Similar to the pattern observed in people with substance abuse disorders, laboratory animals will exhibit escalation of cocaine intake when the drug is available over prolonged periods of time. Here, we investigated the contribution of behavioral contingency of cocaine administration on escalation of cocaine intake and gene expression in the dorsal medial prefrontal cortex (dmPFC) in adult male rats. Rats were allowed to self-administer intravenous cocaine (0.25 mg/infusion) under either limited cocaine-(1 h/day), prolonged cocaine-(6 h/day), or limited cocaine-(1 h/day) plus yoked cocaine-access (5 h/day); a control group received access to saline (1 h/day). One day after the final self-administration session, the rats were euthanized and the dmPFC was removed for quantification of mRNA expression of critical glutamatergic signaling genes, Homer2, Grin1, and Dlg4, as these genes and brain region have been previously implicated in addiction, learning, and memory. All groups with cocaine-access showed escalated cocaine intake during the first 10 min of each daily session, and within the first 1 h of cocaine administration. Additionally, the limited-access + yoked group exhibited more non-reinforced lever responses during self-administration sessions than the other groups tested. Lastly, Homer2, Grin1, and Dlg4 mRNA were impacted by both duration and mode of cocaine exposure. Only prolonged-access rats exhibited increases in mRNA expression for Homer2, Grin1, and Dlg4 mRNA. Taken together, these findings indicate that both contingent and non-contingent "excessive" cocaine exposure supports escalation behavior, but the behavioral contingency of cocaine-access has distinct effects on the patterning of operant responsiveness and changes in mRNA expression.
Estradiol modulates the rewarding and reinforcing properties of cocaine in females, including an increase in selection of cocaine over alternative reinforcers. However, the effects of estradiol on male cocaine self-administration behavior are less studied despite equivalent levels of estradiol in the brains of adult males and females, estradiol effects on motivated behaviors in males that share underlying neural substrates with cocaine reinforcement as well as expression of estrogen receptors in the male brain. Therefore, we sought to characterize the effects of estradiol in males on choice between concurrently-available cocaine and food reinforcement as well as responding for cocaine or food in isolation. Male castrated rats (n=46) were treated daily with estradiol benzoate (EB) (5μg/0.1, S.C.) or vehicle (peanut oil) throughout operant acquisition of cocaine (1mg/kg, IV; FI20 sec) and food (3×45mg; FI20 sec) responding, choice during concurrent access and cocaine and food reinforcement under progressive ratio (PR) schedules. EB increased cocaine choice, both in terms of percent of trials on which cocaine was selected and the proportion of rats exhibiting a cocaine preference as well as increased cocaine, but not food, intake under PR. Additionally, within the EB treated group, cocaine-preferring rats exhibited enhanced acquisition of cocaine, but not food, reinforcement whereas no acquisition differences were observed across preferences in the vehicle treated group. These findings demonstrate that estradiol increases cocaine choice in males similarly to what is observed in females.
Early life stress exposure, including prenatal stress (PNS), influences subsequent risk for many disorders, including substance abuse, and these effects interact with genetic factors to determine risk for disease. We previously demonstrated gene X environmental interactions across the BXD recombinant inbred mouse strain panel and their progenitor strains in PNS modulation of cocaine‐induced reward and locomotion. Critical to dissecting genetic interactions with PNS is consideration of the modes of stress transmission to the offspring. Both maternal neuroendocrine responses during stress and subsequent maternal‐offspring interactions following stress may serve as transmission modes for PNS‐induced changes in cocaine responsiveness. Therefore, we characterized the maternal stress response by measuring restraint stress‐induced plasma corticosterone (CORT) during gestation as well as effects of restraint stress on dam‐pup contact in the first 10 postnatal days in BXD and progenitor mouse strains. Restraint stress interacted with strain to affect plasma CORT levels and dam‐pup contact, indicating heritable variation of the maternal stress response. Furthermore, strain‐level variance in maternal stress response correlated to the impact on cocaine response exhibited by adult offspring. These findings implicate multiple modes of maternal stress response in alterations of offspring drug responsiveness and indicate that assessment of maternal endocrine and behavioral responses during early life can be utilized to dissect the complex intersection of maternal factors, the response of the offspring and genetics.
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