Transcript Amanda Jonas - USD Biology

CP-154,526, a CRF type-1 receptor
antagonist, attenuates the cue-and
methamphetamine-induced reinstatement
of extinguished methamphetamineseeking behavior in rats
Moffett and Goeders (2007)
Presented by
Amanda Jonas
Acquisition of psychostimulant
self-administration
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Repeated tail pinch
Social Stress
Social Isolation
Electric Footshock
Ketoconazole
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Corticosterone synthesis inhibitor
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Inhibits 11β-hydroxylase
Decrease low-dose cocaine self-administration
Also used to treat fungal infections
Shown to partially attenuate increases in plasma
corticosterone
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Reinstatement of cocaine-seeking behavior
Exposure to electric footshock
Cocaine pretreatment
CP-154,526
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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 startleinduced rise in plasma corticosterone and
adrenocorticotropic hormone (ACTH)
Extinction/Reinstatement Model
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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
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Acute exposure to a stressor
Stimuli previously paired with the drug
Acute exposure to the self-administered
drug
Hypothalamo-pituitary-adrenal
(HPA) axis
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Role in acquisition and maintenance of
psychostimulant self-administration
Potential role in relapse
Purpose
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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
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CP-154,526 and Ketoconazole will
attenuate the cue- and methamphetamineinduced reinstatement of
methamphetamine-seeking behavior in a
manner similar to cocaine-trained rats
Subjects
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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
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Implanted with chronic indwelling jugular
catheters
22-gauge cannula guide
i.c.v CP-154,526 infusions
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Implanted with a 22-gauge guide cannula
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Into the right or left lateral cerebral ventricle
Apparatus
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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
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Trained to self-administer methamphetamine by
pressing a lever under a continuous schedule of
reinforcement
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2-h daily sessions 5 days a week
Two levers
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Methamphetamine (Active)
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Stimulus light illuminated when methamphetamine available
Inactive
Extinction
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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
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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
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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 selfadministration training
Cue-induced for i.c.v CP-154,526
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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
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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 selfadministration training
Comparisons
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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
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Received a minimum of 5 selfadministration retraining sessions before
being placed back into extinction
Tested for reinstatement a maximum of 3
times using only one stimulus
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Once after receiving vehicle
Twice after receiving different doses of the
test drugs
Figure 3a
Figure 3b
Figure 4
Table 1
Food Training
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Trained to respond under a fixed-interval (F1)
schedule of food reinforcement during daily 1-h
sessions
Initially trained on a FI25 schedule
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Stimulus light about food lever illuminated every 25
s
Food pellet presented when lever was pressed
when it was illuminated
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Houselight illuminated and a tone (66 dB) presented
for 5.6 d
Food Training continued
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Fixed interval was gradually raised to F150
schedule
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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
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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
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Tested a maximum of 3 times
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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
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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
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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
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lead to stimulating the release of CRF to increase
plasma corticosterone
Discussion continued
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Potential value of the development of CRH
receptor antagonists as aids in preventing
relapse in drug-dependent individuals
Thank you!