Decoupling Dopamine Synthesis from Impulsive Action, Risk-Related Decision-Making, and Propensity to Cocaine Intake: A Longitudinal [18F]-FDOPA PET Study in Roman High- and Low-Avoidance Rats.

Impulsive action and risk-related decision-making (RDM) are two facets of impulsivity linked to a hyperdopaminergic release in the striatum and an increased propensity to cocaine intake. We previously showed that with repeated cocaine exposure, this initial hyperdopaminergic release is blunted in impulsive animals, potentially signaling drug-induced tolerance. Whether such dopaminergic dynamics involve changes in dopamine (DA) synthesis as a function of impulsivity is currently unknown. Here, we investigated the predictive value of DA synthesis for impulsive action, RDM, and the propensity to take cocaine in a rat model of vulnerability to cocaine abuse. Additionally, we assessed the effects of cocaine intake on these variables. Rats were tested sequentially in the rat Gambling Task (rGT) and were scanned with positron emission tomography and [18F]-FDOPA to respectively assess both impulsivity facets and striatal DA synthesis before and after cocaine self-administration (SA). Our results revealed that baseline striatal levels of DA synthesis did not significantly predict impulsive action, RDM, or a greater propensity to cocaine SA in impulsive animals. Besides, we showed that impulsive action, but not RDM, predicted higher rates of cocaine taking. However, chronic cocaine exposure had no impact on DA synthesis, nor affected impulsive action and RDM. These findings indicate that the hyper-responsive DA system associated with impulsivity and a propensity for cocaine consumption, along with the reduction in this hyper-responsive DA state in impulsive animals with a history of cocaine use, might not be mediated by dynamic changes in DA synthesis.

Repeated Cocaine Intake Differentially Impacts Striatal D2/3 Receptor Availability, Psychostimulant-Induced Dopamine Release, and Trait Behavioral Markers of Drug Abuse.

Current research indicates that altered dopamine (DA) transmission in the striatum contributes to impulsivity and novelty-seeking, and it may mediate a link concerning a higher susceptibility to drug abuse. Whether increased susceptibility to drug abuse results from a hyperdopaminergic or hypodopaminergic state is still debated. Here, we simultaneously tracked changes in DA D2/3 receptor (D2/3R) availability and amphetamine-(AMPH)-induced DA release in relation to impulsivity and novelty-seeking prior to, and following, cocaine self-administration (SA) in Roman high- (RHA) and low- (RLA) avoidance rats. We found that high-impulsive/high novelty-seeking RHA rats exhibited lower D2/3R availabilities and higher AMPH-induced DA release in the striatum that predicted higher levels of cocaine intake compared with RLAs. Cocaine SA did not alter striatal D2/3R availability or impulsivity in RHA or RLA rats. Critically, cocaine exposure led to a baseline-dependent blunting of stimulated DA release in high-impulsive/high novelty-seeking RHA rats only, and to a baseline-dependent increase in novelty-seeking in low-impulsive/low novelty-seeking RLA rats only. Altogether, we propose that susceptibility to drug abuse results from an innate hyper-responsive DA system, promoting impulsive action and novelty-seeking, and producing stronger initial drug-reinforcing effects that contribute to the initiation and perpetuation of drug use. However, with repeated cocaine use, a tolerance to drug-induced striatal DA elevations develops, leading to a compensatory increase in drug consumption to overcome the reduced reward effects.

Motor impulsivity but not risk-related impulsive choice is associated to drug intake and drug-primed relapse.

Introduction: Motor impulsivity and risk-related impulsive choice have been proposed as vulnerability factors for drug abuse, due to their high prevalence in drug abusers. However, how these two facets of impulsivity are associated to drug abuse remains unclear. Here, we investigated the predictive value of both motor impulsivity and risk-related impulsive choice on characteristics of drug abuse including initiation and maintenance of drug use, motivation for the drug, extinction of drug-seeking behavior following drug discontinuation and, finally, propensity to relapse. Methods: We used the Roman High- (RHA) and Low- Avoidance (RLA) rat lines, which display innate phenotypical differences in motor impulsivity, risk-related impulsive choice, and propensity to self-administer drugs. Individual levels of motor impulsivity and risk-related impulsive choice were measured using the rat Gambling task. Then, rats were allowed to self-administer cocaine (0.3 mg/kg/infusion; 14 days) to evaluate acquisition and maintenance of cocaine self-administration, after which motivation for cocaine was assessed using a progressive ratio schedule of reinforcement. Subsequently, rats were tested for their resistance to extinction, followed by cue-induced and drug-primed reinstatement sessions to evaluate relapse. Finally, we evaluated the effect of the dopamine stabilizer aripiprazole on reinstatement of drug-seeking behaviors. Results: We found that motor impulsivity and risk-related impulsive choice were positively correlated at baseline. Furthermore, innate high levels of motor impulsivity were associated with higher drug use and increased vulnerability to cocaine-primed reinstatement of drug-seeking. However, no relationships were observed between motor impulsivity and the motivation for the drug, extinction or cue-induced reinstatement of drug-seeking. High levels of risk-related impulsive choice were not associated to any aspects of drug abuse measured in our study. Additionally, aripiprazole similarly blocked cocaine-primed reinstatement of drug-seeking in both high- and low-impulsive animals, suggesting that aripiprazole acts as a D2/3R antagonist to prevent relapse independently of the levels of impulsivity and propensity to self-administer drugs. Discussion: Altogether, our study highlights motor impulsivity as an important predictive factor for drug abuse and drug-primed relapse. On the other hand, the involvement of risk-related impulsive choice as a risk factor for drug abuse appears to be limited.

