Striatum, Dopamine and Automatism in Cocaine Addiction and Relapse : Pharmacological and Behavioral Investigation

L'un des aspects les plus problématiques de l’addiction est la vulnérabilité à la rechute qui persiste même longtemps après la disparition des symptômes de sevrage. Les modèles rongeurs d'auto-administration (AA) démontrent que la réexposition à la drogue, les stimuli associés à la drogue ou le stress sont des déclencheurs majeurs de la rechute. Bien que les différentes catégories de drogues varient dans leurs mécanismes pharmacologiques primaires, elles partagent toutes un effet aigu d'augmentation des niveaux de dopamine (DA) dans le striatum. Après une utilisation répétée, les propriétés addictives des psychostimulants tels que la cocaïne (COC) sont sous-tendues par la mise en place de neuroadaptations persistantes dans le système DA (SDA) mésocorticolimbique. Le striatum est une cible majeure du SDA et, dans cette région, la DA agit sur deux familles de récepteurs (D1R et D2R) séparées positionnées sur les neurones épineux moyens (NEM) et donnant naissance à deux voies de sorties striatales différenciées et ayant des rôles différents dans l’addiction.Des travaux antérieurs dans notre équipe ont montré une implication différentielle de ces deux sous-types de récepteurs DA sur le rétablissement du comportement de recherche de COC. Alors que l'administration systémique d'un agoniste D2R induisait de puissants effets de rétablissement de recherche de cocaïne sur des rats entraînés à s'autoadministrer de la COC, l'administration systémique de l'agoniste D1R n’avait aucun effet (Dias et al, 2003).Les sous-régions ventrale (noyau accumbens) et dorsale du striatum (caudate putamen) sont modulées par l’innervation dopaminergique du mésencéphale ventral (VTA, substance noire) et la plasticité induite par la cocaïne dans ces circuits est supposée sous-tendre plusieurs aspects du comportement de recherche de drogue (Pierce and Vanderschuren, 2010). C’est pourquoi la première section de ce travail comprend une description de trois expériences réalisées dans le but d'étudier la participation des récepteurs DA du striatum au niveau ventral et dorsal à la réinstallation du comportement de recherche de cocaïne.For many, drug taking may continue on an occasional basis for a long time; however, some individuals lose control of their drug use and are unable to stop. The transition from casual use to addiction is accompanied by drug-induced changes in the brain, followed by associated changes in behavioral functions. One of the most problematic aspects of addiction is the enduring vulnerability to relapse that persists even long after withdrawal symptoms have abated. Rodent models of drug self-administration (SA) show that re-exposure to the drug itself, drug associated cues or stress are major triggers of relapse. While different classes of drugs vary in their primary pharmacological mechanisms, they all share an acute effect of raising dopamine (DA) levels in the striatum. Following repeated use, the addictive properties of psychostimulants such as cocaine (COC) are believed to take place through the induction of neuroadaptations within the mesocorticolimbic DA system.The striatum is a major target of the DA system, where DA acts on two families of metabotropic receptors (D1-like or D2-like) that are segregated into two pathways of medium spiny neurons (MSNs) and have different roles in addiction and relapse. For instance, while systemic D2 receptor (D2R) stimulation induces reinstatement of COC seeking in rats, D1 receptor (D1R) stimulation does not. DA signaling in the nucleus accumbens (NAcc) responds to rewarding and aversive stimuli; in turn, the dorsolateral striatum (DLS) plays a key role in the transition to compulsive use, and the habitual aspects of drug-seeking after prolonged drug SA. Despite several works examining their role in relapse, the results remain somewhat unclear. Given their critical but differential involvement in COC seeking, here we investigated the role of D1R and D2R receptors of the NAcc and DLS in relapse, employing pharmacological manipulations, as well as assessing their protein expression using an animal model of COC SA. Our results showed a double dissociation between the actions of both DA receptors (DARs) in the striatum. Pharmacological activation of the D1R, but not D2R of the NAcc induces reinstatement of COC seeking, whereas the same effect is triggered by the activation of D2R, but not D1R of the DLS. Also, the reinstating effects of the systemic D2R stimulation is blocked by D1R or D2R antagonists injected into the NAcc or D1R antagonist into the DLS, while being blunted by the D2R inhibition in the DLS. These results convey an interaction between both receptor subtypes, likely relying on ascending spiraling connections associating the ventral and the dorsal striatum through midbrain-reaching loops. Finally, we found the reinstatement of COC seeking elicited by D1R or D2R agonists in either region is not due to changes in DAr expression.These results enticed us to examine the behavioral mechanisms underpinning reinstating behavior. Though initially goal-directed, COC seeking is argued to become habitual after extended training. This progression is believed to initially elicit functional changes within the NAcc, and gradually hijack the circuitry of the dorsal striatum. The activation of D1R in the NAcc and D2R in the DLS has been associated with the processing of rewarding properties and habitual responding for drugs, respectively. Therefore, we aimed to assess whether the reinstatement of COC seeking triggered by the D2R stimulation within the DLS would involve incentive motivational or reinforcing processes likely underlying those induced by the D1R stimulation within the NAcc. Also, we aimed to assess whether the D1R stimulation within the NAcc involves the overtaking of the behavioral control by habitual stimulus-response mechanisms which may be involved in the reinstatement of drug-seeking after the D2R stimulation in the DLS