Background
Although considerable evidence implicates dopamine D1-receptor signaling in the nucleus
accumbens in motivation for cocaine during early stages of addiction, less is known
with regard to its role after the development of addiction. Here, we examined its
role in the development of an addicted phenotype in intact male and female rats, and
in female rats that were either resistant or vulnerable to developing this phenotype.
Methods
Intact males, females, and ovariectomized (OVX) females with and without estradiol
(vulnerable, OVX+E; resistant, OVX+Veh) were given either short access (ShA) (three
fixed-ratio 1 sessions, maximum of 20 infusions) or 24-hour extended access (ExA)
to cocaine for 10 days (4 trials/hour). Motivation for cocaine was assessed after
a 14-day abstinence period with a progressive-ratio schedule. Once responding stabilized,
the effects of intra-accumbens infusion of the D1-receptor antagonist, SCH-23390 (0,
.3, 1.0, 3.0 µg), were examined.
Results
Motivation for cocaine was markedly higher after abstinence from ExA versus ShA self-administration
in intact males and females, indicating the development of an addicted phenotype in
these groups. Motivation for cocaine was also higher than ShA control subjects in
OVX+E but not OVX+Veh females after ExA self-administration, confirming the categorization
of these groups as vulnerable versus resistant. After ExA self-administration, intact
males and females and OVX+E but not OVX+Veh females were less sensitive to the effects
of D1-receptor antagonism as compared with their ShA counterparts.
Conclusions
These results suggest that the role of D1-receptor signaling, although critical in
“nonaddicted” stages, becomes diminished once addiction has developed.
Key Words
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Article info
Publication history
Published online: November 06, 2013
Accepted:
September 26,
2013
Received in revised form:
August 29,
2013
Received:
April 4,
2013
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Diminished Role for Dopamine D1 Receptors in Cocaine Addiction?Biological PsychiatryVol. 76Issue 1
- PreviewDopamine D1-like receptors are directly involved in the generation of reward-related signals in the brain. In drug-naïve animals, selective stimulation of D1 receptors is sufficient to support acquisition and maintenance of self-administration behavior (1). Blockade of D1 receptors strongly attenuates the rewarding effects of psychostimulant drugs such as cocaine and amphetamine, and D1 receptor knockout mice fail to acquire cocaine self-administration behavior (1). D1 receptors are positively coupled to stimulatory G proteins and adenylate cyclase, and can facilitate excitatory input to D1-expressing neurons in striatal reward regions.
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