Concurrent measures of impulsive action and choice are partially related and differentially modulated by dopamine D1- and D2-like receptors in a rat model of impulsivity.

Impulsivity is a multidimensional construct, but the relationships between its constructs and their respective underlying dopaminergic underpinnings in the general population remain unclear. A cohort of Roman high- (RHA) and low- (RLA) avoidance rats were tested for impulsive action and risky decision-making in the rat gambling task, and then for delay discounting in the delay-discounting task to concurrently measure the relationships among the three constructs of impulsivity using a within-subject design. Then, we evaluated the effects of dopaminergic drugs on the three constructs of impulsivity, considering innate differences in impulsive behaviors at baseline. Risky decision-making and delay-discounting were positively correlated, indicating that both constructs of impulsive choice are related. Impulsive action positively correlated with risky decision-making but not with delay discounting, suggesting partial overlap between impulsive action and impulsive choice. RHAs showed a more impulsive phenotype in the three constructs of impulsivity compared to RLAs, demonstrating the comorbid nature of impulsivity in a population of rats. Amphetamine increased impulsive action and had no effect on risky decision-making regardless of baseline levels of impulsivity, but it decreased delay discounting only in high impulsive RHAs. In contrast, while D1R and D3R agonism as well as D2/3R partial agonism decreased impulsive action regardless of baseline levels of impulsivity, D2/3R agonism decreased impulsive action exclusively in high impulsive RHAs. Irrespective of baseline levels of impulsivity, risky decision-making was increased by D1R and D2/3R agonism but not by D3R agonism or D2/3R partial agonism. Finally, while D1R and D3R agonism, D2/3R partial agonism and D2R blockade increased delay discounting irrespective of baseline levels of impulsivity, D2/3R agonism decreased it in low impulsive RLAs only. These findings indicate that the acute effects of dopamine drugs were partially overlapping across dimensions of impulsivity, and that only D2/3R agonism showed baseline-dependent effects on impulsive action and impulsive choice.

Efectos de la inactivación sistémica de los receptores GR y MR sobre el daño rápido en la recuperación de la memoria espacial inducido por corticosterona / Systemic Inactivation of GR and MR Receptors on Corticosterone-induced rapid damage in Spatial Memory Recovery

Estudios previos de nuestro laboratorio han mostrado que diez minutos después de la administración sistémica de corticosterona se dificulta la recuperación de la memoria espacial en el laberinto de Barnes, sin embargo se desconocen los mecanismos que subyacen a este efecto. Dado que los glucocorticoides ejercen sus acciones a través de los receptores de tipo GR y MR, en el presente estudio se evaluó la participación de estos receptores en el efecto perjudicial rápido de la corticosterona sobre la memoria espacial. Para ello 37 ratas Wistar macho fueron entrenadas en la tarea y 24h después recibieron una inyección subcutánea de antagonista GR, antagonista MR o vehículo. 50min después los animales fueron inyectados con corticosterona o vehículo por vía intraperitoneal y 10min después se evaluó la recuperación de la memoria espacial. Los resultados mostraron que la corticosterona perjudicó rápidamente la recuperación de la memoria espacial a largo plazo, pues los animales inyectados con esta hormona presentaron mayores latencias de escape, mayor número de errores, mayor número de exploraciones y mayor distancia recorrida hasta alcanzar la meta; un efecto revertido solamente con la administración del antagonista MR. Este hallazgo concuerda con estudios in vitro donde se muestra que los efectos rápidos de la corticosterona sobre la trasmisión glutamatérgica en el hipocampo están mediados por los receptores MR.

Previous studies of our laboratory have shown that it is difficult to recover the spatial memory in the Barnes maze ten minutes after a systemic administration of corticosterone; however the mechanisms that underlie this effect are unknown. Considering glucocorticoids exert their actions through GR and MR type receptors, the present study evaluated the participation of these receptors in the rapid damaging effect of corticosterone on spatial memory. For this, 37 male Wistar rats were trained on the task and 24 h afterwards they received a subcutaneous injection of GR antagonist, MR antagonist or vehicle. 50 min later the animals were injected with corticosterone or vehicle intraperitoneally and 10 min later, the spatial memory recovery was evaluated. The results indicated that corticosterone rapidly impaired spatial long-term memory recovery, as animals injected with this hormone presented higher escape latencies, more errors, higher exploration and greater traveled distance to reach the goal; an effect reverted only with the administration of the MR antagonist. This finding agrees with in vitro studies showing that the rapid effects of corticosterone on glutamatergic transmission in the hippocampus are mediated by MR receptors.