Archival Report| Volume 76, ISSUE 1, P8-14, July 01, 2014

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Diminished Role of Dopamine D1-Receptor Signaling with the Development of an Addicted Phenotype in Rats

Published:November 06, 2013DOI:


      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.


      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.


      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.


      These results suggest that the role of D1-receptor signaling, although critical in “nonaddicted” stages, becomes diminished once addiction has developed.

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      • Diminished Role for Dopamine D1 Receptors in Cocaine Addiction?
        Biological PsychiatryVol. 76Issue 1
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          Dopamine 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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