1. The Effect of an Irreversible Receptor Antagonist on Cocaine Self-Administration Behavior in Rats
Thao Minh Nguyen, Hanna Dasenbrock, Andrew B. Norman
University of Cincinnati College of Medicine, Department of Pharmacology and Cell Biophysics
Methods Discussion
• Cocaine self-administration behavior is regulated according to
pharmacological principles, and can be predicted using a
mathematical model following the equation T=ln(1+Du/Dst)/k,
where T=time between self-administrations, Du=unit dose, Dst=
satiety threshold, and k=first order elimination rate constant (fig
2).
• The construction of hand made catheters is vital to conducting
self-administration studies. Commercially available versions are
not effective and cannot be used for this highly quantitative
research.
• Optimization of the catheter construction process has greatly
contributed to the Norman lab and facilitated several ongoing
studies
• The receptors underlying the regulation of self-administration
behavior (most likely dopamine) remain the same both before
and after EEDQ treatment.
• Further understanding the mechanisms underlying this addictive
behavior may lead to targets for future therapies.
• Norman AB, Tabet MR, Norman MK, Tsibulsky VL. Using the self-administration
of apomorphine and cocaine to measure the
pharmacodynamic potencies and pharmacokinetics of competitive
dopamine receptor antagonists. J Neurosci Methods. 2011.
• Tsibulsky VL, Norman AB. Satiety threshold: a quantitative model of
maintained cocaine self-administration. Brain Res. 1999 Aug
21;839(1):85-93.
Male Sprague-Dawley rats (275-500 g) were implanted with either jugular or femoral catheters. These specialized cathetersare
handmade in our lab (figs 3 and 4). Rats were trained to reliably self-administer cocaine (fig 5). Rats were allowed to self-administer 20
doses of 3000 nmol/kg. Time between lever presses was recorded. Baseline intervals were recorded at for at least 4 days prior to
experimentation. To investigate the receptors underlying this behavior, during a self-administration session, rats were injected with
eticlopride (20 nmol/kg i.v). The ratio of mean inter-injection intervals before eticlopride/ the peak cocaine concentration after eticlopride
injection was calculated. This was repeated 3 times for each rat. Next, rats were injected with EEDQ (1 mg/kg in 10% ethanol/90%
saline). The protocol above was repeated, where eticlopride was injected during self-administration and the concentration ratio was
recorded. The data was graphed and analyzed using SigmaPlot.
Results Citations
Introduction
• Self-administration of cocaine (fig 1) in rats is a commonly used and
accepted model of addiction (fig 2 and 5). This behavior is highly
regulated and can be modeled using pharmacological principles.
• There is interest in developing models of sustained elevated cocaine
intake and in understanding the mechanisms underlying this behavior.
• It has been shown that irreversible angatonism of receptors using
EEDQ (N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) will increase
cocaine intake, and that the behavior gradually returns to baseline in
about a week.
• EEDQ and cocaine are both non-selective, so is it difficult to know if
the same receptors are mediating the response before and after
EEDQ injection. Therefore, eticlopride, a selective D2 dopamine
receptor antagonist was used.
All INJ
0 60 120 180 240
15000
10000
5000
0
Eticlopride injection i.v
Figure 6: Representitive session showing the addition of the competitive
dopamine antagonist eticlopride (20 nmol/kg i.v) during self-administration
increases the rate of cocaine consumption both before (red) and after (black)
EEDQ treatment. n=5
Table 1: The magnitude of effect of eticlopride is the same both
before and after EEDQ injection. Shown is the ratio of average
baseline intervals to the peak concentration after eticlopride
injection both before and after EEDQ treatment ±SEM. p=0.36
n=5
Time (minutes)
Cocaine amount in the
body(nmol/kg)
Figure 1: Mechanism of action of cocaine (NIDA)
Acknowledgments
• Student Achievement in Research and Scholarship (STARS)
Program: Ohio Board of Regents, Stephanie Davis, Cheri
Westmoreland.
• Norman Lab:Felicia Gooden, Mike Tabet, Michelle Nieman, and
Vladimir Tsibulsky.
Figure 3: Process of catheter
construction
Figure 5: Rat self-administering
cocaine in a chamber
Rat
Number
Ratio before
EEDQ
Ratio after
EEDQ
1 2.1 ±0.1 2.2
2 2.1 ±0.1 2
3 1.8 ±0.1 1.9
4 2.1 ±0.2 2.2
5 2.2 ±0.2 2.1
Average
2
2.1
COCAINE SELF-ADMINISTRATION MODEL
0 60 120 180 COCAINE AMOUNT IN THE BODY (mg/kg)
0.5 1.0 2.0 mg/kg
Satiety Threshold (Dst)
Priming Threshold
SESSION TIME (min)
4.0
3.6
3.2
2.8
2.4
2.0
1.6
1.2
0.8
0.4
0.0
Figure 2: Concentration of cocaine during a self-administration
session.
Figure 4: Close up of catheter
construction