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

Abstract

Background While considerable evidence implicates DA D1-receptor signaling in the nucleus accumbens in motivation for cocaine during early stages of addiction, less is known regarding its role following 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; 3 fixed-ratio 1 sessions, maximum of 20 infusions) or 24-hr extended access (ExA) to cocaine for 10 days (4 trials/hr). Motivation for cocaine was assessed following a 14-day abstinence period using a progressive-ratio schedule. Once responding stabilized, the effects of intra-accumbens infusion of the D1-receptor antagonist, SCH-23390 (0, 0.3, 1.0, 3.0 μg), were examined. Results Motivation for cocaine was markedly higher following 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 controls in OVX+E, but not OVX+Veh females following ExA self-administration, confirming the categorization of these groups as vulnerable versus resistant. Following 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 to their ShA counterparts. Conclusions These results suggest that the role of D1-receptor signaling, though critical in “non-addicted” stages, becomes diminished once addiction has developed.

More Cocaine—More Glutamate—More Addiction

“…This finding shows that a glutamatergic mechanism is involved in escalated performance in a PR session following extended, but not short-access, sessions of cocaine self-administration. Also, these data nicely complement the authors' earlier report showing that D1 dopamine receptor antagonism reduced short-access motivation for cocaine but had a lesser affect on extended-access subjects (5). Considering these two studies together, the authors have provided an evidence base for concluding that although dopamine supports the reinforcing effect of cocaine, when larger quantities of cocaine are used the motivation to take drug comes to depend more on glutamate transmission in the NAcore.…”

A Shift in the Role of Glutamatergic Signaling in the Nucleus Accumbens Core With the Development of an Addicted Phenotype

“…However, short access conditions do not capture critical features of cocaine addiction in humans, including compulsive use and an enhanced motivation to use the drug. Extended access procedures have been developed in animals that incorporate these characteristics (13–15), and may be useful for determining the underlying neurobiological mechanisms associated with the development of addiction. For example, rats given extended access to cocaine self-administer high levels of the drug in binge/abstinent patterns, and following abstinence, show an enhanced motivation to obtain the drug as assessed (14–15).…”

Diminished Role for Dopamine D1 Receptors in Cocaine Addiction?

“…In this issue of Biological Psychiatry , Ramôa, Lynch and colleagues utilized progressive ratio testing in rats to assess the ability of local D1 receptor blockade in the nucleus accumbens to reduce motivation for cocaine following extended access conditions that promote escalation and the development of addicted phenotypes (6). After initial acquisition of self-administration behavior, they split rats into one of two groups; 1) rats with short daily access that were allowed to self-administer a maximum of 20 cocaine injections a day, or 2) rats with extended 24-hour access to cocaine for a maximum of 96 injections available each day.…”

“…Interestingly, the study found that ovariectomized female rats fail to exhibit enhanced motivation for cocaine following extended access self-administration, unless they were given estradiol replacement treatment (6). This suggests that estradiol is necessary for vulnerability to transit to more cocaine-addicted states in females.…”