RESUMEN

Individual differences in drug use emerge soon after initial exposure, and only a fraction of individuals who initiate drug use go on to develop a substance use disorder. Variability in vulnerability to establishing drug self-administration behavior is also evident in preclinical rodent models. Latent characteristics that underlie this variability and the relationship between early drug use patterns and later use remain unclear. Here, we attempt to determine whether propensity to establish cocaine self-administration is related to subsequent cocaine self-administration behavior in male Sprague-Dawley rats (n = 14). Prior to initiating training, we evaluated basal locomotor and anxiety-like behavior in a novel open field test. We then trained rats to self-administer cocaine in daily 3 h cocaine (0.75 mg/kg/infusion) self-administration sessions until acquisition criteria (≥30 active lever presses with ≥70 % responding on the active lever in one session) was met and divided rats into Early and Late groups by median-split analysis based on their latency to meet acquisition criteria. After each rat met acquisition criteria, we gave them 10 additional daily cocaine self-administration sessions. We then conducted a progressive ratio, cocaine-induced locomotor sensitivity test, and non-reinforced cocaine seeking test after two weeks of forced abstinence. Early Learners exhibited significantly less locomotion after an acute injection of cocaine, but the groups did not differ in any other behavioral parameter examined. These results indicate that cocaine self-administration acquisition latency is not predictive of subsequent drug-taking behavior, but may be linked to physiological factors like drug sensitivity that can predispose rats to learn the operant task.

Asunto(s)

Cocaína , Locomoción , Ratas Sprague-Dawley , Autoadministración , Animales , Masculino , Cocaína/farmacología , Cocaína/administración & dosificación , Ratas , Locomoción/efectos de los fármacos , Locomoción/fisiología , Inhibidores de Captación de Dopamina/farmacología , Inhibidores de Captación de Dopamina/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Trastornos Relacionados con Cocaína/fisiopatología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ansiedad/fisiopatología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología

RESUMEN

Neuronal ensembles in the medial prefrontal cortex mediate cocaine self-administration via projections to the nucleus accumbens. We have recently shown that neuronal ensembles in the prelimbic cortex form rapidly to mediate cocaine self-administration. However, the role of neuronal ensembles within the nucleus accumbens in initial cocaine-seeking behaviour remains unknown. Here, we sought to expand the current literature by testing the necessity of the cocaine self-administration ensemble in the nucleus accumbens core (NAcCore) 1 day after male and female rats acquire cocaine self-administration by using the Daun02 inactivation procedure. We found that disrupting the NAcCore ensembles after a no-cocaine reward-seeking test increased subsequent cocaine seeking, while disrupting NAcCore ensembles following a cocaine self-administration session decreased subsequent cocaine seeking. We then characterized neuronal cell type in the NAcCore using RNAscope in situ hybridization. In the no-cocaine session, we saw reduced dopamine D1 type neuronal activation, while in the cocaine self-administration session, we found preferential dopamine D1 type neuronal activity in the NAcCore.

Asunto(s)

Cocaína , Comportamiento de Búsqueda de Drogas , Neuronas , Núcleo Accumbens , Autoadministración , Animales , Núcleo Accumbens/efectos de los fármacos , Cocaína/farmacología , Masculino , Femenino , Ratas , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Neuronas/efectos de los fármacos , Recompensa , Inhibidores de Captación de Dopamina/farmacología , Refuerzo en Psicología , Receptores de Dopamina D1 , Trastornos Relacionados con Cocaína/fisiopatología , Ratas Sprague-Dawley , Corteza Prefrontal/efectos de los fármacos

RESUMEN

Substance use disorder (SUD) is a chronic relapsing condition characterized by continued use of drugs despite negative consequences. SUD is thought to involve disordered learning and memory wherein drug-paired cues gain increased salience, and ultimately drive craving and relapse. These types of associations are thought to be encoded within sparsely distributed sets of neurons, called neuronal ensembles, that drive encoded behaviors through synchronous activity of the participant neurons. We have previously found that Fos-expressing neuronal ensembles within the prefrontal cortex are required for well-trained cocaine seeking. However, less is known about how quickly cortical neuronal ensembles form during the initiation of cocaine seeking behavior. Here, we seek to further elucidate the role of Fos-expressing neuronal ensembles within the prelimbic cortex (PL) after the initial acquisition of cocaine self-administration (SA), or, after 10 days of additional SA training (well-trained). We trained Fos-LacZ transgenic rats to lever press for cocaine under an FR1 schedule of reinforcement. Once rats met acquisition criteria for cocaine self-administration, we ablated Fos-expressing neuronal ensembles in the PL using the Daun02 inactivation method, either 1 or 10 days after the rats met the acquisition criteria. Targeted ablation of Fos-expressing neuronal ensembles in the PL attenuated active lever pressing both 1 day and 10 days after rats acquired cocaine self-administration. Together, this suggests that Fos-expressing neuronal ensembles rapidly form in the PL and continue to mediate maintained cocaine seeking behavior.