testing the same as ketoconazole CP-154,526 or vehicle was injected 30 min

before the session After testing, returned to self-administration

training and eventually retested Each rat received vehicle and CP-154,526 on

separated occasions using a counter-balanced design

Figure 1a

Figure 1b

Table 2

Figure 2

Methamphetamine-induced reinstatement Conditions identical to extinction Ketoconazole, CP-154,526, or vehicle was

injected 30 min before the start of the test session in the home cage

Before the start of the session, rats received a single methamphetamine priming infusion

After reinstatement training, rats returned to self-administration training

Comparisons Effects of ketoconazole 50 mg/kg vs. vehicle on

responding after a 0.12 mg/kg priming infusion Ability of CP-154,526 20 mg/kg dose vs. vehicle

to attenuate methamphetamine-primed reinstatement at the 0.12 mg/kg dose

Effects of two doses of CP-154,526 (20 mg/kg and 40 mg/kg) vs. vehicle on 0.24 mg/kg methamphetamine-induced reinstatement

Retesting Received a minimum of 5 self-

administration retraining sessions before being placed back into extinction

Tested for reinstatement a maximum of 3 times using only one stimulus Once after receiving vehicle Twice after receiving different doses of the

test drugs

Figure 3a

Figure 3b

Figure 4

Table 1

Food Training Trained to respond under a fixed-interval (F1)

schedule of food reinforcement during daily 1-h sessions

Initially trained on a FI25 schedule Stimulus light about food lever illuminated every 25

s Food pellet presented when lever was pressed

when it was illuminated Houselight illuminated and a tone (66 dB) presented

for 5.6 d

Food Training continued Fixed interval was gradually raised to F150

schedule Used to produce rates of responding that were similar

to methamphetamine self-administration

Training continued until 3 consecutive sessions with less than a 10% variation in active lever responding occurred

Tested on the following day (identical to training sessions)

Food Training continued Pretreated with either CP-154,526 or vehicle 30

min before the start of the test session in the home cage

Number of active lever responses during the test session were compared to those on the last day of training

Returned to food training for a minimum of 5 sessions before being tested with a different drug or dose

Food Training continued Tested a maximum of 3 times

Once after receiving vehicle Twice after receiving different doses of CP-154,526

Six of the rats used in this experiment, implanted with catheters and used in addition to naïve rats for ketoconaxole

3 months elapsed before the reinstatment test session

Table 3

Discussion Ketoconazole and Cp-154,526 reversed the

cue-induced reinstatement of methamphetamine seeking

CP-154,526 attenuated the cue-induced reinstatement of methamphetamine seeking and methamphetamine-induced reinstatement

Discussion continued Results indicate that CRF, but not corticosterone,

plays a crucial role in the ability of environmental cues and priming injections to stimulate methamohetamine seeking

The cues paired with self-administration methamphetamine as well as priming infusions of methamphetamine may have acted as stressors during the reinstatement test session lead to stimulating the release of CRF to increase

plasma corticosterone

Discussion continued Potential value of the development of CRH

receptor antagonists as aids in preventing relapse in drug-dependent individuals

Thank you!