Blockade of D3 receptor prevents changes in DAT and D3R expression in the mesolimbic dopaminergic circuit produced by social stress- and cocaine prime-induced reinstatement of cocaine-CPP

Abstract

<jats:sec><jats:title>Background:</jats:title><jats:p> Cocaine may cause persistent changes in the brain, which are more apparent in DA transporter (DAT) and DA receptor availability within the nucleus accumbens (NAc). On the other hand, the DA D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for substance use disorders. </jats:p></jats:sec><jats:sec><jats:title>Aims:</jats:title><jats:p> This study aims to assess the impact of selective D3R antagonism on DAT and D3R after reinstatement of cocaine preference (CPP) induced by an acute session of social defeat stress (SDS) and a cocaine prime in mice after a period of abstinence. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Male mice were conditioned with 25 mg/kg of cocaine for 4 days. After 60 days of extinction training mice were pretreated with the selective D3R antagonist SB-277011A before the re-exposure to a priming dose of cocaine or to a single SDS session. CPP scores were determined and levels of DAT, D3R, phospho Akt (pAkt) and phospho mTOR (pmTOR) were assessed in the NAc shell. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> An increase in DAT and D3R expression was seen in the NAc after both a cocaine prime- and SDS-induced reinstatement of CPP. Pretreatment with SB-277011A blocked elevated DAT and D3R expression as well as SDS-induced reinstatement. By contrast, the blockade of D3R did not modified the cocaine prime-induced CPP. Changes in DAT and D3R expression do not seem to occur via the canonic pathway involving Akt/mTOR. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> Our results suggest that the selective D3R antagonist ability to inhibit DAT and D3R up-regulation could represent a possible mechanism for its behavioral effects in cocaine-memories reinstatement induced by social stress. </jats:p></jats:sec>

Distinct regulation of dopamine D3 receptor in the basolateral amygdala and dentate gyrus during the reinstatement of cocaine CPP induced by drug priming and social stress

“…In accordance with our previous studies [25,26], this work shows that the blockade of D3R inhibited the reinstatement of cocaine-CPP induced by social stress but was not able to prevent the reactivation of cocaine-CPP elicited by a drug-prime, pointing out that D3R modulates differently the reinstatement of drug-seeking behaviours depending upon the stimulus that triggers relapse.…”

“…Although not significantly, we observed that D3R levels tended to increase in the BLA of mice that reinstated cocaine-CPP under both conditions. These data parallel with recent results of our laboratory revealing a significant enhancement of D3R expression in the NAc of mice that reinstated cocaine-CPP after a drug prime or social defeat [26], and are in line also with studies that reported increased D3R in the reward system of human cocaine addicts and mice conditioned to cocaine cues [54,55]. This augment has been related to the association of cocaine effects with environmental contexts and not to the drug of abuse per se [55].…”

“…However, Sutton & Caron (2015) [77] reported increased mTORC1 activity in the NAc after acute cocaine administration that was related with enhanced locomotor activity. In addition, we observed augmented levels of pmTOR in the NAc after the reinstatement of cocaine-CPP induced by both a drug prime and acute social stress, that were antagonized by D3R blockade [26]. While mTOR activity changes in the NAc, BLA and DG of cocaine primed mice could be argued to be dependent on the drug, it must be noticed that socially stressed animals that did not receive cocaine showed similar modifications after CPP reactivation.…”

“…after morphine self-administration [87]. Besides, levels of phosphorylated Akt, mTOR and P70S6K were significantly enhanced in the hippocampal CA3, but not in the CA1, NAc or VTA following morphine-CPP [88], and reactivation of cocaine-CPP induced by social stress did not modify mTOR phosphorylation in the NAc [26]. Altogether, ours and prior findings demonstrate that the regulation of mTOR pathway by drugs of abuse and drug-related behaviours is intricated and might be conditioned by the stimuli and the brain areas implicated in their response.…”

“…We have previously reported that the administration of the D3R antagonist SB-277011-A blocked the reinstatement of cocaine-induced CPP elicited by social and physiological stressors but not by a drug prime [25,26]. It is known that the conditioned stimuli associated with drugs of abuse provoke intense craving and the activation of some brain areas, such as the BLA [18], which is critical in relapse [2,27].…”