Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

Early life experiences program lifelong responses to stress. In agreement, resilience and vulnerability to psychopathologies, such as posttraumatic stress disorder (PTSD), have been suggested to depend on the early background. New therapies have targeted memory reconsolidation as a strategy to modify the emotional valence of traumatic memories. Here, we used animal models to study the molecular mechanism through which early experiences may later affect aversive memory reconsolidation. Handling (H)—separation of pups from dams for 10 min—or maternal separation (MS) — 3-h separation—were performed from PDN1–10, using non-handled (NH) litters as controls. Adult males were trained in a contextual fear conditioning (CFC) task; 24 h later, a short reactivation session was conducted in the conditioned or in a novel context, followed by administration of midazolam 3 mg/kg i.p. (mdz), known to disturb reconsolidation, or vehicle; a test session was performed 24 h after. The immunocontent of relevant proteins was studied 15 and 60 min after memory reactivation in the dorsal hippocampus (dHc) and basolateral amygdala complex (BLA). Mdz-treated controls (NH) showed decreased freezing to the conditioned context, consistent with reconsolidation impairment, but H and MS were resistant to labilization. Additionally, MS males showed increased freezing to the novel context, suggesting fear generalization; H rats showed lower freezing than the other groups, in accordance with previous suggestions of reduced emotionality facing adversities. Increased levels of Zif268, GluN2B, β-actin and polyubiquitination found in the BLA of all groups suggest that memory reconsolidation was triggered. In the dHc, only NH showed increased Zif268 levels after memory retrieval; also, a delay in ERK1/2 activation was found in H and MS animals. We showed here that reconsolidation of a contextual fear memory is insensitive to interference by a GABAergic drug in adult male rats exposed to different neonatal experiences; surprisingly, we found no differences in the reconsolidation process in the BLA, but the dHc appears to suffer temporal desynchronization in the engagement of reconsolidation. Our results support a hippocampal-dependent mechanism for reconsolidation resistance in models of early experiences, which aligns with current hypotheses for the etiology of PTSD.