Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress

Abstract

Rationale The combination of several risk factors (sex, a prior underlying psychiatric condition, or early drug initiation) could induce the emergence of negative affect during cocaine abstinence and increase the risk of developing addiction. However, most prior preclinical studies have been centered in male rodents, traditionally excluding females from these analyses. Objectives To ascertain the behavioral and neurochemical consequences of adolescent cocaine exposure when the combination of several risk factors is present (female, early-life stress). Methods Whole litters of Sprague–Dawley rats were exposed to maternal deprivation for 24 h on postnatal day (PND) 9. Cocaine was administered in adolescence (15 mg/kg/day, i.p., PND 33–39). Negative affect was assessed by several behavioral tests (forced swim, open field, novelty-suppressed feeding, sucrose preference). Hippocampal cell fate markers were evaluated by western blot (FADD, Bax, cytochrome c) or immunohistochemistry (Ki-67; cell proliferation). Results Maternal deprivation is a suitable model of psychiatric vulnerability in which to study the impact of adolescent cocaine in female rats. While adolescent cocaine did not alter affective-like behavior during adolescence, a pro-depressive–like state emerged during adulthood, exclusively in rats re-exposed to cocaine during abstinence. FADD regulation by cocaine in early-life stressed female rats might contribute to certain hippocampal neuroadaptations with some significance to the observed induced negative affect. Conclusions Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress, highlighting the risk of early drug initiation during adolescence for the emergence of negative reinforcement during abstinence likely driving cocaine addiction vulnerability, also in female rats.

Exploring pharmacological options for adolescent depression: a preclinical evaluation with a sex perspective

“…However, this lack of behavioral impact is accompanied by changes in neurochemical markers in the hippocampus (i.e., increased pro-apoptotic FADD [ 71 ]), a brain region particularly responsive to stress, suggesting a negative impact induced by this procedure. Moreover, the combination of maternal separation with a different stressor (i.e., drug administration during adolescence) induced negative affect [ 71 , 72 ], in line with the literature reporting the “two-hit” hypothesis in the development of neuropsychiatric illnesses (a combination of two or more major disruptions are needed at specific time points during development). Moreover, it is important to remember that the forced-swim test is a good test to measure antidepressant-like responses, but not necessarily to phenotype a depressive-like response (reviewed by [ 73 ]).…”

“…To model a more robust depressive-like phenotype we would have needed other preclinical approaches that include more aggressive and/or prolonged procedures that might have even interfered with the timing of the adolescent treatment (e.g., [ 19 ]). Therefore, early-life stress modeled with maternal separation, although failed to show baseline changes in affective-like behavior with the tests performed (as previously described in [ 71 , 72 ]), proved differences in the effectiveness of the selected drug treatments, both in adolescence and adulthood, presenting itself as a good platform in which to explore novel antidepressant options for adolescence with a sex perspective.…”

“…In this context, reproducibility in rodent behavioral research is a topic of great debate and concern and varies for each model depending on the particular experimental conditions. Particularly, we have used this specific paradigm of maternal separation (24 h from PND 9 to 10) in our group for some time now, publishing four independent studies including hundreds of rats [ 3 , 48 , 71 , 72 ]. The main conclusion of all of them is that, in our hands, depriving Sprague-Dawley pups 24 h from their mom from PND 9 to PND 10, seems to be a mild procedure in terms of altering affective-like responses, at least with the behavioral tests that we normally utilize (e.g., forced-swim test, novelty-suppressed feeding, and sucrose preference).…”

Adolescent cocaine differentially impacts psychomotor sensitization and epigenetic profiles in adult male rats with divergent affective phenotypes

“…Since no behavioral differences were observed between both groups (data not shown), rats were combined in a group of 20 rats in which to evaluate the impact of adult cocaine exposure with no prior history of cocaine on the emergence of psychomotor sensitization. This selected cocaine regimen was previously shown to induce psychomotor sensitization in adult outbred ( 42 ) and bHR rats ( 43 ), and to induce long-term behavioral changes [e.g., ( 44 – 47 )] when given at this time-window during early-mid adolescence.…”

Dopamine receptor 1 on CaMKII-positive neurons within claustrum mediates adolescent cocaine exposure-induced anxiety-like behaviors and electro-acupuncture therapy

“…Adolescent experience of drug abuse increases risk of developing psychiatric disorders that even persists into adulthood, which is a big public heath concern worldwide (3)(4)(5)(6)(7)(8). Previously, we found that adolescent cocaine exposure (ACE) increased anxiety-like behaviors in mice of adulthood (9,10), which is generally believed as critical factor for driving relapse to drugs in later life (11,12).…”