Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

Abstract

Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of cFos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement.

Distinct Populations of Neurons Activated by Heroin and Cocaine in the Striatum as Assessed by catFISH

“…Although the functional significance of these differences remains to be fully explored, they might have implications for both research and treatment. It is remarkable, for example, that the functional or anatomic integrity of the dopaminergic system is required for the reinforcing properties of cocaine but not of heroin (Ettenberg et al, 1982;Pettit et al, 1984;Pisanu et al, 2015), that distinct projections from the PFC to the shell of the NAcc are implicated in the relapse to cocaine versus heroin seeking after abstinence (Peters et al, 2008;Bossert et al, 2012), and that basic environmental manipulations gate in opposite directions the reinforcing, affective, and neurobiological responses to heroin versus cocaine in rats and humans (Uslaner et al, 2001;Ferguson et al, 2004;Caprioli et al, 2007aCaprioli et al, , 2008Caprioli et al, , 2009Paolone et al, 2007;Celentano et al, 2009;Montanari et al, 2015;Avvisati et al, 2016;De Pirro et al, 2018;De Luca et al, 2019).…”

Nucleus accumbens shell and core dopamine responsiveness to sucrose in rats: role of response contingency and discriminative/conditioned cues

“…Because of this, the activation of shell DA transmission might be intrinsically rewarding, whereas DA release in other terminal areas (NAc core, dorsal striatum and prefrontal cortex) might play more cognitive functions, such as signalling reward for learning purposes (Schultz et al ., ). This hypothesis is consistent with the rewarding and reinforcing properties of amphetamine‐like and cocaine‐like psychostimulants, which preferentially increase DA in the NAc shell (Di Chiara & Bassareo, ; Lecca et al ., ) and depend for their reinforcing properties on DA receptors in this area (Pisanu et al ., ). The suppression of DA activation in the core during responding for sucrose might be related to the need to prevent species‐specific, automatic actions that would interfere with goal‐directed action under conditions, such as those of FR1 responding, that do not require a decision among different reward options (Saddoris et al ., ).…”

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…While the mechanisms behind these adaptive and overconsumption behaviors may seem distinct, the behaviors are known to share in common their functioning through dopamine in the nucleus accumbens shell. Levels and release of accumbal dopamine are increased in response to adaptive behaviors, including food intake (Martel & Fantino, 1996), the waking state (Lena et al, 2005), mating behavior (Pfaus et al, 1990), and maternal behavior (Champagne et al, 2004), and also prior to these behaviors (Champagne et al, 2004), with dopamine seemingly contributing to their initiation (Pisanu et al, 2015). Similarly, accumbal dopamine levels are increased by the intake of rewarding substances, including palatable foods high in fat or sugar (Rada, Avena, Barson, Hoebel, & Leibowitz, 2012; Rada, Avena, & Hoebel, 2005; Sahr et al, 2008) and drugs of abuse such as alcohol (Howard, Schier, Wetzel, Duvauchelle, & Gonzales, 2008), nicotine (Cadoni & Di Chiara, 2000; Pontieri, Tanda, Orzi, & Di Chiara, 1996), and cocaine (Pontieri, Tanda, & Di Chiara, 1995), and they are also elevated prior to the initiation of their intake (Cacciapaglia, Saddoris, Wightman, & Carelli, 2012; Doyon et al, 2003; Suto, Ecke, You, & Wise, 2010).…”